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    Clinical Trial Results:
    A Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

    Summary
    EudraCT number
    		 2014-003698-41
    Trial protocol
    		 SE   EE   LV   DK   FI   AT   CZ   NL   HU   ES   RO   GR   DE   IT   GB   PL  
    Global end of trial date
    19 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jun 2024
    First version publication date
    23 Jun 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-3475-048
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02358031
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck: KEYNOTE-048
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Participants with recurrent or metastatic (R/M) squamous cell cancer of the head and neck (HNSCC) will be randomly assigned to receive pembrolizumab monotherapy [pembro mono], pembrolizumab plus chemotherapy with a platinum-based drug (cisplatin or carboplatin) and 5-Fluorouracil (5-FU) [pembro combo], or cetuximab plus a platinum-based drug (cisplatin or carboplatin) and 5-FU [control]. The overall primary study hypotheses are as follows in all participants and in participants with Programmed Cell Death Ligand 1 (PD-L1) positive expression defined by Combined Positive Score (CPS) ≥1 and CPS ≥20: 1) pembrolizumab monotherapy prolongs progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR), prolongs overall survival (OS) compared to standard treatment, and 2) pembrolizumab combination therapy prolongs PFS per RECIST 1.1 by BICR and prolongs OS compared to standard treatment.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Australia: 51
    Country: Number of subjects enrolled
    Austria: 33
    Country: Number of subjects enrolled
    Brazil: 81
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    Chile: 9
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Czechia: 26
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Greece: 19
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 67
    Country: Number of subjects enrolled
    Latvia: 14
    Country: Number of subjects enrolled
    Malaysia: 12
    Country: Number of subjects enrolled
    Mexico: 27
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Norway: 16
    Country: Number of subjects enrolled
    Peru: 3
    Country: Number of subjects enrolled
    Philippines: 20
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    Switzerland: 16
    Country: Number of subjects enrolled
    Taiwan: 37
    Country: Number of subjects enrolled
    Thailand: 28
    Country: Number of subjects enrolled
    Türkiye: 26
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 131
    Worldwide total number of subjects
    882
    EEA total number of subjects
    254
    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)
    565
    From 65 to 84 years
    315
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants with first line recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were recruited to examine the efficacy and safety of pembrolizumab monotherapy (pembro mono) versus pembrolizumab plus chemotherapy (pembro combo) versus cetuximab plus chemotherapy (control).

    Pre-assignment
    Screening details
    		 Of 1228 participants screened, 882 were randomized: pembro mono, pembro combo, or control arms. 22 participants in the control arm enrolled during an enrollment pause of pembro combo arm and were omitted from efficacy analyses between the respective arms. Per protocol, second course events were not included in efficacy or safety endpoints.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pembrolizumab Monotherapy (Pembro Mono)
    Arm description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA®, MK-3475
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years)

    Arm title
    		 Pembrolizumab + Chemotherapy (Pembro Combo)
    Arm description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years); plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months]); plus 5-Fluorouracil (5-FU) 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA®, MK-3475
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years)

    Investigational medicinal product name
    5-Fluorouracil (5-FU)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months])

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin at a target Area Under the Curve of 5 (AUC 5) IV on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m^2 IV Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])

    Arm title
    		 Cetuximab + Chemotherapy (Control)
    Arm description
    		 Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months] for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity

    Investigational medicinal product name
    5-FU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months])

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AUC 5 IV Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg/m^2 IV Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months])

    Number of subjects in period 1
    		Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Started
    301
    281
    300
    Treated
    300
    276
    287
    Pembro Mono v Control Efficacy Analyses
    301
    0 [1]
    300
    Pembro Combo v Control Efficacy Analyses
    0 [2]
    281
    278
    Received Second Course of Pembrolizumab
    8
    6
    0
    Completed
    2
    1
    0
    Not completed
    299
    280
    300
         Consent withdrawn by subject
    19
    14
    18
         Death
    253
    237
    266
         Sponsor Decision
    26
    28
    16
         Lost to follow-up
    1
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Per protocol, efficacy analyses were performed by comparing the Pembro Combo arm versus the Control arm. Due to a pause in enrollment in the Pembro Combo arm, only the concurrent control arm is used for their comparison.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Per protocol, efficacy analyses were performed by comparing the Pembro Mono arm versus the Control arm. Due to a pause in enrollment in the Pembro Combo arm, only the concurrent control arm is used for their comparison.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Pembrolizumab Monotherapy (Pembro Mono)
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year).

    Reporting group title
    Pembrolizumab + Chemotherapy (Pembro Combo)
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years); plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months]); plus 5-Fluorouracil (5-FU) 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year).

    Reporting group title
    Cetuximab + Chemotherapy (Control)
    Reporting group description
    		 Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months] for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]).

    Reporting group values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control) Total
    Number of subjects
    		 301 281 300 882
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 190 180 195 565
        From 65-84 years
    		 110 100 105 315
        85 years and over
    		 1 1 0 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 61.2 ( 9.4 ) 60.7 ( 9.8 ) 61.0 ( 10.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 51 57 39 147
        Male
    		 250 224 261 735
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 5 3 6 14
        Asian
    		 58 60 54 172
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 4 11 6 21
        White
    		 219 203 224 646
        More than one race
    		 12 4 9 25
        Unknown or Not Reported
    		 3 0 1 4
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 46 45 44 135
        Not Hispanic or Latino
    		 233 213 231 677
        Unknown or Not Reported
    		 22 23 25 70
    Eastern Cooperative Group (ECOG) Performance Status
    An ECOG Performance Status of 0 (Fully active, able to carry on all pre-disease performance without restriction) or 1 (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature) was required for inclusion in the trial.
    Units: Subjects
        ECOG = 0
    		 118 110 117 345
        ECOG = 1
    		 183 171 183 537
    Human Papillomavirus (HPV) Status
    HPV status for oropharynx cancer as determined by p16 immunohistochemistry (IHC) (positive vs. negative); HPV status for participants without oropharynx cancer was considered HPV negative.
    Units: Subjects
        HPV Positive
    		 63 60 67 190
        HPV Negative
    		 238 221 233 692
    PD-L1 TPS Status
    The Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) Status indicates the degree by which participants tumors stain positive for PD-L1 by IHC staining (i.e. strongly positive or not strongly positive). Participants with a TPS ≥50% were classified as PD-L1 “strongly positive” and participants with a TPS <50% were classified as “not strongly positive."
    Units: Subjects
        Strongly Positive
    		 67 66 66 199
        Not Strongly Positive
    		 234 215 234 683
    PD-L1 CPS ≥1 Status
    The PD-L1 Combined Positive Score (CPS) Status indicates tumor PD-L1 positivity using both tumor cells and inflammatory cells that are positive for PD-L1 by IHC. The number of participants with CPS<1 and CPS≥1 at baseline is presented. Participants with a CPS<1 were classified as PD-L1 negative and participants with a CPS≥1 were classified as PD-L1 positive.
    Units: Subjects
        CPS<1
    		 44 39 45 128
        CPS ≥1
    		 257 242 255 754
    PD-L1 CPS ≥20 Status
    The PD-L1 CPS Status indicates tumor PD-L1 positivity using both tumor cells and inflammatory cells that are positive for PD-L1 by IHC. The number of participants with CPS<20 and CPS ≥20 at baseline is presented.
    Units: Subjects
        CPS <20
    		 167 154 175 496
        CPS ≥20
    		 133 126 122 381
        Missing
    		 1 1 3 5

    End points

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    End points reporting groups
    Reporting group title
    Pembrolizumab Monotherapy (Pembro Mono)
    Reporting group description
    		 Participants received pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year).

    Reporting group title
    Pembrolizumab + Chemotherapy (Pembro Combo)
    Reporting group description
    		 Participants received pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to ~2 years); plus cisplatin 100 mg/m^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months]); plus 5-Fluorouracil (5-FU) 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]). Qualified participants who received the first course of pembrolizumab but continued to experience disease progression may have, at the investigator’s discretion, initiated a second course of pembrolizumab at the same dose and schedule of 200 mg IV on Day 1 of each 3-week cycle for up to 17 cycles (up to ~1 year).

    Reporting group title
    Cetuximab + Chemotherapy (Control)
    Reporting group description
    		 Participants received cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum [up to ~4 months] for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum [up to ~4 months]).

