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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GS-6624 Combined with FOLFIRI as Second Line Treatment for Metastatic KRAS Mutant Colorectal Adenocarcinoma that has Progressed Following a First Line Oxaliplatin- and Fluoropyrimidine-Containing Regimen

    Summary
    EudraCT number
    		 2011-003754-61
    Trial protocol
    		 IT   ES   DE   PL  
    Global end of trial date
    27 Feb 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    03 Apr 2019
    First version publication date
    15 Jul 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Adding 1 missing SAE and typo to a non-serious AE.

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-295-0203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01479465
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    27 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study was to compare the additive efficacy of simtuzumab (SIM; GS-6624) versus placebo in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) as measured by improvement in progression-free survival (PFS) in adults with metastatic KRAS mutant colorectal adenocarcinoma who have progressed following a first line oxaliplatin- and fluoropyrimidine-containing regimen.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2011
    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
    Poland: 17
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    United States: 148
    Country: Number of subjects enrolled
    Russian Federation: 29
    Worldwide total number of subjects
    266
    EEA total number of subjects
    89
    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)
    175
    From 65 to 84 years
    90
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States, Russia, and the European Union (EU). The first participant was screened on 15 December 2011. The last study visit occurred on 27 February 2015.

    Pre-assignment
    Screening details
    		 358 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Note: Part A was open-label and nonrandomized, while Part B was randomized and double-blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SIM (Part A)
    Arm description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 for one 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Simtuzumab 700 mg prepared by reconstituting vials of simtuzumab in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRI consisted of l-leucovorin (LV) 200 mg/m^2 or dl-LV 400 mg/m^2 as a 2-hour infusion, and irinotecan 180 mg/m^2 given as a 90-minute infusion in 500 mL dextrose 5% via a Y-connector, followed by bolus fluorouracil (FU) 400 mg/m^2 and a 46-hour infusion FU 2400 mg/m^2

    Arm title
    		 SIM 200 mg (Part B)
    Arm description
    		 SIM 200 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Simtuzumab 200 mg prepared by reconstituting vials of simtuzumab and placebo in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRI consisted of LV 200 mg/m^2 or dl-LV 400 mg/m^2 as a 2-hour infusion, and irinotecan 180 mg/m^2 given as a 90-minute infusion in 500 mL dextrose 5% via a Y-connector, followed by bolus FU 400 mg/m^2 and a 46-hour infusion FU 2400 mg/m^2

    Arm title
    		 SIM 700 mg (Part B)
    Arm description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Simtuzumab
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Simtuzumab 700 mg prepared by reconstituting vials of simtuzumab in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRI consisted of LV 200 mg/m^2 or dl-LV 400 mg/m^2 as a 2-hour infusion, and irinotecan 180 mg/m^2 given as a 90-minute infusion in 500 mL dextrose 5% via a Y-connector, followed by bolus FU 400 mg/m^2 and a 46-hour infusion FU 2400 mg/m^2

    Arm title
    		 Placebo (Part B)
    Arm description
    		 Placebo followed by FOLFIRI on Days 1 and 15 of each 28-day cycle
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo prepared by reconstituting vials of simtuzumab placebo in sterile 0.9% sodium chloride USP solution

    Investigational medicinal product name
    FOLFIRI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FOLFIRI consisted of LV 200 mg/m^2 or dl-LV 400 mg/m^2 as a 2-hour infusion, and irinotecan 180 mg/m^2 given as a 90-minute infusion in 500 mL dextrose 5% via a Y-connector, followed by bolus FU 400 mg/m^2 and a 46-hour infusion FU 2400 mg/m^2

    Number of subjects in period 1 [1]
    		SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Started
    11
    85
    84
    80
    Completed Follow-up
    11
    85
    84
    80
    Completed
    0
    0
    0
    0
    Not completed
    11
    85
    84
    80
         Adverse event, serious fatal
    -
    2
    1
    2
         Subject Withdrew Consent
    -
    2
    1
    4
         Adverse event, non-fatal
    -
    4
    3
    -
         Death
    -
    -
    1
    -
         Investigator's Discretion
    1
    2
    4
    3
         Study Discontinued by Sponsor
    -
    5
    3
    7
         Subject Request
    1
    4
    2
    3
         Lost to follow-up
    -
    1
    -
    -
         Disease Progression
    9
    65
    69
    61
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 6 participants who were randomized but not treated are not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SIM (Part A)
    Reporting group description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 for one 28-day cycle

