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    Clinical Trial Results:
    Prospective, randomised, controlled, multi-centre Phase III study for rapid identification of low risk patients after surgical partial liver resection through application of the LiMAx test

    Summary
    EudraCT number
    		 2010-023095-31
    Trial protocol
    		 DE  
    Global end of trial date
    01 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Dec 2017
    First version publication date
    07 Dec 2017
    Other versions
    Summary report(s)
    		 Study_Report_Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    HUM-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01785082
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Humedics GmbH
    Sponsor organisation address
    Marie-Elisabeth-Lüdersstr. 1, Berlin, Germany, 10625
    Public contact
    Clinical Trials Information, Humedics GmbH, +49 30 590083 240, alexander.helmke@humedics.de
    Scientific contact
    Clinical Trials Information, Humedics GmbH, +49 30 590083 240, alexander.helmke@humedics.de
    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
    17 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate efficacy, safety and benefit/risk analysis of a intravenously administered 13C-methacetin solution as a diagnostic agent for the measurement of liver function according to the LiMAx procedure compared to a control group representing the clinical standard of care in patients undergoing partial liver resection. To show the impact on diagnostic thinking and therapeutic decision making based on a modified postoperative management (fast-track procedure) with direct transfer of patients with sufficient liver status from the recovery room to the general ward. By evaluating the clinical outcome and safety of the diagnostic approach of the LiMAx test, a benefit for the patient due to improved patient management compared to the standard of care procedure should be demonstrated. As decisive target parameter for the decision on postoperative management under fast-track procedure, a postoperative LiMAx value of >150 μg/kg/h was to be established.
    Protection of trial subjects
    Performance of a LiMAx test with the CE-certified measurement device of the company Humedics GmbH under use of the CE certified disposable accessories (breathing mask set) provided by the company. Selection of study sites with capacity for potential double room occupancy planning (general ward and INT) for transfer from the recovery room for patients of the LiMAx group: In the event of unforeseeable events in the LiMAx group, if a transfer according to the result of the LiMAx test is not medically justifiable, beds are reserved for transfer. Evaluation of the extra-hepatic reasons that stand contrary to a primary transfer to general ward: The specific exception (non-transfer to general ward due to extra-hepatic reasons) from the primary decision for transfer to general ward is in both test positive cases (LiMAx value > 150 µg/kg/h, respectively transfer according to OP plan to general ward in the control group) evaluated in the recovery room. Criteria assessed by the responsible physician in the recovery room: 1. Relevant subsequent bleeding 2. No spontaneous respiration or no sufficient oxygenation under a maximum of 2 l/min oxygen with spontaneous respiration 3. Not sufficiently awake and responsive 4. Not treatable delirium 5. Haemodynamically unstable 6. No satisfactory level of analgesia Or due to a different medical decision with justification
    Background therapy
    		 -
    Evidence for comparator
    		 usual clinical standard transfer practice
    Actual start date of recruitment
    23 Jan 2013
    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
    Germany: 149
    Worldwide total number of subjects
    149
    EEA total number of subjects
    149
    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)
    94
    From 65 to 84 years
    55
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 6 sites in Germany

    Pre-assignment
    Screening details
    		 149 patients were assessed for eligibility; of which 1 patient was a screening failure (violation of one inclusion criterion) excluded and not randomised. An additional 25 randomised patients were excluded and replaced in accordance with the study protocol.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    As the randomisation took place after completion of the surgery planning, the surgeon was blinded with regard to the assignment of the patient to the LiMAx or the control group. The correctness of the primary transfer to INT was retrospectively assessed in both groups. The post-operatively recorded patient data of all patients who were primarily transferred to INT are assessed in a blinded procedure by an independent committee.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LiMAx group
    Arm description
    		 Perioperative management of the patients according to the fast-track procedure (Novum) comprising pre- and postoperative measurement of the liver function by means of the LiMAx test. Therefore, the investigational medicinal product was administered twice. The postoperative LiMAx test was performed in the recovery room.
    Arm type
    		 Experimental

    Investigational medicinal product name
    13C-Methacetin Solution for Injection (formerly named 13C-Methacetin Solution for Infusion)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0.4% 13C-Methacetin Solution Dosage: 2 mg/kg body weight-adjusted

    Arm title
    		 Control group
    Arm description
    		 Perioperative management of the patients according to the clinical standard of care (standard transfer practice based on defined treatment and diagnostic algorithms)
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		LiMAx group Control group
    Started
    76
    72
    Surgery according to protocol
    58
    57
    Completed
    58
    57
    Not completed
    18
    15
         Complications during operation
    1
    -
         Surgery not performed according to protocol
    13
    12
         LiMAx test postoperative not feasible
    3
    -
         Protocol deviation
    1
    3
    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: 149 patients were assessed for eligibility; of which 1 patient was a screening failure (violation of one inclusion criterion) excluded and not randomised.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LiMAx group
    Reporting group description
    		 Perioperative management of the patients according to the fast-track procedure (Novum) comprising pre- and postoperative measurement of the liver function by means of the LiMAx test. Therefore, the investigational medicinal product was administered twice. The postoperative LiMAx test was performed in the recovery room.