    Primary: Pembro Combo vs Control: Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in All Participants

    		 Close Top of page
    End point title
    		 Pembro Combo vs Control: Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in All Participants
    End point description
    PFS is the time from randomization to first documented progressive disease (PD) per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the sum of diameters (SOD) of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol PFS in the pembro combo versus the control arm was a pre-specified primary analysis of the Intent-To-Treat (ITT) population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. PFS is reported here for the first course, for all participants in the pembro combo and control arm. Per protocol PFS was compared separately between all participants of the pembro mono and control arm and is presented later.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [1]
    281
    278
    Units: Months
        median (confidence interval 95%)
    ( to )
    4.9 (4.7 to 6.1)
    5.2 (4.9 to 6.1)
    Notes
    [1] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 PFS in All Participants
    Statistical analysis description
    PFS in all participants of the pembro combo arm was compared to PFS in all participants of the control arm to address the sixth primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21211 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.11
    Notes
    [2] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Combo vs Control: PFS per RECIST 1.1 by BICR in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1

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    End point title
    		 Pembro Combo vs Control: PFS per RECIST 1.1 by BICR in Participants With Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurrs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by immunohistochemistry (IHC) as Combined Positive Score ≥1 (CPS ≥1). 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. PFS is reported here for the first course of treatment, for all participants in the pembro combo and control arm with CPS ≥1. Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [3]
    242
    235
    Units: Months
        median (confidence interval 95%)
    ( to )
    5.1 (4.7 to 6.2)
    5.0 (4.8 to 6.0)
    Notes
    [3] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 PFS in participants with CPS≥1
    Statistical analysis description
    PFS in CPS ≥1 participants of the pembro combo arm was compared to PFS in CPS ≥1 participants of the control arm to address the fifth primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03697 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.02
    Notes
    [4] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Combo vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Combo vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as Combined Positive Score ≥20 (CPS ≥20). 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. PFS is reported here for the first course, for all participants in the pembro combo and control arm with CPS ≥20. Per protocol, PFS was compared separately between CPS ≥20 participants of the pembro mono and control arm and is presented later.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [5]
    126
    110
    Units: Months
        median (confidence interval 95%)
    ( to )
    5.8 (4.7 to 7.6)
    5.3 (4.9 to 6.3)
    Notes
    [5] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 PFS in participants with CPS≥20
    Statistical analysis description
    PFS in CPS ≥20 participants of the pembro combo arm was compared to PFS in CPS ≥20 participants of the control arm to address the fourth primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02951 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.01
    Notes
    [6] - One-sided p-value based on log-rank test stratified by ECOG and HPV status.

    Primary: Pembro Combo vs Control: Overall Survival (OS) in All Participants

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    End point title
    		 Pembro Combo vs Control: Overall Survival (OS) in All Participants
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. OS is reported here for the first course, for all participants in the pembro combo and control arm. Per protocol, OS was compared separately between all participants of the pembro mono arm and control arm and is presented later.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [7]
    281
    278
    Units: Months
        median (confidence interval 95%)
    ( to )
    13.0 (10.9 to 14.7)
    10.7 (9.3 to 11.7)
    Notes
    [7] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 OS in All Participants
    Statistical analysis description
    OS in all participants of the pembro combo arm was compared to OS in all participants of the control arm to address the fourteenth primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00025 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.87
    Notes
    [8] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥1
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS≥1. 20 participants in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. OS is reported here for the first course, for all participants in the pembro combo arm and control arm with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. Per protocol, OS was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [9]
    242
    235
    Units: Months
        median (confidence interval 95%)
    ( to )
    13.6 (10.7 to 15.5)
    10.4 (9.1 to 11.7)
    Notes
    [9] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 OS in participants with CPS≥1
    Statistical analysis description
    OS in CPS ≥1 participants of the pembro combo arm was compared to OS in CPS ≥1 participants of the control arm to address the twelfth primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0 [10]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.8
    Notes
    [10] - p-value = 0.00002; One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Combo vs Control: OS in Participants With PD-L1 CPS ≥20
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro combo arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. OS is reported here for the first course, for all participants in the pembro combo and control arm with CPS≥20. Per protocol, OS was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [11]
    126
    110
    Units: Months
        median (confidence interval 95%)
    ( to )
    14.7 (10.3 to 19.3)
    11.0 (9.2 to 13.0)
    Notes
    [11] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 OS in participants with CPS≥20
    Statistical analysis description
    OS in CPS ≥20 participants of the pembro combo arm was compared to OS in CPS ≥20 participants of the control arm to address the eleventh primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00044 [12]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.82
    Notes
    [12] - One-sided p-value based on log-rank test stratified by ECOG and HPV status.

    Primary: Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in All Participants

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    End point title
    		 Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in All Participants
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment. PFS is reported here for the first course, for all participants in the pembro mono arm and control arm. Per protocol, PFS was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    301
    0 [13]
    300
    Units: Months
        median (confidence interval 95%)
    2.3 (2.2 to 3.3)
    ( to )
    5.2 (4.9 to 6.1)
    Notes
    [13] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 PFS in All Participants
    Statistical analysis description
    PFS in all participants of the pembro mono arm was compared to PFS in all participants of the control arm to address the third primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    601
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9983 [14]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.09
         upper limit
    		 1.53
    Notes
    [14] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. PFS is reported here for the first course, for all participants in the pembro mono and control arm with CPS≥1. Per protocol, PFS was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    257
    0 [15]
    255
    Units: Months
        median (confidence interval 95%)
    3.2 (2.2 to 3.4)
    ( to )
    5.0 (4.8 to 6.0)
    Notes
    [15] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 PFS in participants with CPS≥1
    Statistical analysis description
    PFS in CPS ≥1 participants of the pembro mono arm was compared to PFS in CPS ≥1 participants of the control arm to address the second primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8958 [16]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.36
    Notes
    [16] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Mono vs Control: PFS per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. PFS is reported here for the first course, for all participants in the pembro mono and control arm with CPS ≥20. Per protocol, PFS was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    133
    0 [17]
    122
    Units: Months
        median (confidence interval 95%)
    3.4 (3.2 to 3.8)
    ( to )
    5.3 (4.8 to 6.3)
    Notes
    [17] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 PFS in participants with CPS≥20
    Statistical analysis description
    PFS in CPS ≥20 participants of the pembro mono arm was compared to PFS in CPS ≥20 participants of the control arm to address the first primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46791 [18]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.29
    Notes
    [18] - One-sided p-value based on log-rank test stratified by ECOG and HPV status.

    Primary: Pembro Mono vs Control: OS in All Participants

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    End point title
    		 Pembro Mono vs Control: OS in All Participants
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment. OS is reported here for the first course, for all participants in the pembro mono and control arm. Per protocol, OS was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    301
    0 [19]
    300
    Units: Months
        median (confidence interval 95%)
    11.5 (10.3 to 13.4)
    ( to )
    10.7 (9.3 to 11.7)
    Notes
    [19] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 OS in All Participants
    Statistical analysis description
    OS in all participants of the pembro mono arm was compared to OS in all participants of the control arm to address the tenth primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    601
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01985 [20]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.99
    Notes
    [20] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥1
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. OS is reported here for the first course, for all participants in the pembro mono and control arm with CPS ≥1. Per protocol, OS was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    257
    0 [21]
    255
    Units: Months
        median (confidence interval 95%)
    12.3 (10.8 to 14.3)
    ( to )
    10.3 (9.0 to 11.5)
    Notes
    [21] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 OS in participants with CPS≥1
    Statistical analysis description
    OS in CPS ≥1 participants of the pembro mono arm was compared to OS in CPS ≥1 participants of the control arm to address the eighth primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG, HPV status and PD-L1 status.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00133 [22]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 0.9
    Notes
    [22] - One-sided p-value based on log-rank test stratified by ECOG, HPV status and PD-L1 status.

    Primary: Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Mono vs Control: OS in Participants With PD-L1 CPS ≥20
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. Per protocol, OS in the pembro mono arm versus the control arm was a pre-specified primary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. OS is reported here for the first course, for all participants in the pembro mono arm and control arm with CPS ≥20. Per protocol, OS was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Primary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    133
    0 [23]
    122
    Units: Months
        median (confidence interval 95%)
    14.8 (11.5 to 20.6)
    ( to )
    10.7 (8.8 to 12.8)
    Notes
    [23] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 OS in participants with CPS≥20
    Statistical analysis description
    OS in CPS ≥20 participants of the pembro mono arm was compared to OS in CPS ≥20 participants of the control arm to address the seventh primary hypothesis. The comparison was based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG and HPV status.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001 [24]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.78
    Notes
    [24] - One-sided p-value based on log-rank test stratified by ECOG and HPV status.