    Reporting group title
    SIM 200 mg (Part B)
    Reporting group description
    		 SIM 200 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group title
    SIM 700 mg (Part B)
    Reporting group description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group title
    Placebo (Part B)
    Reporting group description
    		 Placebo followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B) Total
    Number of subjects
    		 11 85 84 80 260
    Age categorical
    Units: Subjects
        ≥ 65 years
    		 4 36 28 23 91
        < 65 years
    		 7 49 56 57 169
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ± 14.09 62.6 ± 11.39 60.1 ± 9.76 58.8 ± 11.78 -
    Gender categorical
    Units: Subjects
        Female
    		 6 32 48 41 127
        Male
    		 5 53 36 39 133
    Race
    Units: Subjects
        White
    		 8 74 71 67 220
        Black or African American
    		 2 5 7 8 22
        Asian
    		 1 5 1 1 8
        Native Hawaiian or Pacific Islander
    		 0 0 1 1 2
        Not Permitted
    		 0 1 3 3 7
        Missing
    		 0 0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 7 8 5 23
        Not Hispanic or Latino
    		 8 75 73 70 226
        Not Permitted
    		 0 3 3 5 11

    End points

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    End points reporting groups
    Reporting group title
    SIM (Part A)
    Reporting group description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 for one 28-day cycle

    Reporting group title
    SIM 200 mg (Part B)
    Reporting group description
    		 SIM 200 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group title
    SIM 700 mg (Part B)
    Reporting group description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group title
    Placebo (Part B)
    Reporting group description
    		 Placebo followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression-free survival (PFS) was defined as the time from the date of randomization to the earliest event time of a) death regardless of cause, or b) first indication of disease progression. PFS was analyzed using Kaplan-Meier (KM) estimates. Participants in the Full Analysis Set (participants who were randomized and received at least 1 dose of study drug) with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 27 months
    End point values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Number of subjects analysed
    11
    85
    84
    80
    Units: Months
        median (confidence interval 95%)
    5.7 (1.8 to 10)
    5.4 (3.4 to 5.6)
    5.5 (4 to 7.1)
    5.8 (4.9 to 9)
    Statistical analysis title
    		 PFS - SIM 200 mg vs Placebo
    Statistical analysis description
    The difference in PFS among the treatment groups was assessed using Kaplan-Meier methods and the stratified log-rank test, adjusted for the stratification factors.
    Comparison groups
    Placebo (Part B) v SIM 200 mg (Part B)
    Number of subjects included in analysis
    165
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0395 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.06
    Notes
    [1] - P-value was based on a two-sided log-rank test stratified based on the 2 level Eastern Cooperative Oncology Group (ECOG) performance status (0 or > 0) at randomization.
    Statistical analysis title
    		 PFS - SIM 700 mg vs Placebo
    Statistical analysis description
    The difference in PFS among the treatment groups was assessed using Kaplan-Meier methods and the stratified log-rank test, adjusted for the stratification factors.
    Comparison groups
    SIM 700 mg (Part B) v Placebo (Part B)
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1042 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.89
    Notes
    [2] - P-value was based on a two-sided log-rank test stratified based on the 2 level ECOG performance status (0 or > 0) at randomization.

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survivial (OS) was defined as the time from the date of randomization to death regardless of cause. The OS was analyzed using KM estimates. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 33 months
    End point values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Number of subjects analysed
    11
    85
    84
    80
    Units: months
        median (confidence interval 95%)
    9.8 (3.5 to 22.3)
    10.5 (9.2 to 12.6)
    11.4 (9.7 to 15.6)
    16.3 (12 to 19.5)
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective response was assessed by the RECIST criteria (ver. 1.1) as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). Objective response rate (ORR) was defined as the proportion of participants who achieved a CR or PR. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 27 months
    End point values
    		 SIM (Part A) SIM 200 mg (Part B) SIM 700 mg (Part B) Placebo (Part B)
    Number of subjects analysed
    11
    85
    84
    80
    Units: percentage of participants
        number (confidence interval 95%)
    9.1 (0.2 to 41.3)
    5.9 (1.9 to 13.2)
    11.9 (5.9 to 20.8)
    10 (4.4 to 18.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 33 months
    Adverse event reporting additional description
    Safety Analysis Set: participants in the Full Analysis Set grouped for analyses with treatment assignments designated according to the actual study drug received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo (Part B)
    Reporting group description
    		 Placebo followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group title
    SIM 200 mg (Part B)
    Reporting group description
    		 SIM 200 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group title
    SIM 700 mg (Part B)
    Reporting group description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 of each 28-day cycle

