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    Clinical Trial Results:
    Sorafenib alone or in combination with everolimus in patients with unresectable hepatocellular carcinoma. A randomized multicenter phase II trial.

    Summary
    EudraCT number
    		 2009-011884-35
    Trial protocol
    		 HU   AT  
    Global end of trial date
    18 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jan 2023
    First version publication date
    06 Jan 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SAKK 77/08 and SASL 29
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01005199
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    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
    21 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigate if the combination of sorafenib plus everolimus can stop tumor progression, with a sorafenib monotherapy group used to control selection bias. No formal comparison is planned.
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 None
    Evidence for comparator
    		 Sorafenib tosylate is a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus is a potent inhibitor of mTOR-pathway which is frequently activated in HCC. Preclinical data suggested that the combination of both drugs has additive effects compared to monotherapy and may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.
    Actual start date of recruitment
    30 Dec 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Hungary: 45
    Country: Number of subjects enrolled
    Switzerland: 57
    Worldwide total number of subjects
    105
    EEA total number of subjects
    48
    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)
    42
    From 65 to 84 years
    63
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between December 30th, 2009 and February 11th, 2013, 106 eligible patients were registered. One patient did not receive any study treatment and was not considered for analysis.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm SE: Sorafenib and everolimus
    Arm description
    		 Patients receiving sorafenib (S) and everolimus (E)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 400 mg o.i.d.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 5 mg o.i.d.

    Arm title
    		 Arm S: Sorafenib
    Arm description
    		 Patients receiving sorafenib (S)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 400 mg o.i.d.

    Number of subjects in period 1
    		Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Started
    59
    46
    Completed
    59
    46
    Period 2
    Period 2 title
    Treatment phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm SE: Sorafenib and everolimus
    Arm description
    		 Patients receiving sorafenib (S) and everolimus (E)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 400 mg o.i.d.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 5 mg o.i.d.

    Arm title
    		 Arm S: Sorafenib
    Arm description
    		 Patients receiving sorafenib (S)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 400 mg o.i.d.

    Number of subjects in period 2
    		Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Started
    59
    46
    Completed
    59
    46
    Period 3
    Period 3 title
    Follow-up Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm SE: Sorafenib and everolimus
    Arm description
    		 Patients receiving sorafenib (S) and everolimus (E)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 400 mg o.i.d.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 5 mg o.i.d.

    Arm title
    		 Arm S: Sorafenib
    Arm description
    		 Patients receiving sorafenib (S)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Nexavar®
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 400 mg o.i.d.

    Number of subjects in period 3
    		Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Started
    59
    46
    Completed
    0
    0
    Not completed
    59
    46
         Consent withdrawn by subject
    2
    3
         Death
    3
    2
         Other
    7
    2
         Unacceptable toxicity
    17
    9
         Progressive disease
    30
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm SE: Sorafenib and everolimus
    Reporting group description
    		 Patients receiving sorafenib (S) and everolimus (E)

    Reporting group title
    Arm S: Sorafenib
    Reporting group description
    		 Patients receiving sorafenib (S)

    Reporting group values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib Total
    Number of subjects
    		 59 46 105
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 24 18 42
        From 65-84 years
    		 35 28 63
    Gender categorical
    Units: Subjects
        Female
    		 11 6 17
        Male
    		 48 40 88

    End points

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    End points reporting groups
    Reporting group title
    Arm SE: Sorafenib and everolimus
    Reporting group description
    		 Patients receiving sorafenib (S) and everolimus (E)

    Reporting group title
    Arm S: Sorafenib
    Reporting group description
    		 Patients receiving sorafenib (S)
    Reporting group title
    Arm SE: Sorafenib and everolimus
    Reporting group description
    		 Patients receiving sorafenib (S) and everolimus (E)

    Reporting group title
    Arm S: Sorafenib
    Reporting group description
    		 Patients receiving sorafenib (S)
    Reporting group title
    Arm SE: Sorafenib and everolimus
    Reporting group description
    		 Patients receiving sorafenib (S) and everolimus (E)

    Reporting group title
    Arm S: Sorafenib
    Reporting group description
    		 Patients receiving sorafenib (S)

    Subject analysis set title
    Arm SE: Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in Arm SE who received at least one dose of trial medication and have a documented tumor assessment at 12 weeks 7 days (or documented progression any time before or a tumor assessment any time after).