    Secondary: Pembro Combo vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among All Participants

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    End point title
    		 Pembro Combo vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among All Participants
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro combo arm and control arm. Per protocol, the percentage of participants with PFS at 6 months was compared separately between all participants of the pembro mono arm and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [25]
    281
    278
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    44.7 (38.8 to 50.5)
    44.9 (38.9 to 50.8)
    Notes
    [25] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Combo vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo versus control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro combo and control arm with CPS ≥1. Per protocol, PFS rate at 6 months was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [26]
    242
    235
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    44.9 (38.5 to 51.1)
    43.3 (36.9 to 49.6)
    Notes
    [26] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Combo vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro combo and control arm with CPS≥20. Per protocol, PFS rate at 6 months was compared separately between CPS ≥20 participants of the pembro mono and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [27]
    126
    110
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    49.4 (40.3 to 57.9)
    47.2 (37.5 to 56.2)
    Notes
    [27] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among All Participants

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    End point title
    		 Pembro Combo vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among All Participants
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro combo and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between all participants of the pembro mono and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [28]
    281
    278
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    17.2 (13.0 to 21.9)
    13.6 (9.8 to 18.1)
    Notes
    [28] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Combo vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants with in the pembro combo arm and control arm with CPS≥1. Per protocol, PFS rate at 12 months was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [29]
    242
    235
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    19.7 (14.8 to 25.0)
    12.5 (8.6 to 17.3)
    Notes
    [29] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Combo vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro combo arm versus control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro combo and control arm with CPS ≥20. Per protocol, PFS rate at 12 months was compared separately between CPS ≥20 participants of the pembro mono and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [30]
    126
    110
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    23.9 (16.7 to 31.7)
    14.0 (8.2 to 21.3)
    Notes
    [30] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Combo vs Control: Objective Response Rate (ORR) per RECIST 1.1 by BICR in All Participants

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    End point title
    		 Pembro Combo vs Control: Objective Response Rate (ORR) per RECIST 1.1 by BICR in All Participants
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. by BICR. Per protocol, ORR in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. 22 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro combo arm and control arm. Per protocol, ORR was compared separately between all participants of the pembro mono arm and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [31]
    281
    278
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    35.6 (30.0 to 41.5)
    36.3 (30.7 to 42.3)
    Notes
    [31] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 ORR in all participants
    Statistical analysis description
    ORR in all participants of the pembro combo arm was compared to ORR in all participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.574 [32]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 7.2
    Notes
    [32] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Combo vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. by BICR. Per protocol, ORR in the pembro combo arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro combo arm and control arm with CPS ≥1. Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro mono arm and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [33]
    242
    235
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    36.4 (30.3 to 42.8)
    35.7 (29.6 to 42.2)
    Notes
    [33] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 ORR in participants with CPS≥1
    Statistical analysis description
    ORR in CPS ≥1 participants of the pembro combo arm was compared to ORR in CPS ≥1 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4586 [34]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 9.1
    Notes
    [34] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs Control: Change From Baseline to Week 15 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score

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    End point title
    		 Pembro Combo vs Control: Change From Baseline to Week 15 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Combined Score
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire to assess the quality of life (QoL) of cancer patients. Responses to "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating a better overall outcome. Per protocol change from baseline (BL) to Week 15 in GHS/QoL combined score, for the first course, in all participants of the pembro combo versus control arm was a pre-specified secondary analysis; and compared separately between all participants of pembro mono and control arm, as presented later. All participants in the pembro combo and control arm who got ≥1 dose of study drug and had assessments available at- or post-BL up to Week 15 were analyzed. 20 in the control arm in an enrollment pause of pembro combo arm were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 15
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [35]
    268
    259
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    ( to )
    1.17 (-1.79 to 4.12)
    0.77 (-2.22 to 3.76)
    Notes
    [35] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 Change from Baseline: EORTC QLQ-C30 Items 29 & 30
    Statistical analysis description
    Change from baseline to Week 15 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro combo arm and the control arm. Comparison based on constrained longitudinal data analysis (cLDA) model with GHS/QoL score as response variable and treatment by visit interaction, stratification factors (ECOG [0 vs. 1], HPV status [Positive vs. Negative] and PD-L1 TPS status [Strongly Positive, Not Strongly Positive]) as covariates.
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.839 [36]
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.46
         upper limit
    		 4.26
    Notes
    [36] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Combo vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. by BICR. Per protocol, ORR in the pembro combo arm versus the control arm as a pre-specified secondary analysis of the ITT population, consisting of consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. 12 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro combo arm and control arm with CPS≥20. Per protocol, ORR was compared separately between CPS ≥20 participants of the pembro mono arm and control arm and is presented later.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [37]
    126
    110
    Units: Percentage of Participants
        number (confidence interval 95%)
    ( to )
    42.9 (34.1 to 52.0)
    38.2 (29.1 to 47.9)
    Notes
    [37] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 ORR in participants with CPS≥20
    Statistical analysis description
    ORR in CPS ≥20 participants of the pembro combo arm was compared to ORR in CPS ≥20 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1) and HPV status (Positive vs. Negative).
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2161 [38]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 17.4
    Notes
    [38] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs Control: Time to Deterioration (TTD) in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Kaplan-Meier Method)

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    End point title
    		 Pembro Combo vs Control: Time to Deterioration (TTD) in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score (Kaplan-Meier Method)
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire assessing QoL of cancer patients. Response to "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall QoL during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating a better outcome. TTD is the time from BL to first onset of a ≥10-point decrease from BL in GHS/QoL score. Per protocol TTD for the first course, in all participants of pembro combo versus control arm was a pre-specified secondary analysis; TTD in pembro mono versus control arm was presented later. All participants in the pembro combo and control arms who completed EORTC QLQ-C30 and got ≥1 dose of study drug were analyzed. 20 in the control arm enrolled during an enrollment pause of the pembro combo arm were excluded. 9999: Value not reached due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 12 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [39]
    270
    260
    Units: Months
        median (confidence interval 95%)
    ( to )
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [39] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 TTD: EORTC QLQ-C30 Items 29 & 30
    Statistical analysis description
    TTD in GHS/QoL combined score was compared between all participants of the pembro combo arm and the control arm. Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9497 [40]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 2
    Notes
    [40] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs Control: TTD in the EORTC QLQ- Head and Neck Module 35 (H&N35) Pain Score (Kaplan-Meier Method)

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    End point title
    		 Pembro Combo vs Control: TTD in the EORTC QLQ- Head and Neck Module 35 (H&N35) Pain Score (Kaplan-Meier Method)
    End point description
    ORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). Responses to the Pain scale (Items 31-34) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to first onset of a ≥10-point decrease from BL. Per protocol TTD in Pain Score for first course, in all participants of pembro combo versus control arm was a pre-specified secondary analysis; TTD in pembro mono versus control arm was presented later. All participants in the pembro combo and control arm who got ≥1 dose of study drug and completed EORTC QLQ-H&N35 were analyzed, 20 participants enrolled in the control arm during an enrollment pause of the pembro combo arm were excluded. 9999: Value not reached due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 12 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [41]
    268
    260
    Units: Months
        median (confidence interval 95%)
    ( to )
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [41] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 TTD: EORTC QLQ-H&N35 Pain Score
    Statistical analysis description
    TTD in EORTC QLQ-H&N35 Pain Score was compared between all participants of the pembro combo arm and the control arm. Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    528
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9476 [42]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 2.02
    Notes
    [42] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Combo vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score (Kaplan-Meier Method)

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    End point title
    		 Pembro Combo vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score (Kaplan-Meier Method)
    End point description
    EORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). Responses to Swallowing scale (Items 35-38) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to the first onset of a ≥10-point decrease from BL. Per protocol TTD for the first course, in all participants of the pembro combo versus control arm was a pre-specified secondary analysis; TTD in pembro mono versus control arm was presented later. All participants in the pembro combo and control arm who completed the EORTC QLQ-H&N35 and got ≥1 dose of study drug were analyzed; 20 enrolled in control arm during an enrollment pause of the pembro combo arm were excluded. 9999: Value not reached due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 12 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    0 [43]
    268
    260
    Units: Months
        median (confidence interval 95%)
    ( to )
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [43] - Per protocol, the Pembro Mono Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 TTD: EORTC QLQ-H&N35 Swallowing Score
    Statistical analysis description
    TTD in EORTC QLQ-H&N35 Swallowing Score was compared between all participants of the pembro combo arm and the control arm. Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab + Chemotherapy (Pembro Combo) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    528
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5836 [44]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.59
    Notes
    [44] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among All Participants