    Reporting group title
    SIM (Part A)
    Reporting group description
    		 SIM 700 mg followed by FOLFIRI on Days 1 and 15 for one 28-day cycle

    Serious adverse events
    		 Placebo (Part B) SIM 200 mg (Part B) SIM 700 mg (Part B) SIM (Part A)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 80 (33.75%)
    24 / 85 (28.24%)
    17 / 84 (20.24%)
    4 / 11 (36.36%)
         number of deaths (all causes)
    3
    2
    2
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant ascites
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour thrombosis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava occlusion
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    2 / 84 (2.38%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 85 (2.35%)
    2 / 84 (2.38%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract inflammation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 85 (3.53%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 85 (1.18%)
    2 / 84 (2.38%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 85 (2.35%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 85 (3.53%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    2 / 84 (2.38%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 80 (2.50%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (Part B) SIM 200 mg (Part B) SIM 700 mg (Part B) SIM (Part A)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 80 (95.00%)
    80 / 85 (94.12%)
    79 / 84 (94.05%)
    11 / 11 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 85 (2.35%)
    4 / 84 (4.76%)
    1 / 11 (9.09%)
         occurrences all number
    3
    2
    5
    2
    Flushing
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 85 (2.35%)
    0 / 84 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    0
    2
    Peripheral coldness
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    34 / 80 (42.50%)
    38 / 85 (44.71%)
    43 / 84 (51.19%)
    9 / 11 (81.82%)
         occurrences all number
    47
    55
    70
    19
    Asthenia
         subjects affected / exposed
    12 / 80 (15.00%)
    13 / 85 (15.29%)
    12 / 84 (14.29%)
    2 / 11 (18.18%)
         occurrences all number
    22
    33
    26
    2
    Mucosal inflammation
         subjects affected / exposed
    10 / 80 (12.50%)
    14 / 85 (16.47%)
    7 / 84 (8.33%)
    3 / 11 (27.27%)
         occurrences all number
    11
    17
    18
    5
    Pyrexia
         subjects affected / exposed
    11 / 80 (13.75%)
    10 / 85 (11.76%)
    11 / 84 (13.10%)
    1 / 11 (9.09%)
         occurrences all number
    21
    11
    17
    1
    Oedema peripheral
         subjects affected / exposed
    4 / 80 (5.00%)
    14 / 85 (16.47%)
    10 / 84 (11.90%)
    0 / 11 (0.00%)
         occurrences all number
    4
    15
    12
    0
    Chest pain
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 85 (1.18%)
    5 / 84 (5.95%)
    0 / 11 (0.00%)
         occurrences all number
    4
    1
    5
    0
    Malaise
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 85 (1.18%)
    5 / 84 (5.95%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    5
    1
    Catheter site pain
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    Chest discomfort
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    Catheter site rash
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    2
    Feeling abnormal
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Axillary pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Feeling jittery
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 80 (12.50%)
    10 / 85 (11.76%)
    14 / 84 (16.67%)
    1 / 11 (9.09%)
         occurrences all number
    10
    10
    18
    1
    Dyspnoea
         subjects affected / exposed
    10 / 80 (12.50%)
    9 / 85 (10.59%)
    11 / 84 (13.10%)
    0 / 11 (0.00%)
         occurrences all number
    11
    11
    13
    0
    Epistaxis
         subjects affected / exposed
    10 / 80 (12.50%)
    5 / 85 (5.88%)
    4 / 84 (4.76%)
    0 / 11 (0.00%)
         occurrences all number
    13
    5
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 80 (3.75%)
    0 / 85 (0.00%)
    8 / 84 (9.52%)
    1 / 11 (9.09%)
         occurrences all number
    4
    0
    9
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 85 (2.35%)
    4 / 84 (4.76%)
    1 / 11 (9.09%)
         occurrences all number
    3
    2
    4
    1
    Hiccups
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    2 / 11 (18.18%)
         occurrences all number
    1
    1
    1
    2
    Dyspnoea exertional
         subjects affected / exposed
    0 / 80 (0.00%)