    Subject analysis set title
    Arm S: Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients in Arm S who received at least one dose of trial medication and have a documented tumor assessment at 12 weeks +/-7 days (or documented progression any time before or no missing assessment any time after).

    Primary: PE | Progression free survival (PFS) at 12 weeks

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    End point title
    		 PE | Progression free survival (PFS) at 12 weeks [1]
    End point description
    For the primary endpoint, progression was strictly defined according to RECIST (version 1.1). In other words, clinical progression was not counted as “Progression”.
    End point type
    Primary
    End point timeframe
    From trial registration until week 12.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses for the primary endpoint were conducted rather against the comparator (Arm S) than historical data. For treatment Arm SE, 33 out of 50 (66.0%) patients were progression free. The null hypothesis for this treatment arm was that the true proportion of PFS at 12 weeks is less than or equal to 55%. Having a p- value of 0.059, which was larger than 0.05, the null hypothesis could not be rejected at the 5% significance level.
    End point values
    		 Arm SE: Per Protocol Set Arm S: Per Protocol Set
    Number of subjects analysed
    50
    43
    Units: Patients (%)
        number (confidence interval 95%)
    66 (53.5 to 100)
    69.8 (56.3 to 100)
    No statistical analyses for this end point

    Secondary: SE | Objective Response (OR)

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    End point title
    		 SE | Objective Response (OR)
    End point description
    OR was defined as having complete response (CR) or partial response (PR) as best response. For this endpoint, patients in the safety population having at least one tumor assessment were considered as evaluable. Best responses in Arm SE were CR = 0.0% patients, PR = 10.2% patients, stable disease (SD) = 67.8% patients; progressive disease (PD) = 15.3% patients and missing data for 6.8% patients; in Arm S best responses were CR = 0.0% patients, PR = 0.0% patients, SD = 80.4% patients, PD = 19.6% patients and missing data for 0.0% patients.
    End point type
    Secondary
    End point timeframe
    From registration until end of treatment
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    55 [2]
    46
    Units: Patients with OR (%)
        number (confidence interval 95%)
    10.9 (4.1 to 22.2)
    0.0 (0.0 to 7.7)
    Notes
    [2] - 55 patients in the safety population had at least one tumor assessment.
    No statistical analyses for this end point

    Secondary: SE | Disease stabilization (DS)

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    End point title
    		 SE | Disease stabilization (DS)
    End point description
    DS was defined as having CR, PR or SD as best response.
    End point type
    Secondary
    End point timeframe
    From registration until end of study.
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    55 [3]
    46
    Units: Patients with DS (%)
        number (confidence interval 95%)
    83.6 (71.2 to 92.2)
    80.4 (66.1 to 90.6)
    Notes
    [3] - 55 patients in the safety population had at least one tumor assessment.
    No statistical analyses for this end point

    Secondary: SE | Duration of DS

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    End point title
    		 SE | Duration of DS
    End point description
    Duration of DS was calculated from the time that measurement criteria (CR, PR or SD) were met for the first time until documented tumor progression or death due to tumor. The duration of DS was censored if a second line treatment was started, the patient was lost to follow up or tumor assessments were outstanding or the patient died without documented tumor progression (and no tumor progression reported before). Patients without a tumor progression were censored at the time of the last tumor assessment. In Arm SE there were 46 evaluable patients with 39 events and seven patients beeing censored. In Arm S there were 37 evaluable patients with 30 events and seven patients beeing censored.
    End point type
    Secondary
    End point timeframe
    From the time that measurement criteria (CR, PR or SD) were met for the first time until documented tumor progression or death due to tumor.
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    46 [4]
    37 [5]
    Units: Duration of DS (months)
        median (confidence interval 95%)
    6.7 (4.1 to 9.4)
    6.7 (3.5 to 8.8)
    Notes
    [4] - 46 patients with DS (i.e. CR, PR or SD).
    [5] - 37 patients with DS (i.e. CR, PR or SD).
    Statistical analysis title
    		 Kaplan-Meier Analysis / Cox regression
    Statistical analysis description
    Hazard ratio for duration of DS [Arm SE vs. Arm S]
    Comparison groups
    Arm SE: Sorafenib and everolimus v Arm S: Sorafenib
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.4

    Secondary: SE | Progression free survival (PFS)