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    End point title
    		 Pembro Mono vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among All Participants
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro mono arm and control arm. Per protocol, PFS rate at 6 months was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    301
    0 [45]
    300
    Units: Percentage of Participants
        number (confidence interval 95%)
    26.2 (21.4 to 31.3)
    ( to )
    45.7 (39.9 to 51.3)
    Notes
    [45] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Mono vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Mono vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants in the pembro mono arm and control arm with CPS≥1. Per protocol, the percentage of participants with PFS at 6 months was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    257
    0 [46]
    255
    Units: Percentage of Participants
        number (confidence interval 95%)
    28.7 (23.3 to 34.4)
    ( to )
    43.9 (37.6 to 49.9)
    Notes
    [46] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Mono vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Mono vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥1
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro mono and control arm with CPS≥1. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥1 participants of the pembro combo and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    257
    0 [47]
    255
    Units: Percentage of Participants
        number (confidence interval 95%)
    20.6 (15.9 to 25.8)
    ( to )
    13.6 (9.6 to 18.2)
    Notes
    [47] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: Pembro Mono vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among All Participants

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    End point title
    		 Pembro Mono vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among All Participants
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro mono arm and control arm. Per protocol, the percentage of participants with PFS at 12 months was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    301
    0 [48]
    300
    Units: Percentage of Participants
        number (confidence interval 95%)
    17.6 (13.5 to 22.1)
    ( to )
    15.0 (11.2 to 19.4)
    Notes
    [48] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Mono vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Mono vs Control: Percentage of Participants with PFS at 6 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
    End point description
    PFS is the time from randomization to first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. The percentage of participants with PFS (PFS rate) at 6 months is reported here, for the first course, for all participants with in the pembro mono arm and control arm with CPS≥20. Per protocol, PFS rate at 6 months was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    133
    0 [49]
    122
    Units: Percentage of Participants
        number (confidence interval 95%)
    33.0 (25.2 to 41.0)
    ( to )
    46.6 (37.5 to 55.2)
    Notes
    [49] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Mono vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Mono vs Control: Percentage of Participants with PFS at 12 Months per RECIST 1.1 by BICR Among Participants With PD-L1 CPS ≥20
    End point description
    PFS is the time from randomization the first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is ≥20% increase in the SOD of target lesions and an additional absolute increase of ≥5 mm. The appearance of ≥1 new lesions is also PD. Per protocol, PFS in the pembro mono arm versus the control arm as a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS≥20. The percentage of participants with PFS (PFS rate) at 12 months is reported here, for the first course, for all participants in the pembro mono and control arm with CPS≥20. Per protocol, the percentage of participants with PFS at 12 months was compared separately between CPS ≥20 participants of the pembro combo and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    133
    0 [50]
    122
    Units: Percentage of Participants
        number (confidence interval 95%)
    23.5 (16.6 to 31.1)
    ( to )
    15.1 (9.3 to 22.2)
    Notes
    [50] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    No statistical analyses for this end point

    Secondary: Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in All Participants

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    End point title
    		 Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in All Participants
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. by BICR. Per protocol, ORR in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro mono and control arm. Per protocol, ORR was compared separately between all participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    301
    0 [51]
    300
    Units: Percentage of Participants
        number (confidence interval 95%)
    16.9 (12.9 to 21.7)
    ( to )
    36.0 (30.6 to 41.7)
    Notes
    [51] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 Pembro Mono vs Control: ORR in all subjects
    Statistical analysis description
    ORR in all participants of the pembro mono arm was compared to ORR in all participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive , Not Strongly Positive).
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    601
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [52]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    -19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.8
         upper limit
    		 -12.1
    Notes
    [52] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1

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    End point title
    		 Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥1
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. by BICR. Per protocol, ORR in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥1. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro mono and control arm with CPS≥1. Per protocol, ORR was compared separately between CPS ≥1 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    257
    0 [53]
    255
    Units: Percentage of Participants
        number (confidence interval 95%)
    19.1 (14.5 to 24.4)
    ( to )
    34.9 (29.1 to 41.1)
    Notes
    [53] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 Pembro Mono vs Control: ORR subjects with CPS ≥1
    Statistical analysis description
    ORR in CPS ≥1 participants of the pembro mono arm was compared to ORR in CPS ≥1 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1 [54]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    -15.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.4
         upper limit
    		 -8.3
    Notes
    [54] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20

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    End point title
    		 Pembro Mono vs Control: ORR per RECIST 1.1 by BICR in Participants With PD-L1 CPS ≥20
    End point description
    ORR was defined as the percentage of participants in the analysis population who have a CR (disappearance of all target lesions) or a PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1. by BICR. Per protocol, ORR in the pembro mono arm versus the control arm was a pre-specified secondary analysis of the ITT population, consisting of all randomized participants during active enrollment with PD-L1 biomarker positive expression defined by IHC as CPS ≥20. The percentage of participants who experienced CR or PR is reported here as the ORR, for the first course, for all participants in the pembro mono and control arm with CPS≥20. Per protocol, ORR was compared separately between CPS ≥20 participants of the pembro combo arm and control arm and is presented earlier.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    133
    0 [55]
    122
    Units: Percentage of Participants
        number (confidence interval 95%)
    23.3 (16.4 to 31.4)
    ( to )
    36.1 (27.6 to 45.3)
    Notes
    [55] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 ORR in participants with CPS≥20
    Statistical analysis description
    ORR in CPS ≥20 participants of the pembro mono arm was compared to ORR in CPS ≥20 participants of the control arm. The comparison was based on Miettinen & Nurminen method stratified by ECOG (0 vs. 1) and HPV status (Positive vs. Negative).
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9869 [56]
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in ORR Percentage
    Point estimate
    -12.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.8
         upper limit
    		 -1.5
    Notes
    [56] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs Control: Change From Baseline to Week 15 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score

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    End point title
    		 Pembro Mono vs Control: Change From Baseline to Week 15 in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire to assess the quality of life (QoL) of cancer patients. Responses to "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall quality of life during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized by linear transformation so that scores ranged from 0 to 100; a higher score indicating a better overall outcome. Per protocol, change from baseline to Week 15 in GHS/QoL combined score, for the first course, in all participants of the pembro mono versus control arm was a pre-specified secondary analysis; and compared separately between all participants of pembro combo and control arm and is presented earlier. All participants in the pembro mono arm and the control arm who got ≥1 dose of study drug and had assessments available at baseline or post-baseline up to Week 15 were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 15
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    294
    0 [57]
    279
    Units: Score on a Scale
        least squares mean (confidence interval 95%)
    0.85 (-1.90 to 3.59)
    ( to )
    0.60 (-2.19 to 3.40)
    Notes
    [57] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 Change from Baseline: EORTC QLQ-C30 Items 29 & 30
    Statistical analysis description
    Change from baseline to Week 15 in EORTC-QLQ-C30 GHS/QoL combined score was compared between all participants of the pembro mono arm and the control arm. Comparison based on cLDA model with GHS/QoL score as response variable and treatment by visit interaction, stratification factors (ECOG [0 vs. 1], HPV status [Positive vs. Negative] and PD-L1 TPS status [Strongly Positive, Not Strongly Positive]) as covariates.
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    573
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.893 [58]
    Method
    		 constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.34
         upper limit
    		 3.82
    Notes
    [58] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Pain Score

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    End point title
    		 Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Pain Score
    End point description
    EORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). Responses to the Pain scale (Items 31-34) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to first onset of a ≥10-point decrease from BL. Per protocol TTD in Pain Score for first course, in all participants of pembro mono versus control arm was a pre-specified secondary analysis; TTD in pembro combo versus control arm was presented earlier. All participants in the pembro mono and control arm who got ≥1 dose of study drug and completed EORTC QLQ-H&N35 were analyzed. 9999: Value not reached due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 12 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    295
    0 [59]
    280
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    ( to )
    9999 (9999 to 9999)
    Notes
    [59] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 TTD: EORTC QLQ-C30 H&N35 Pain Score
    Statistical analysis description
    TTD in EORTC QLQ-H&N35 Pain Score was compared between all participants of the pembro mono arm and the control arm. Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1501 [60]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.21
    Notes
    [60] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs Control: TTD in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score