    3 / 85 (3.53%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    3
    0
    1
    Atelectasis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Throat tightness
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 80 (11.25%)
    5 / 85 (5.88%)
    8 / 84 (9.52%)
    5 / 11 (45.45%)
         occurrences all number
    10
    5
    10
    6
    Anxiety
         subjects affected / exposed
    5 / 80 (6.25%)
    5 / 85 (5.88%)
    4 / 84 (4.76%)
    3 / 11 (27.27%)
         occurrences all number
    6
    5
    5
    3
    Depression
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 85 (3.53%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences all number
    2
    4
    3
    1
    Agitation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Anger
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Mood swings
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    7 / 80 (8.75%)
    9 / 85 (10.59%)
    6 / 84 (7.14%)
    1 / 11 (9.09%)
         occurrences all number
    9
    11
    6
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 80 (6.25%)
    6 / 85 (7.06%)
    4 / 84 (4.76%)
    0 / 11 (0.00%)
         occurrences all number
    5
    6
    4
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 80 (7.50%)
    4 / 85 (4.71%)
    4 / 84 (4.76%)
    1 / 11 (9.09%)
         occurrences all number
    7
    4
    4
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 80 (5.00%)
    4 / 85 (4.71%)
    5 / 84 (5.95%)
    0 / 11 (0.00%)
         occurrences all number
    4
    4
    6
    0
    Neutrophil count decreased
         subjects affected / exposed
    5 / 80 (6.25%)
    3 / 85 (3.53%)
    3 / 84 (3.57%)
    0 / 11 (0.00%)
         occurrences all number
    6
    3
    4
    0
    International normalised ratio increased
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 85 (2.35%)
    1 / 84 (1.19%)
    1 / 11 (9.09%)
         occurrences all number
    3
    5
    1
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 80 (8.75%)
    9 / 85 (10.59%)
    13 / 84 (15.48%)
    1 / 11 (9.09%)
         occurrences all number
    9
    11
    20
    1
    Dysgeusia
         subjects affected / exposed
    6 / 80 (7.50%)
    6 / 85 (7.06%)
    8 / 84 (9.52%)
    1 / 11 (9.09%)
         occurrences all number
    6
    7
    9
    2
    Neuropathy peripheral
         subjects affected / exposed
    5 / 80 (6.25%)
    7 / 85 (8.24%)
    7 / 84 (8.33%)
    2 / 11 (18.18%)
         occurrences all number
    5
    7
    7
    2
    Headache
         subjects affected / exposed
    4 / 80 (5.00%)
    3 / 85 (3.53%)
    6 / 84 (7.14%)
    1 / 11 (9.09%)
         occurrences all number
    4
    4
    8
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 85 (2.35%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences all number
    4
    2
    3
    3
    Parosmia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    0
    1
    Dizziness postural
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    35 / 80 (43.75%)
    42 / 85 (49.41%)
    40 / 84 (47.62%)
    6 / 11 (54.55%)
         occurrences all number
    81
    77
    91
    14
    Anaemia
         subjects affected / exposed
    19 / 80 (23.75%)
    23 / 85 (27.06%)
    18 / 84 (21.43%)
    3 / 11 (27.27%)
         occurrences all number
    30
    27
    34
    4
    Leukopenia
         subjects affected / exposed
    9 / 80 (11.25%)
    13 / 85 (15.29%)
    13 / 84 (15.48%)
    1 / 11 (9.09%)
         occurrences all number
    35
    24
    43
    5
    Thrombocytopenia
         subjects affected / exposed
    6 / 80 (7.50%)
    10 / 85 (11.76%)
    11 / 84 (13.10%)
    0 / 11 (0.00%)
         occurrences all number
    12
    13
    16
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Eye pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    43 / 80 (53.75%)
    36 / 85 (42.35%)
    42 / 84 (50.00%)
    9 / 11 (81.82%)
         occurrences all number
    93
    58
    92
    15
    Nausea
         subjects affected / exposed
    37 / 80 (46.25%)
    38 / 85 (44.71%)
    42 / 84 (50.00%)
    9 / 11 (81.82%)
         occurrences all number
    93
    60
    100
    17
    Vomiting
         subjects affected / exposed
    25 / 80 (31.25%)
    21 / 85 (24.71%)
    23 / 84 (27.38%)
    5 / 11 (45.45%)
         occurrences all number
    50
    30
    37
    12
    Abdominal pain
         subjects affected / exposed
    18 / 80 (22.50%)
    16 / 85 (18.82%)
    22 / 84 (26.19%)
    4 / 11 (36.36%)
         occurrences all number
    31
    21
    28
    7
    Constipation
         subjects affected / exposed
    17 / 80 (21.25%)
    18 / 85 (21.18%)