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    End point title
    		 SE | Progression free survival (PFS)
    End point description
    PFS was calculated from randomization until first documented tumor progression or death, whichever occurred first. PFS was censored if a second line treatment was started, the patient was lost to follow up or tumor assessments were outstanding (and no tumor progression had been reported before). Patients without a tumor progression were censored at the time of the last tumor assessment. In Arm SE, 55 out of 59 evaluable patients had progression or died, while four patients had not experienced progression or death. In Arm S, 44 out of 46 evaluable patients had progression or died, while two patients had not experienced progression or death.
    End point type
    Secondary
    End point timeframe
    From randomization until first documented tumor progression or death, whichever occurred first.
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    59
    46
    Units: PFS (months)
        median (confidence interval 95%)
    5.2 (4 to 6.8)
    6.6 (4.5 to 8.2)
    Statistical analysis title
    		 Kaplan-Meier Analysis / Cox regression
    Statistical analysis description
    HR for PFS (Arm SE vs. Arm S)
    Comparison groups
    Arm SE: Sorafenib and everolimus v Arm S: Sorafenib
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.4

    Secondary: SE | Time to tumor progression (TTP)

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    End point title
    		 SE | Time to tumor progression (TTP)
    End point description
    TTP was calculated from randomization until first documented tumor progression or tumor-related death. TTP was censored if a second line treatment was started, the patient was lost to follow up or died without documented tumor progression or tumor assessments were outstanding (and no tumor progression reported before). Patients without a tumor progression were censored at the time of the last tumor assessment. In Arm SE, progression or death due to tumor occurred in 50 (out of 59) patients, while nine patients had not experienced progression or death due to tumor. In Arm S, progression or death due to tumor occurred in 39 (out of 46) patients, while seven patients have not experienced progression or death due to tumor.
    End point type
    Secondary
    End point timeframe
    From randomization until first documented tumor progression or tumor related death.
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    59
    46
    Units: Time to TTP (months)
        median (confidence interval 95%)
    6.2 (4.6 to 8.3)
    7.6 (4.5 to 8.3)
    Statistical analysis title
    		 Kaplan-Meier Analysis / Cox regression
    Statistical analysis description
    HR for TTP (Arm SE vs Arm S)
    Comparison groups
    Arm SE: Sorafenib and everolimus v Arm S: Sorafenib
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.4

    Secondary: SE | Overall Survival (OS)

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    End point title
    		 SE | Overall Survival (OS)
    End point description
    OS was calculated from randomization until death. If the patient was lost to follow up or still alive, then OS was censored at the time the patient was last known to be alive. Using the reverse KM estimator, the median follow up time are 39.6 and 48.3 months in treatment arm SE and S, respectively. In Arm SE, death occurred in 46 (out of 59) patients. Eight patients were lost to follow up and five patients were still alive by their third year follow up. In Arm S, death occurred in 42 (out of 46) patients. Since the follow up after treatment termination for each patient was maximum three years, two patients were lost to follow up and two patients were still alive by their third year follow up.
    End point type
    Secondary
    End point timeframe
    From randomization until death
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    59
    46
    Units: OS (months)
        median (confidence interval 95%)
    13 (9.9 to 19.2)
    10 (7.9 to 14.3)
    Statistical analysis title
    		 Kaplan-Meier Analysis / Cox regression (OS)
    Statistical analysis description
    HR for OS (Arm SE vs Arm S)
    Comparison groups
    Arm SE: Sorafenib and everolimus v Arm S: Sorafenib
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2695
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.2
    Statistical analysis title
    		 Kaplan-Meier Analysis / Cox regression (Vit. B12)
    Statistical analysis description
    HR for OS between Vitamin B12 ≥600 and <600 ng/l using a Cox model adjusted for treatment arm (Arm SE vs Arm S), WHO performance status (1 vs 0) and Extrahepatic spread (No vs Yes) || HR (95% CI) Treatment arm: 0.8 [0.5; 1.2] p = 0.2695; HR (95% CI) WHO performance status: 0.7 [0.4; 1.0] p = 0.0691; HR (95% CI) Extrahepatic spread: 0.9 [0.6; 1.4] p = 0.7066
    Comparison groups
    Arm SE: Sorafenib and everolimus v Arm S: Sorafenib
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6924
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.8