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    End point title
    		 Pembro Mono vs Control: TTD in the EORTC QLQ-C30 Global Health Status/Quality of Life (Items 29 and 30) Combined Score
    End point description
    EORTC-QLQ-C30 is a 30-item questionnaire assessing QoL of cancer patients. Response to "How would you rate your overall health during the past week?" (Item 29) and "How would you rate your overall QoL during the past week?" (Item 30) were scored on a 7-point scale (1=Very Poor to 7=Excellent). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating a better outcome. TTD is the time from BL to first onset of a ≥10-point decrease from BL in GHS/QoL score. Per protocol TTD for the first course, in all participants of pembro mono versus control arm was a pre-specified secondary analysis; TTD in pembro combo versus control arm was presented earlier. All participants in the pembro mono and control arms who completed EORTC QLQ-C30 and got ≥1 dose of study drug were analyzed. 9999: Value not reached due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 12 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    294
    0 [61]
    280
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    ( to )
    9999 (9999 to 9999)
    Notes
    [61] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 TTD: EORTC QLQ-C30 Items 29 & 30
    Statistical analysis description
    TTD in GHS/QoL combined score was compared between all participants of the pembro mono arm and the control arm. Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    574
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.953 [62]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 2
    Notes
    [62] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score

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    End point title
    		 Pembro Mono vs Control: TTD in the EORTC QLQ- H&N35 Swallowing Score
    End point description
    EORTC QLQ-H&N35 is a 35-item questionnaire to assess QoL of head and neck cancer patients (7 multi-item scales to assess pain, swallowing, senses, speech, social eating, social contact, sexuality). Responses to Swallowing scale (Items 35-38) were scored on a 4-point scale (1=Not at all to 4=Very much). Raw scores were standardized so scores ranged from 0 to 100; a higher score indicating more problems. TTD is the time from BL to the first onset of a ≥10-point decrease from BL. Per protocol TTD for the first course, in all participants of the pembro mono versus control arm was a pre-specified secondary analysis; TTD in pembro combo versus control arm was presented earlier. All participants in the pembro mono and control arm who completed the EORTC QLQ-H&N35 and got ≥1 dose of study drug were analyzed. 9999: Value not reached due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 12 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    295
    0 [63]
    280
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    ( to )
    9999 (9999 to 9999)
    Notes
    [63] - Per protocol, the Pembro Combo Arm was not analyzed for this endpoint.
    Statistical analysis title
    		 TTD: EORTC QLQ-H&N35 Swallowing Score
    Statistical analysis description
    TTD in EORTC QLQ-H&N35 Swallowing Score was compared between all participants of the pembro mono arm and the control arm. Comparison based on Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG (0 vs. 1), HPV status (Positive vs. Negative) and PD-L1 TPS status (Strongly Positive, Not Strongly Positive).
    Comparison groups
    Pembrolizumab Monotherapy (Pembro Mono) v Cetuximab + Chemotherapy (Control)
    Number of subjects included in analysis
    575
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8751 [64]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.88
    Notes
    [64] - No formal hypothesis testing performed; nominal p-value provided for treatment comparison.

    Secondary: Number of Participants Experiencing an Adverse Event (AE)

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    End point title
    		 Number of Participants Experiencing an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that experienced at least one AE, for the first course of treatment, in subjects who received ≥1 dose of study drug, was reported for each arm.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    300
    276
    287
    Units: Participants
    290
    271
    286
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor’s product was also an AE. The number of participants that experienced at least one AE, for the first course of treatment, in subjects who received ≥1 dose of study drug, was reported for each arm.
    End point type
    Secondary
    End point timeframe
    Up to approximately 47 months
    End point values
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Cetuximab + Chemotherapy (Control)
    Number of subjects analysed
    300
    276
    287
    Units: Participants
    36
    90
    79
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 98 months
    Adverse event reporting additional description
    All Cause Mortality (ACM): all randomized participants. AEs: all randomized participants who got ≥1 dose of study drug. Per protocol, MedDRA preferred terms “Neoplasm progression (NP), Malignant (NP) and Disease progression” not related to study drug are omitted as AEs; ACM and AEs collected and reported separately for pembrolizumab second course.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Pembrolizumab Monotherapy (Pembro Mono)
    Reporting group description
    		 -

    Reporting group title
    Pembrolizumab + Chemotherapy (Pembro Combo)
    Reporting group description
    		 -

    Reporting group title
    Pembrolizumab + Chemotherapy Second Course
    Reporting group description
    		 -

    Reporting group title
    Pembrolizumab Monotherapy Second Course
    Reporting group description
    		 -

    Reporting group title
    Cetuximab + Chemotherapy (Control)
    Reporting group description
    		 -