    21 / 84 (25.00%)
    4 / 11 (36.36%)
         occurrences all number
    23
    23
    37
    5
    Stomatitis
         subjects affected / exposed
    17 / 80 (21.25%)
    14 / 85 (16.47%)
    9 / 84 (10.71%)
    1 / 11 (9.09%)
         occurrences all number
    58
    19
    17
    1
    Abdominal pain upper
         subjects affected / exposed
    6 / 80 (7.50%)
    8 / 85 (9.41%)
    6 / 84 (7.14%)
    2 / 11 (18.18%)
         occurrences all number
    7
    8
    6
    3
    Dyspepsia
         subjects affected / exposed
    7 / 80 (8.75%)
    4 / 85 (4.71%)
    4 / 84 (4.76%)
    3 / 11 (27.27%)
         occurrences all number
    9
    6
    4
    3
    Dry mouth
         subjects affected / exposed
    7 / 80 (8.75%)
    2 / 85 (2.35%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences all number
    7
    3
    3
    1
    Abdominal distension
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 85 (2.35%)
    1 / 84 (1.19%)
    2 / 11 (18.18%)
         occurrences all number
    4
    2
    1
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 80 (3.75%)
    3 / 85 (3.53%)
    1 / 84 (1.19%)
    2 / 11 (18.18%)
         occurrences all number
    3
    3
    1
    2
    Abdominal pain lower
         subjects affected / exposed
    5 / 80 (6.25%)
    0 / 85 (0.00%)
    2 / 84 (2.38%)
    0 / 11 (0.00%)
         occurrences all number
    6
    0
    2
    0
    Dysphagia
         subjects affected / exposed
    4 / 80 (5.00%)
    0 / 85 (0.00%)
    1 / 84 (1.19%)
    2 / 11 (18.18%)
         occurrences all number
    4
    0
    1
    2
    Oral pain
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 85 (3.53%)
    1 / 84 (1.19%)
    1 / 11 (9.09%)
         occurrences all number
    2
    5
    1
    1
    Abdominal discomfort
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 85 (2.35%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    2
    0
    1
    Haematochezia
         subjects affected / exposed
    2 / 80 (2.50%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    0
    2
    Oral mucosal erythema
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    21 / 80 (26.25%)
    20 / 85 (23.53%)
    22 / 84 (26.19%)
    6 / 11 (54.55%)
         occurrences all number
    21
    20
    22
    6
    Dry skin
         subjects affected / exposed
    5 / 80 (6.25%)
    2 / 85 (2.35%)
    5 / 84 (5.95%)
    0 / 11 (0.00%)
         occurrences all number
    5
    4
    6
    0
    Rash
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 85 (4.71%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences all number
    13
    7
    3
    1
    Hyperhidrosis
         subjects affected / exposed
    3 / 80 (3.75%)
    2 / 85 (2.35%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences all number
    3
    2
    4
    1
    Night sweats
         subjects affected / exposed
    4 / 80 (5.00%)
    1 / 85 (1.18%)
    3 / 84 (3.57%)
    0 / 11 (0.00%)
         occurrences all number
    4
    1
    3
    0
    Skin hyperpigmentation
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 85 (2.35%)
    2 / 84 (2.38%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    3
    1
    Swelling face
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Skin disorder
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Skin wrinkling
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    5 / 80 (6.25%)
    3 / 85 (3.53%)
    0 / 84 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    7
    3
    0
    0
    Micturition urgency
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Nocturia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 80 (7.50%)
    9 / 85 (10.59%)
    9 / 84 (10.71%)
    3 / 11 (27.27%)
         occurrences all number
    6
    10
    11
    3
    Arthralgia
         subjects affected / exposed
    4 / 80 (5.00%)
    4 / 85 (4.71%)
    5 / 84 (5.95%)
    1 / 11 (9.09%)
         occurrences all number
    4
    5
    5
    1
    Muscle spasms
         subjects affected / exposed
    5 / 80 (6.25%)
    0 / 85 (0.00%)
    5 / 84 (5.95%)
    1 / 11 (9.09%)
         occurrences all number
    7
    0
    8
    1
    Pain in extremity
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 85 (1.18%)
    6 / 84 (7.14%)
    1 / 11 (9.09%)
         occurrences all number
    5
    1
    7
    2
    Musculoskeletal pain
         subjects affected / exposed
    3 / 80 (3.75%)
    1 / 85 (1.18%)
    5 / 84 (5.95%)
    1 / 11 (9.09%)
         occurrences all number
    8
    1
    5
    1
    Bone pain
         subjects affected / exposed
    2 / 80 (2.50%)
    0 / 85 (0.00%)