    Secondary: SE | Serum alpha fetoprotein (AFP) level

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    End point title
    		 SE | Serum alpha fetoprotein (AFP) level
    End point description
    For this endpoint, patients in the safety population having baseline (non missing) AFP ≥ 1.5 x ULN were considered as evaluable. For each cycle, number of patients having (non missing) AFP, median, minimum and maximum AFP levels were summarized stratified by treatment arm.
    End point type
    Secondary
    End point timeframe
    At each cycle.
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    25 [6]
    28 [7]
    Units: Serum AFP (ng/ml)
    median (full range (min-max))
        Cycle 1
    350 (8 to 76764)
    99 (6 to 440729)
        Cycle 2
    642 (8 to 526474)
    72 (39 to 179813)
        Cycle 3
    283 (7 to 294700)
    229 (7 to 432563)
        Cycle 4
    432 (6 to 137309)
    82 (37 to 608910)
        Cycle 5
    224 (6 to 243365)
    144 (23 to 579998)
        Cycle 6
    339 (26 to 53293)
    112 (30 to 378186)
        Cycle 7
    462 (183 to 79196)
    96 (52 to 490421)
        Cycle 8
    591 (43 to 73246)
    98 (43 to 433950)
        Cycle 9
    324 (43 to 99010)
    102 (81 to 283844)
        Cycle 10
    483 (44 to 128176)
    339 (88 to 361161)
        Cycle 11
    545 (3 to 2017)
    386 (94 to 400836)
        Cycle 12
    616 (71 to 212700)
    2138 (123 to 426065)
        Cycle 13
    355 (109 to 966)
    135 (113 to 3553)
        Cycle 14
    1095 (96 to 2000)
    2919 (146 to 5961)
        Cycle 15
    1810 (90 to 2000)
    5662 (5662 to 5662)
        Cycle 16
    1953 (350 to 2000)
    0 (0 to 0)
        Cycle 17
    350 (350 to 350)
    0 (0 to 0)
        Cycle 18
    2455 (2000 to 2909)
    0 (0 to 0)
        Cycle 19
    3603 (2000 to 5206)
    0 (0 to 0)
        Cycle 20
    1122 (1122 to 1122)
    0 (0 to 0)
        Cycle 21
    8613 (8613 to 8613)
    0 (0 to 0)
        Cycle 22
    10572 (10572 to 10572)
    0 (0 to 0)
        Cycle 23
    12496 (12496 to 12496)
    0 (0 to 0)
        Cycle 24
    0 (0 to 0)
    0 (0 to 0)
        Cycle 25
    22780 (22780 to 22780)
    0 (0 to 0)
        Cycle 26
    0 (0 to 0)
    0 (0 to 0)
        Cycle 27
    31832 (31832 to 31832)
    0 (0 to 0)
        Cycle 28
    0 (0 to 0)
    0 (0 to 0)
        Cycle 29
    0 (0 to 0)
    0 (0 to 0)
        Cycle 30
    77429 (77429 to 77429)
    0 (0 to 0)
    Attachments
    		 SAKK 7708_AFP levels
    Notes
    [6] - N for cycles 1 to 30: 25,15,19,12,15,11,9,8,5,8,5,4,4,3,3,3,1,2,2,1,1,1,1,0,1,0,1,0,0,1
    [7] - N for cycle 1 to 15: 28,14,22,13,17,9,10,7,8,5,6,3,4,2,1
    No statistical analyses for this end point

    Secondary: SE | Viral (re)-activation in patients with chronic hepatitis B/C virus infection

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    End point title
    		 SE | Viral (re)-activation in patients with chronic hepatitis B/C virus infection
    End point description
    HBV/HCV (re)-activation was defined as: HBV reactivation: at least 1 log increase in HBV DNA or new appearance of measurable HBV DNA AND LFT (liver function test [ALT]) elevation of 5 x ULN or 3 x baseline LFT value HCV activation: 5 x ULN or 3 x baseline LFT value in the presence of HCV RNA or new appearance of measurable HCV PCR RNA “At least 1 log increase” means that present HBV DNA / previous HBV DNA ≥ 10.
    End point type
    Secondary
    End point timeframe
    At various time points.
    End point values
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Number of subjects analysed
    59
    46
    Units: Patients (%)
    number (not applicable)
        (Re)-activation of HBV | Missing
    5.1
    0.0
        (Re)-activation of HBV | No
    94.9
    100.0
        Activation of HCV | No
    94.9
    93.5
        Activation of HCV | Yes
    5.1
    6.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From registration until end of study.
    Adverse event reporting additional description
    All enrolled patients receiving at least one dose of any of the study drugs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Arm SE: Sorafenib and everolimus
    Reporting group description
    		 Patients receiving sorafenib (S) and everolimus (E)