    Serious adverse events
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Pembrolizumab + Chemotherapy Second Course Pembrolizumab Monotherapy Second Course Cetuximab + Chemotherapy (Control)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    123 / 300 (41.00%)
    165 / 276 (59.78%)
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    142 / 287 (49.48%)
         number of deaths (all causes)
    260
    242
    5
    5
    282
         number of deaths resulting from adverse events
    25
    32
    0
    0
    28
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Cancer pain
         subjects affected / exposed
    2 / 300 (0.67%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic tumour necrosis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypopharyngeal cancer
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Infected neoplasm
         subjects affected / exposed
    3 / 300 (1.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    11 / 300 (3.67%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    2 / 13
    2 / 7
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 0
    0 / 3
    Prostate cancer
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Tumour flare
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Metastases to bone
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Tumour pain
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Deep vein thrombosis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Neurogenic shock
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Thrombophlebitis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Lymphoedema
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypotension
         subjects affected / exposed
    2 / 300 (0.67%)
    4 / 276 (1.45%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Venous thrombosis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Catheter site inflammation
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Asthenia
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 300 (1.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 300 (0.67%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    Complication associated with device
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Chest pain
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    General physical health deterioration
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Hyperthermia
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Localised oedema
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Mucosal inflammation
         subjects affected / exposed
    1 / 300 (0.33%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 300 (0.67%)
    7 / 276 (2.54%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 7
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Peripheral swelling
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 300 (0.67%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Swelling
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoinflammatory disease
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type III immune complex mediated reaction
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypersensitivity
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypoxia
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Hydrothorax
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Haemoptysis
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Epistaxis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Dyspnoea
         subjects affected / exposed
    7 / 300 (2.33%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 9
    1 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Bronchial obstruction
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Interstitial lung disease
         subjects affected / exposed
    1 / 300 (0.33%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    2 / 300 (0.67%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 300 (0.67%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Laryngeal oedema
         subjects affected / exposed
    1 / 300 (0.33%)
    4 / 276 (1.45%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal obstruction
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal fistula
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonitis
         subjects affected / exposed
    3 / 300 (1.00%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary embolism
         subjects affected / exposed
    2 / 300 (0.67%)
    4 / 276 (1.45%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    6 / 287 (2.09%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 0
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Pulmonary mass
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Respiratory failure
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory tract haemorrhage
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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 / 1
    Upper airway obstruction
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Psychiatric disorders
    Stress
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Delirium
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Completed suicide
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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 / 1
    Anxiety
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Suicide attempt
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Product issues
    Stent malfunction
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Device occlusion
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Device leakage
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Device dislocation
         subjects affected / exposed
    0 / 300 (0.00%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    C-reactive protein increased
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Blood potassium decreased
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Blood creatinine increased
         subjects affected / exposed
    0 / 300 (0.00%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Neutrophil count decreased
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Weight decreased
         subjects affected / exposed
    2 / 300 (0.67%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 300 (0.00%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Ankle fracture
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Arterial injury
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Contusion
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Femur fracture
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Gastrostomy failure
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Fall
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Osteoradionecrosis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Heat stroke
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Hip fracture
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Infusion related reaction
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Stoma site discharge
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Spinal compression fracture
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Stoma site pain
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Traumatic fracture
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Tracheal obstruction
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Tibia fracture
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Synovial rupture
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune myocarditis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac arrest
         subjects affected / exposed
    0 / 300 (0.00%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 300 (0.00%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiac failure acute
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Myocardial infarction
         subjects affected / exposed
    3 / 300 (1.00%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    Palpitations
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Myocardial ischaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Tachycardia
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Cerebral infarction
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Cerebral ischaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Carotid artery perforation
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Carotid sinus syndrome
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Vocal cord paralysis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Toxic encephalopathy
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Syncope
         subjects affected / exposed
    0 / 300 (0.00%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Seizure
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Restless legs syndrome
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Presyncope
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Ischaemic stroke
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 300 (0.33%)
    14 / 276 (5.07%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    9 / 287 (3.14%)
         occurrences causally related to treatment / all
    1 / 1
    13 / 17
    0 / 0
    0 / 0
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 300 (0.00%)
    17 / 276 (6.16%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    15 / 287 (5.23%)
         occurrences causally related to treatment / all
    0 / 0
    15 / 17
    0 / 0
    0 / 0
    11 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematotoxicity
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Leukopenia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 300 (0.00%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 300 (0.00%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 300 (0.33%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Colitis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Constipation
         subjects affected / exposed
    2 / 300 (0.67%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Enterocolitis
         subjects affected / exposed
    2 / 300 (0.67%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Duodenal ulcer
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    4 / 300 (1.33%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Diarrhoea
         subjects affected / exposed
    2 / 300 (0.67%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastric perforation
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastric haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Haemorrhoids
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Haematochezia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Haematemesis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal toxicity
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Intestinal perforation
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Mouth haemorrhage
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pancreatitis acute
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Oesophageal fistula
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Nausea
         subjects affected / exposed
    0 / 300 (0.00%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    8 / 287 (2.79%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
    0 / 0
    0 / 0
    8 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oral cavity fistula
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumoperitoneum
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 300 (0.00%)
    8 / 276 (2.90%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tongue oedema
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Umbilical hernia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 300 (0.00%)
    5 / 276 (1.81%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    5 / 287 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
    0 / 0
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    2 / 300 (0.67%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pruritus
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Rash
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Psoriasis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin haemorrhage
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Skin necrosis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Acute kidney injury
         subjects affected / exposed
    4 / 300 (1.33%)
    5 / 276 (1.81%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 4
    5 / 5
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal failure
         subjects affected / exposed
    0 / 300 (0.00%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Renal tubular necrosis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Tubulointerstitial nephritis
         subjects affected / exposed
    2 / 300 (0.67%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Adrenal insufficiency
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypophysitis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypopituitarism
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Arthralgia
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Joint swelling
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Fistula
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Neck pain
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Rhabdomyolysis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Polyarthritis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Abdominal infection
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Atypical pneumonia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Bacteraemia
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Bronchitis
         subjects affected / exposed
    2 / 300 (0.67%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 300 (0.67%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus gastrointestinal infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Device related infection
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Device related sepsis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Extradural abscess
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Escherichia infection
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Herpes zoster
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Gastroenteritis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Encephalitis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Infection
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Medical device site abscess
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Klebsiella sepsis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Influenza
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Medical device site infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Otitis media
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Osteomyelitis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Oral candidiasis
         subjects affected / exposed
    2 / 300 (0.67%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Neutropenic sepsis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Penile infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia bacterial
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia aspiration
         subjects affected / exposed
    5 / 300 (1.67%)
    8 / 276 (2.90%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    20 / 300 (6.67%)
    23 / 276 (8.33%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    20 / 287 (6.97%)
         occurrences causally related to treatment / all
    1 / 25
    7 / 25
    0 / 0
    0 / 0
    7 / 24
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 0
    3 / 6
    Peritonitis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Septic shock
         subjects affected / exposed
    1 / 300 (0.33%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 6
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    5 / 5
    0 / 0
    0 / 0
    0 / 2
    Sepsis
         subjects affected / exposed
    6 / 300 (2.00%)
    4 / 276 (1.45%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 300 (0.33%)
    4 / 276 (1.45%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelitis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary sepsis
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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 / 1
    Stoma site infection
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Tracheitis
         subjects affected / exposed
    1 / 300 (0.33%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheostomy infection
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Staphylococcal infection
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Soft tissue infection
         subjects affected / exposed
    3 / 300 (1.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Urinary tract infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Vascular device infection
         subjects affected / exposed
    2 / 300 (0.67%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Wound infection
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 300 (0.33%)
    5 / 276 (1.81%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    7 / 7
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 300 (0.33%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    4 / 287 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hyperglycaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypercalcaemia
         subjects affected / exposed
    4 / 300 (1.33%)
    3 / 276 (1.09%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 3
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences causally related to treatment / all
    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
    Hyperkalaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 300 (0.33%)
    4 / 276 (1.45%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 4
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 300 (0.33%)
    7 / 276 (2.54%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 7
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    2 / 300 (0.67%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 300 (0.00%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pembrolizumab Monotherapy (Pembro Mono) Pembrolizumab + Chemotherapy (Pembro Combo) Pembrolizumab + Chemotherapy Second Course Pembrolizumab Monotherapy Second Course Cetuximab + Chemotherapy (Control)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    265 / 300 (88.33%)
    266 / 276 (96.38%)
    6 / 6 (100.00%)
    6 / 8 (75.00%)
    278 / 287 (96.86%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 300 (2.00%)
    10 / 276 (3.62%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    21 / 287 (7.32%)
         occurrences all number
    8
    11
    0
    0
    33
    Hypertension
         subjects affected / exposed
    13 / 300 (4.33%)
    18 / 276 (6.52%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    16 / 287 (5.57%)
         occurrences all number
    14
    27
    0
    0
    19
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    12 / 300 (4.00%)
    17 / 276 (6.16%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    18 / 287 (6.27%)
         occurrences all number
    12
    18
    0
    0
    21
    Mucosal inflammation
         subjects affected / exposed
    12 / 300 (4.00%)
    80 / 276 (28.99%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    80 / 287 (27.87%)
         occurrences all number
    15
    131
    0
    1
    137
    Malaise
         subjects affected / exposed
    6 / 300 (2.00%)
    21 / 276 (7.61%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    8 / 287 (2.79%)
         occurrences all number
    6
    25
    0
    2
    10
    Fatigue
         subjects affected / exposed
    81 / 300 (27.00%)
    95 / 276 (34.42%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    101 / 287 (35.19%)