    2 / 84 (2.38%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    3
    1
    Muscular weakness
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 85 (2.35%)
    0 / 84 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    0
    2
    Muscle atrophy
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Muscle tightness
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 80 (7.50%)
    5 / 85 (5.88%)
    9 / 84 (10.71%)
    0 / 11 (0.00%)
         occurrences all number
    8
    7
    9
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 80 (6.25%)
    4 / 85 (4.71%)
    2 / 84 (2.38%)
    0 / 11 (0.00%)
         occurrences all number
    5
    4
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 85 (2.35%)
    2 / 84 (2.38%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    2
    1
    Pneumonia
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 85 (2.35%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    2
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 85 (1.18%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    0
    1
    Infection
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 85 (0.00%)
    0 / 84 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    22 / 80 (27.50%)
    14 / 85 (16.47%)
    21 / 84 (25.00%)
    5 / 11 (45.45%)
         occurrences all number
    29
    17
    35
    7
    Hypokalaemia
         subjects affected / exposed
    8 / 80 (10.00%)
    8 / 85 (9.41%)
    10 / 84 (11.90%)
    0 / 11 (0.00%)
         occurrences all number
    11
    11
    13
    0
    Dehydration
         subjects affected / exposed
    4 / 80 (5.00%)
    5 / 85 (5.88%)
    6 / 84 (7.14%)
    3 / 11 (27.27%)
         occurrences all number
    5
    6
    7
    3
    Hyperglycaemia
         subjects affected / exposed
    2 / 80 (2.50%)
    4 / 85 (4.71%)
    3 / 84 (3.57%)
    1 / 11 (9.09%)
         occurrences all number
    2
    4
    5
    2
    Hypomagnesaemia
         subjects affected / exposed
    5 / 80 (6.25%)
    2 / 85 (2.35%)
    3 / 84 (3.57%)
    0 / 11 (0.00%)
         occurrences all number
    8
    2
    7
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 85 (2.35%)
    2 / 84 (2.38%)
    1 / 11 (9.09%)
         occurrences all number
    1
    2
    2
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 85 (1.18%)
    1 / 84 (1.19%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 85 (0.00%)
    2 / 84 (2.38%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2011
    The protocol was revised to provide specific guidance on dose modification for study drug and FOLFIRI.
    07 Nov 2011
    The protocol was revised to exclude subjects with metastatic BRAF mutant colorectal adenocarcinoma, to further clarify the dose modification for FOLFIRI, to specify enrolled subjects must have experienced radiographic disease progression following first line therapy, and to clarify that prior irinotecan therapy for metastatic disease was not permitted, but prior adjuvant therapy with irinotecan was allowed.
    08 Mar 2012
    The protocol was revised in response to questions received during the European Voluntary Harmonization Procedure assessment (to specify that the KRAS mutated, histologically confirmed adenocarcinoma of the colon or rectum was not to be amenable to complete surgical resection, to specify that the subject must have received first-line combination therapy containing oxaliplatin and a fluoropyrimidine with or without bevacizumab for metastatic disease, to specify that the subject must not be a candidate for further oxaliplatin, to clarify cardiac conditions and define hypertension parameters that would exclude subjects from the study, to describe emergency unblinding procedures, and to add an interim analysis.
    05 Sep 2012
    The protocol was revised to include analyses for systemic biomarkers related to complete response (CR) pathophysiology or GS-6624 mechanism of action such as circulating LOXL2 and TIMP-1 levels and to clarify inclusion/exclusion criteria.
    20 Mar 2014
    The protocol was revised to change the assessment of progressive disease for PFS from Independent Radiology Review to determination by Principal Investigator, to remove the interim analysis, and to indicate that Gilead would assess the continuation of the development of SIM in colorectal cancer if the primary objective of the study was not met and could decide to prematurely discontinue the 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.
    There were no limitations affecting the analysis or results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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