    Reporting group title
    Arm S: Sorafenib
    Reporting group description
    		 Patients receiving sorafenib (S)

    Serious adverse events
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 59 (49.15%)
    14 / 46 (30.43%)
         number of deaths (all causes)
    46
    42
         number of deaths resulting from adverse events
    13
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
    Additional description: Arm SE-[1]: Abdom. pain in context of tumor progression (TP); [2]: Worse. of general condition in context of TP leading to death; [3]: Death due to hepat. failure in context of TP | Arm S-[1]: Decomp. liver cirrhos. in context of TP leading to death
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Tumour pain
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood phosphorus decreased
    Additional description: [1]: Phoshate serum low Grade 4 in context of diarrhea
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
    Additional description: Confusion Grade 2, somnolence/repressed level of consciousness Grade 3 due to repeated opoid overdose
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
    Additional description: Arm SE: one patient: Fatigue Grade 3 with anorexia Grade 2 in context of persisting diarrhea Grade 2 and fever Grade 1; one patient: Fatigue Grade 4 (due to progressive disease)
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Performance status decreased
    Additional description: Worsening of performance status (constitutional symptoms Grade 2 other)
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
    Additional description: Arm SE - [1]: Death due to tumor progression
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Disease progression
    Additional description: [1]: Confusion Grade 4 due to hepatic encephalopathy in context of hyperammonemia associated with progressive disease
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
    Additional description: Arm SE: Pain Grade 3 due to osteoarthrosis, discus hernia, antelisthesis and anal fissure | Arm S: Pain Grade 4 due to coxarthrosis (Arthralgia)
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Gastric ulcer haemorrhage
    Additional description: Anemia Grade 3 due to gastric ulcer bleeding
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
    Additional description: One patient: Fatigue Grade 2-3 and ascites Grade 3
         subjects affected / exposed
    0 / 59 (0.00%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
    Additional description: Gastrointestinal hemorrhage Grade 2 and diarrhea Grade 2
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
    Additional description: Hematochezia due to hemorrhoids (hemorrhage Grade 2 GI anus)
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
    Additional description: [1]: Hemorrhagic-erosive antrum gastritis Grade 3
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: Arm SE: Abdominal pain NOS Grade 3, fatigue Grade 3, weight loss Grade 1 | Arm S: Abdominal pain Grade 3, fever Grade 2
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
    Additional description: Arm S - [1]: Hypoglycemia Grade 4 due to hepatic failure
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    2 / 3
    0 / 1
    Hepatic function abnormal
    Additional description: Arm SE - [two patients]: Liver dysfunction Grade 3, ascites Grade 3, fatigue Grade 3 | Arm S - [one patient]: Hepatic dysfunction (bilirubin Grade 3, AST Grade 3, ALT Grade 2, albumin Grade 2)
         subjects affected / exposed
    2 / 59 (3.39%)
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Hepatic cirrhosis
    Additional description: Arm SE: [1]: Worsening of general condition in context of hepatic cirrhosis decompensation with weight loss Grade 3 and ascites Grade 3 | Arm S: Encephalopathy Grade 3 in context of liver cirrhosis
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
    Additional description: [1]: Epistaxis (hemorrhage Grade 3) with anticoagulation treatment
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
    Additional description: [1]: Dyspnea Grade 3 in context of everolimus induced non-infectious pneumonitis Grade 3 and pulmonary fibrosis
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    Additional description: [1]: Sudden dyspnea Grade 5, syncope Grade 5
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
    Additional description: One event: [1] Leg ulcer Grade 3 in context of leg edema Grade 3; one event: [2] Ulcers (ankle L) in context of leg edema; Hyperammonemia Leg ulcers Ankle edema
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
    Additional description: [1]: Hand-foot syndrome Grade 3, nausea Grade 3, weight loss Grade 3, fatigue Grade 3