         occurrences all number
    94
    133
    1
    1
    162
    Asthenia
         subjects affected / exposed
    16 / 300 (5.33%)
    46 / 276 (16.67%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    43 / 287 (14.98%)
         occurrences all number
    16
    75
    0
    0
    64
    Pyrexia
         subjects affected / exposed
    36 / 300 (12.00%)
    41 / 276 (14.86%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    37 / 287 (12.89%)
         occurrences all number
    41
    69
    0
    0
    46
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    2 / 300 (0.67%)
    7 / 276 (2.54%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    4 / 287 (1.39%)
         occurrences all number
    3
    8
    0
    1
    4
    Rhinitis allergic
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences all number
    1
    0
    1
    0
    2
    Productive cough
         subjects affected / exposed
    17 / 300 (5.67%)
    11 / 276 (3.99%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    6 / 287 (2.09%)
         occurrences all number
    20
    11
    0
    0
    6
    Oropharyngeal pain
         subjects affected / exposed
    9 / 300 (3.00%)
    14 / 276 (5.07%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    21 / 287 (7.32%)
         occurrences all number
    9
    15
    0
    0
    24
    Increased upper airway secretion
         subjects affected / exposed
    3 / 300 (1.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 287 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    Haemoptysis
         subjects affected / exposed
    12 / 300 (4.00%)
    11 / 276 (3.99%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    8 / 287 (2.79%)
         occurrences all number
    12
    14
    1
    0
    10
    Epistaxis
         subjects affected / exposed
    5 / 300 (1.67%)
    9 / 276 (3.26%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    22 / 287 (7.67%)
         occurrences all number
    6
    11
    0
    0
    34
    Dyspnoea
         subjects affected / exposed
    35 / 300 (11.67%)
    19 / 276 (6.88%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    18 / 287 (6.27%)
         occurrences all number
    43
    20
    0
    0
    27
    Cough
         subjects affected / exposed
    40 / 300 (13.33%)
    53 / 276 (19.20%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    37 / 287 (12.89%)
         occurrences all number
    48
    65
    1
    0
    53
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 300 (5.00%)
    12 / 276 (4.35%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    15 / 287 (5.23%)
         occurrences all number
    15
    13
    0
    0
    18
    Insomnia
         subjects affected / exposed
    21 / 300 (7.00%)
    28 / 276 (10.14%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    24 / 287 (8.36%)
         occurrences all number
    23
    31
    0
    1
    30
    Investigations
    Blood uric acid increased
         subjects affected / exposed
    1 / 300 (0.33%)
    2 / 276 (0.72%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences all number
    1
    4
    1
    0
    3
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    4 / 300 (1.33%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    7 / 287 (2.44%)
         occurrences all number
    4
    6
    0
    2
    10
    Blood potassium increased
         subjects affected / exposed
    0 / 300 (0.00%)
    7 / 276 (2.54%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences all number
    0
    16
    1
    0
    3
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences all number
    2
    0
    1
    0
    4
    Blood creatinine increased
         subjects affected / exposed
    12 / 300 (4.00%)
    37 / 276 (13.41%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    24 / 287 (8.36%)
         occurrences all number
    19
    61
    1
    1
    50
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 300 (5.67%)
    20 / 276 (7.25%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    25 / 287 (8.71%)
         occurrences all number
    22
    25
    0
    1
    37
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 300 (4.33%)
    19 / 276 (6.88%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    22 / 287 (7.67%)
         occurrences all number
    18
    23
    0
    1
    48
    Lymphocyte count decreased
         subjects affected / exposed
    10 / 300 (3.33%)
    15 / 276 (5.43%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    13 / 287 (4.53%)
         occurrences all number
    16
    33
    0
    2
    34
    White blood cell count decreased
         subjects affected / exposed
    4 / 300 (1.33%)
    36 / 276 (13.04%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    46 / 287 (16.03%)
         occurrences all number
    6
    76
    0
    0
    110
    Weight decreased
         subjects affected / exposed
    42 / 300 (14.00%)
    43 / 276 (15.58%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    59 / 287 (20.56%)
         occurrences all number
    43
    50
    1
    0
    65
    Platelet count decreased
         subjects affected / exposed
    3 / 300 (1.00%)
    53 / 276 (19.20%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    49 / 287 (17.07%)
         occurrences all number
    4
    98
    0
    0
    80
    Neutrophil count decreased
         subjects affected / exposed
    1 / 300 (0.33%)
    50 / 276 (18.12%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    55 / 287 (19.16%)
         occurrences all number
    1
    85
    0
    0
    106
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    14 / 300 (4.67%)
    28 / 276 (10.14%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    39 / 287 (13.59%)
         occurrences all number
    16
    34
    0
    0
    62
    Dysgeusia
         subjects affected / exposed
    9 / 300 (3.00%)
    18 / 276 (6.52%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    16 / 287 (5.57%)
         occurrences all number
    9
    19
    0
    0
    19
    Headache
         subjects affected / exposed
    36 / 300 (12.00%)
    32 / 276 (11.59%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    24 / 287 (8.36%)
         occurrences all number
    42
    39
    2
    0
    36
    Neuropathy peripheral
         subjects affected / exposed
    1 / 300 (0.33%)
    16 / 276 (5.80%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    8 / 287 (2.79%)
         occurrences all number
    1
    18
    0
    0
    10
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 300 (0.67%)
    16 / 276 (5.80%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    7 / 287 (2.44%)
         occurrences all number
    2
    17
    0
    0
    9
    Presyncope
         subjects affected / exposed
    1 / 300 (0.33%)
    6 / 276 (2.17%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences all number
    1
    7
    1
    0
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    61 / 300 (20.33%)
    153 / 276 (55.43%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    128 / 287 (44.60%)
         occurrences all number
    82
    210
    1
    6
    251
    Neutropenia
         subjects affected / exposed
    6 / 300 (2.00%)
    90 / 276 (32.61%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    93 / 287 (32.40%)
         occurrences all number
    14
    135
    0
    0
    194
    Thrombocytopenia
         subjects affected / exposed
    6 / 300 (2.00%)
    74 / 276 (26.81%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    71 / 287 (24.74%)
         occurrences all number
    6
    111
    0
    0
    148
    Leukopenia
         subjects affected / exposed
    4 / 300 (1.33%)
    37 / 276 (13.41%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    41 / 287 (14.29%)
         occurrences all number
    5
    57
    0
    0
    87
    Lymphopenia
         subjects affected / exposed
    7 / 300 (2.33%)
    9 / 276 (3.26%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    16 / 287 (5.57%)
         occurrences all number
    10
    20
    0
    0
    58
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 300 (0.33%)
    17 / 276 (6.16%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    19 / 287 (6.62%)
         occurrences all number
    1
    17
    0
    0
    21
    Eye disorders
    Vision blurred
         subjects affected / exposed
    7 / 300 (2.33%)
    5 / 276 (1.81%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    6 / 287 (2.09%)
         occurrences all number
    7
    5
    1
    0
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 300 (0.67%)
    9 / 276 (3.26%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    19 / 287 (6.62%)
         occurrences all number
    2
    11
    0
    0
    27
    Gastritis
         subjects affected / exposed
    2 / 300 (0.67%)
    3 / 276 (1.09%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences all number
    2
    3
    1
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 300 (0.00%)
    3 / 276 (1.09%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences all number
    0
    3
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    20 / 300 (6.67%)
    31 / 276 (11.23%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    27 / 287 (9.41%)
         occurrences all number
    21
    37
    0
    0
    28
    Dyspepsia
         subjects affected / exposed
    10 / 300 (3.33%)
    15 / 276 (5.43%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    24 / 287 (8.36%)
         occurrences all number
    11
    18
    0
    1
    28
    Dry mouth
         subjects affected / exposed
    17 / 300 (5.67%)
    20 / 276 (7.25%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    10 / 287 (3.48%)
         occurrences all number
    18
    23
    1
    0
    12
    Diarrhoea
         subjects affected / exposed
    44 / 300 (14.67%)
    77 / 276 (27.90%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    96 / 287 (33.45%)
         occurrences all number
    54
    121
    1
    2
    191
    Constipation
         subjects affected / exposed
    59 / 300 (19.67%)
    101 / 276 (36.59%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    95 / 287 (33.10%)
         occurrences all number
    62
    145
    3
    0
    134
    Gastrointestinal pain
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Apical granuloma
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    7 / 300 (2.33%)
    11 / 276 (3.99%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    19 / 287 (6.62%)
         occurrences all number
    7
    13
    0
    1
    24
    Vomiting
         subjects affected / exposed
    33 / 300 (11.00%)
    90 / 276 (32.61%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    77 / 287 (26.83%)
         occurrences all number
    43
    155
    0
    0
    123
    Tongue haemorrhage
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    9 / 300 (3.00%)
    67 / 276 (24.28%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    77 / 287 (26.83%)
         occurrences all number
    9
    104
    0
    0
    121
    Oral pain
         subjects affected / exposed
    7 / 300 (2.33%)
    18 / 276 (6.52%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    14 / 287 (4.88%)
         occurrences all number
    7
    18
    1
    0
    14
    Nausea
         subjects affected / exposed
    49 / 300 (16.33%)
    140 / 276 (50.72%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    146 / 287 (50.87%)
         occurrences all number
    58
    271
    1
    0
    273
    Glossitis
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences all number
    0
    1
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 300 (0.33%)
    15 / 276 (5.43%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    15 / 287 (5.23%)
         occurrences all number
    1
    15
    0
    0
    15
    Skin fissures
         subjects affected / exposed
    0 / 300 (0.00%)
    2 / 276 (0.72%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    38 / 287 (13.24%)
         occurrences all number
    0
    3
    0
    0
    50
    Rash pruritic
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences all number
    0
    0
    1
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    9 / 300 (3.00%)
    9 / 276 (3.26%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    16 / 287 (5.57%)
         occurrences all number
    9
    10
    0
    0
    24
    Rash
         subjects affected / exposed
    31 / 300 (10.33%)
    30 / 276 (10.87%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    112 / 287 (39.02%)
         occurrences all number
    43
    37
    0
    3
    160
    Psoriasis
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 300 (0.67%)
    4 / 276 (1.45%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    22 / 287 (7.67%)
         occurrences all number
    2
    6
    0
    0
    37
    Dry skin
         subjects affected / exposed
    13 / 300 (4.33%)
    10 / 276 (3.62%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    38 / 287 (13.24%)
         occurrences all number
    16
    11
    1
    0
    49
    Dermatitis acneiform
         subjects affected / exposed
    8 / 300 (2.67%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    84 / 287 (29.27%)
         occurrences all number
    9
    1
    0
    0
    130
    Pruritus
         subjects affected / exposed
    32 / 300 (10.67%)
    24 / 276 (8.70%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    32 / 287 (11.15%)
         occurrences all number
    39
    26
    1
    0
    51
    Renal and urinary disorders
    Nocturia
         subjects affected / exposed
    0 / 300 (0.00%)
    1 / 276 (0.36%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 287 (0.35%)
         occurrences all number
    0
    1
    2
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 300 (0.33%)
    5 / 276 (1.81%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 287 (0.70%)
         occurrences all number
    1
    6
    1
    0
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    55 / 300 (18.33%)
    45 / 276 (16.30%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    18 / 287 (6.27%)
         occurrences all number
    57
    48
    1
    1
    22
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    18 / 300 (6.00%)
    28 / 276 (10.14%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    21 / 287 (7.32%)
         occurrences all number
    22
    30
    1
    0
    26
    Arthralgia
         subjects affected / exposed
    23 / 300 (7.67%)
    22 / 276 (7.97%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    18 / 287 (6.27%)
         occurrences all number
    29
    32
    1
    1
    20
    Back pain
         subjects affected / exposed
    21 / 300 (7.00%)
    12 / 276 (4.35%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    12 / 287 (4.18%)
         occurrences all number
    22
    15
    0
    0
    13
    Fibromyalgia
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 287 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Joint effusion
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 287 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    4 / 300 (1.33%)
    22 / 276 (7.97%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    17 / 287 (5.92%)
         occurrences all number
    4
    24
    0
    0
    25
    Bronchitis
         subjects affected / exposed
    5 / 300 (1.67%)
    7 / 276 (2.54%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    6 / 287 (2.09%)
         occurrences all number
    6
    8
    0
    1
    8
    Paronychia
         subjects affected / exposed
    1 / 300 (0.33%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    39 / 287 (13.59%)
         occurrences all number
    1
    0
    0
    0
    55
    Pharyngitis
         subjects affected / exposed
    3 / 300 (1.00%)
    2 / 276 (0.72%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    4 / 287 (1.39%)
         occurrences all number
    3
    2
    1
    1
    4
    Viral infection
         subjects affected / exposed
    0 / 300 (0.00%)
    0 / 276 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 287 (0.35%)
         occurrences all number
    0
    0
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 300 (5.00%)
    11 / 276 (3.99%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    14 / 287 (4.88%)
         occurrences all number
    18
    12
    0
    1
    18
    Tooth infection
         subjects affected / exposed
    1 / 300 (0.33%)
    1 / 276 (0.36%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 287 (1.05%)
         occurrences all number
    1
    3
    0
    1
    3
    Rhinitis
         subjects affected / exposed
    2 / 300 (0.67%)
    4 / 276 (1.45%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    3 / 287 (1.05%)
         occurrences all number
    2
    5
    1
    0
    4
    Pneumonia
         subjects affected / exposed
    12 / 300 (4.00%)
    19 / 276 (6.88%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    12 / 287 (4.18%)
         occurrences all number
    15
    22
    0
    0
    12
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 300 (3.33%)
    23 / 276 (8.33%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    15 / 287 (5.23%)
         occurrences all number
    11
    31
    0
    4
    22
    Hypocalcaemia
         subjects affected / exposed
    2 / 300 (0.67%)
    17 / 276 (6.16%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    22 / 287 (7.67%)
         occurrences all number
    2
    23
    0
    0
    49
    Hyperuricaemia
         subjects affected / exposed
    7 / 300 (2.33%)
    6 / 276 (2.17%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 287 (1.05%)
         occurrences all number
    9
    9
    0
    1
    14
    Hyperkalaemia
         subjects affected / exposed
    8 / 300 (2.67%)
    17 / 276 (6.16%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    18 / 287 (6.27%)
         occurrences all number
    10
    25
    0
    0
    49
    Hyperglycaemia
         subjects affected / exposed
    19 / 300 (6.33%)
    15 / 276 (5.43%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    23 / 287 (8.01%)
         occurrences all number
    28
    23
    0
    0
    42
    Hypokalaemia
         subjects affected / exposed
    23 / 300 (7.67%)
    30 / 276 (10.87%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    53 / 287 (18.47%)
         occurrences all number
    28
    43
    1
    0
    90
    Dehydration
         subjects affected / exposed
    8 / 300 (2.67%)
    12 / 276 (4.35%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    16 / 287 (5.57%)
         occurrences all number
    8
    12
    0
    0
    20
    Decreased appetite
         subjects affected / exposed
    44 / 300 (14.67%)
    78 / 276 (28.26%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    81 / 287 (28.22%)
         occurrences all number
    51
    101
    0
    1
    112
    Hypercalcaemia
         subjects affected / exposed
    12 / 300 (4.00%)
    17 / 276 (6.16%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    8 / 287 (2.79%)
         occurrences all number
    12
    23
    0
    0
    9
    Hypomagnesaemia
         subjects affected / exposed
    12 / 300 (4.00%)
    42 / 276 (15.22%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    115 / 287 (40.07%)
         occurrences all number
    12
    62
    0
    0
    270
    Hyponatraemia
         subjects affected / exposed
    26 / 300 (8.67%)
    34 / 276 (12.32%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    36 / 287 (12.54%)
         occurrences all number
    31
    53
    0
    0
    72
    Hypophosphataemia
         subjects affected / exposed
    8 / 300 (2.67%)
    12 / 276 (4.35%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    26 / 287 (9.06%)
         occurrences all number
    10
    18
    4
    0
    45