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
    Additional description: [1]: Renal failure (creatinine Grade 1), hyponatrema Grade 4 and fatigue Grade 2
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Soft tissue necrosis
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Peritonitis
    Additional description: Fatigue Grade 3 and Peritonitis Grade 3
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis intestinal perforated
    Additional description: Diarrhea Grade 3 with perforated diverticulitis, pericolonic aszites and abscess formation
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Arm SE - [one patient]: Febrile neutropenia Grade 3 associated with pneumonia (infection Grade 3 documented clinically)
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Peritonitis bacterial
    Additional description: [1]: Fever Grade 1 due to suspected bacterial peritonitis (infection Grade 3 with normal ANC)
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
    Additional description: [1]: Hypokalemia Grade 4, diarrhea Grade 3 and creatinine Grade 1
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm SE: Sorafenib and everolimus Arm S: Sorafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 59 (100.00%)
    46 / 46 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    3 / 59 (5.08%)
    4 / 46 (8.70%)
         occurrences all number
    4
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    27 / 59 (45.76%)
    21 / 46 (45.65%)
         occurrences all number
    30
    23
    Embolism
         subjects affected / exposed
    5 / 59 (8.47%)
    0 / 46 (0.00%)
         occurrences all number
    5
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    37 / 59 (62.71%)
    33 / 46 (71.74%)
         occurrences all number
    45
    38
    Pyrexia
         subjects affected / exposed
    12 / 59 (20.34%)
    4 / 46 (8.70%)
         occurrences all number
    13
    7
    Ulcer
         subjects affected / exposed
    2 / 59 (3.39%)
    4 / 46 (8.70%)
         occurrences all number
    2
    4
    Oedema peripheral
         subjects affected / exposed
    11 / 59 (18.64%)
    7 / 46 (15.22%)
         occurrences all number
    12
    8
    Influenza like illness
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 46 (2.17%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    6 / 59 (10.17%)
    3 / 46 (6.52%)
         occurrences all number
    8
    3
    Cough
         subjects affected / exposed
    9 / 59 (15.25%)
    4 / 46 (8.70%)
         occurrences all number
    15
    4
    Dyspnoea
         subjects affected / exposed
    8 / 59 (13.56%)
    4 / 46 (8.70%)
         occurrences all number
    11
    4
    Pneumonitis
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Dysphonia
         subjects affected / exposed
    4 / 59 (6.78%)
    6 / 46 (13.04%)
         occurrences all number
    4
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 59 (13.56%)
    3 / 46 (6.52%)
         occurrences all number
    9
    3
    Anxiety
         subjects affected / exposed
    5 / 59 (8.47%)
    3 / 46 (6.52%)
         occurrences all number
    5
    3
    Confusional state
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Haemoglobin
         subjects affected / exposed
    6 / 59 (10.17%)
    1 / 46 (2.17%)
         occurrences all number
    6
    2
    Neutrophil count
         subjects affected / exposed
    5 / 59 (8.47%)
    1 / 46 (2.17%)
         occurrences all number
    9
    1
    Weight decreased
         subjects affected / exposed
    31 / 59 (52.54%)
    20 / 46 (43.48%)
         occurrences all number
    35
    21
    Oral cavity examination
         subjects affected / exposed
    11 / 59 (18.64%)
    5 / 46 (10.87%)
         occurrences all number
    13
    5
    Alanine aminotransferase
         subjects affected / exposed
    19 / 59 (32.20%)
    16 / 46 (34.78%)
         occurrences all number
    26
    18
    Aspartate aminotransferase
         subjects affected / exposed
    8 / 59 (13.56%)
    5 / 46 (10.87%)
         occurrences all number
    8
    6
    Blood alkaline phosphatase
         subjects affected / exposed
    3 / 59 (5.08%)
    4 / 46 (8.70%)
         occurrences all number
    4
    4
    Blood bilirubin
         subjects affected / exposed
    17 / 59 (28.81%)
    19 / 46 (41.30%)
         occurrences all number
    24
    26
    Blood cholesterol
         subjects affected / exposed
    7 / 59 (11.86%)
    0 / 46 (0.00%)
         occurrences all number
    10
    0
    Blood creatinine
         subjects affected / exposed
    3 / 59 (5.08%)
    3 / 46 (6.52%)
         occurrences all number
    3
    4
    Gamma-glutamyltransferase
         subjects affected / exposed
    2 / 59 (3.39%)
    4 / 46 (8.70%)
         occurrences all number
    2
    4
    Nervous system disorders
    Taste disorder
         subjects affected / exposed
    2 / 59 (3.39%)
    4 / 46 (8.70%)
         occurrences all number
    2
    4
    Dizziness
         subjects affected / exposed
    4 / 59 (6.78%)
    3 / 46 (6.52%)
         occurrences all number
    4
    3
    Headache
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 46 (2.17%)
         occurrences all number
    3
    2
    Blood and lymphatic system disorders
    Platelets abnormal
         subjects affected / exposed
    14 / 59 (23.73%)
    4 / 46 (8.70%)
         occurrences all number
    15
    5
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    10 / 59 (16.95%)
    7 / 46 (15.22%)
         occurrences all number
    10
    7
    Colitis
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Constipation
         subjects affected / exposed
    6 / 59 (10.17%)
    6 / 46 (13.04%)
         occurrences all number
    6
    6
    Diarrhoea
         subjects affected / exposed
    39 / 59 (66.10%)
    22 / 46 (47.83%)
         occurrences all number
    50
    28
    Dry mouth
         subjects affected / exposed
    4 / 59 (6.78%)
    3 / 46 (6.52%)
         occurrences all number
    4
    4
    Dysphagia
         subjects affected / exposed
    0 / 59 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    3
    Dyspepsia
         subjects affected / exposed
    4 / 59 (6.78%)
    2 / 46 (4.35%)
         occurrences all number
    4
    2
    Haemorrhoids
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 46 (0.00%)
         occurrences all number
    4
    0
    Nausea
         subjects affected / exposed
    12 / 59 (20.34%)
    8 / 46 (17.39%)
         occurrences all number
    14
    8
    Vomiting
         subjects affected / exposed
    6 / 59 (10.17%)
    7 / 46 (15.22%)
         occurrences all number
    7
    8
    Abdominal pain
         subjects affected / exposed
    18 / 59 (30.51%)
    10 / 46 (21.74%)
         occurrences all number
    28
    12
    Proctalgia
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 46 (6.52%)
         occurrences all number
    2
    3
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 46 (6.52%)
         occurrences all number
    2
    3
    Alopecia
         subjects affected / exposed
    0 / 59 (0.00%)
    9 / 46 (19.57%)
         occurrences all number
    0
    9
    Dry skin
         subjects affected / exposed
    5 / 59 (8.47%)
    4 / 46 (8.70%)
         occurrences all number
    6
    4
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    17 / 59 (28.81%)
    15 / 46 (32.61%)
         occurrences all number
    20
    17
    Pruritus
         subjects affected / exposed
    7 / 59 (11.86%)
    6 / 46 (13.04%)
         occurrences all number
    7
    6
    Rash
         subjects affected / exposed
    16 / 59 (27.12%)
    11 / 46 (23.91%)
         occurrences all number
    17
    14
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 59 (6.78%)
    3 / 46 (6.52%)
         occurrences all number
    4
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 59 (6.78%)
    1 / 46 (2.17%)
         occurrences all number
    4
    1
    Pain in extremity
         subjects affected / exposed
    4 / 59 (6.78%)
    2 / 46 (4.35%)
         occurrences all number
    4
    2
    Arthralgia
         subjects affected / exposed
    4 / 59 (6.78%)
    3 / 46 (6.52%)
         occurrences all number
    4
    3
    Myalgia
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 46 (4.35%)
         occurrences all number
    5
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 46 (4.35%)
         occurrences all number
    3
    2
    Urinary tract infection
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 46 (2.17%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    6 / 59 (10.17%)
    5 / 46 (10.87%)
         occurrences all number
    6
    5
    Decreased appetite
         subjects affected / exposed
    20 / 59 (33.90%)
    16 / 46 (34.78%)
         occurrences all number
    32
    19
    Dehydration
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 46 (0.00%)
         occurrences all number
    3
    0
    Hyperglycaemia
         subjects affected / exposed
    18 / 59 (30.51%)
    0 / 46 (0.00%)
         occurrences all number
    25
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    7 / 59 (11.86%)
    0 / 46 (0.00%)
         occurrences all number
    9
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 59 (1.69%)
    3 / 46 (6.52%)
         occurrences all number
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26884590
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