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2015
    Amendment 1 included an increase in sample size. The sample size increased from 750 to 780 based on prevalence of strongly positive PD-L1 expression seen in data from the HNSCC cohorts in other MK-3475 Pembrolizumab studies. Added PFS hypothesis for pembrolizumab in combination with chemotherapy vs. standard treatment in subjects with strongly positive PD-L1 expression.
    06 Sep 2015
    Amendment 5 included changes to OS. OS was changed from a secondary objective to a primary objective, and biomarker population was updated to include PD-L1 ≥20% CPS, ≥10% CPS, ≥1% CPS. Sample size increased from 780 to 825 due to these changes. The strongly positive PD-L1 enrichment population was removed. Added QOL secondary objectives. Changed ORR, DOR, and PFS per irRECIST from secondary to exploratory objectives. Modified inclusion and exclusion criteria.
    06 Apr 2017
    Amendment 7 included references to PD-L1 10% Combined Positive Score were removed; only the 20% and 1% cut points are planned to be analyzed.
    13 Sep 2017
    Amendment 8 included follow-up time was increased at the interim and final analyses by 3 months to achieve data maturity at these timepoints.
    27 Nov 2017
    Amendment 9 included dose modification guidelines were updated per health authority feedback. Hypotheses for PFS and OS superiority in biomarker positive subpopulation were added. Follow-up time was increased at the second interim analysis and final analysis to allow adequate follow-up time to assess long-term effects of pembrolizumab. Language was added to enable survival follow-up activities throughout the study at timepoints specified by the Sponsor.
    30 Jan 2019
    Amendment 10 modified to indicate the number of expected events, rather than required events, references to “event-driven” were removed, and text was modified to describe the timing of the final analysis to account for the scenario if the number of deaths for one hypothesis accumulates slower than expected to prevent the trial continuing for an unreasonable period for the final analysis.
    21 Apr 2020
    Amendment 11 corrected the typographical error "co-primary" that appears at the end of the second paragraph in Section 4.2.3.1.1 has been corrected to "dual-primary" to indicate that the 2 primary endpoints in the study, OS and PFS, were "dual-primary" endpoints rather than "co-primary" endpoints. As a result, the study is considered positive if a statistically significant result is determined for either of these endpoints. This error has appeared in all versions of the protocol starting with amendment 048-05, dated 05-AUG-2016.
    10 Jun 2021
    Amendment 12 updated the pembrolizumab dose modification table and toxicity management guidelines for irAEs, in line with FDA request to harmonize the presentation of safety information across all FDA-approved PD-1/L-1 antibody prescribing information. To align with the updated SmPC for cetuximab.
    21 Jul 2022
    Amendment 13 added language to allow subjects to roll over to a pembrolizumab extension study.

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

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

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