    Reporting group title
    Control group
    Reporting group description
    		 Perioperative management of the patients according to the clinical standard of care (standard transfer practice based on defined treatment and diagnostic algorithms)

    Reporting group values
    		 LiMAx group Control group Total
    Number of subjects
    		 76 72 148
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 43 51 94
        From 65-84 years
    		 33 21 54
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.5 ± 13.2 56.2 ± 14.6 -
    Gender categorical
    Units: Subjects
        Female
    		 32 33 65
        Male
    		 44 39 83
    Race
    Units: Subjects
        Caucasian
    		 76 72 148
    Reasons for surgery
    Baseline disease characteristics
    Units: Subjects
        HCC (hepatocellular carcinoma)
    		 13 8 21
        CCC (cholangiocelluar carcinoma)
    		 9 5 14
        Liver metastases - colorectal
    		 27 34 61
        Liver metastases - melanoma
    		 3 1 4
        Adenoma (liver)
    		 4 4 8
        Focal nodular hyperplasia
    		 2 3 5
        Other
    		 7 12 19
        Other liver metastases
    		 11 5 16
    Relevant concomitant diseases
    Baseline disease characteristics
    Units: Subjects
        Chronic hepatitis B
    		 1 1 2
        Chronic hepatitis C
    		 0 0 0
        Non-alcoholic steatohepatitis (NASH)
    		 3 1 4
        Autoimmune hepatitis
    		 0 0 0
        Primary biliary cirrhosis (PBC)
    		 0 0 0
        Primary sclerotic cholangitis (PSC)
    		 0 0 0
        Liver cirrhosis
    		 0 0 0
        Hepatic steatosis
    		 14 10 24
        None
    		 58 60 118
    Previous surgery or therapy
    Baseline disease characteristics
    Units: Subjects
        Yes
    		 70 69 139
        No
    		 6 3 9
    Intake of medication 30 days before inclusion
    Baseline disease characteristics
    Units: Subjects
        Yes
    		 57 55 112
        No
    		 19 17 36
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 78.7 ± 16.6 80.1 ± 16.8 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 170.6 ± 8.6 171.8 ± 9.0 -
    Subject analysis sets

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomized patients (n=148, LiMAx group: n=76, control group: n=72).

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The following patients were included in the modified Intention-to-treat population: 1. Randomised patients (control group). 2. Randomised patients with a postoperative LiMAx test (LiMAx group). 3. None of the following exceptions occurred: a. The planned liver resection was not done or was postponed for more than 72 hours. b. The required OPS code (5-502) was changed during surgery and/or surgery discontinued due to extended tumour progression. c. Death of patient during surgery. d. The planned liver resection had to be extended by an unplanned surgery concerning other solid organs. e. Leukocyte count was less than 1/nl before surgery (visit 4a). f. Elevated measures of ALT or AST, higher than 1000 units/l before surgery . (n=118, LiMAx group: n=58, control group: n=60)

    Subject analysis sets values
    		 Safety mITT
    Number of subjects
    148
    118
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    94
    77
        From 65-84 years
    54
    41
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    57.9 ± 13.9
    56.9 ± 14.2
    Gender categorical
    Units: Subjects
        Female
    65
    53
        Male
    83
    65
    Race
    Units: Subjects
        Caucasian
    148
    118
    Reasons for surgery
    Baseline disease characteristics
    Units: Subjects
        HCC (hepatocellular carcinoma)
    21
    18
        CCC (cholangiocelluar carcinoma)
    14
    10
        Liver metastases - colorectal
    61
    44
        Liver metastases - melanoma
    4
    4
        Adenoma (liver)
    8
    8
        Focal nodular hyperplasia
    5
    4
        Other
    19
    18
        Other liver metastases
    16
    12
    Relevant concomitant diseases
    Baseline disease characteristics
    Units: Subjects
        Chronic hepatitis B
    2
    2
        Chronic hepatitis C
    0
    0
        Non-alcoholic steatohepatitis (NASH)
    4
    4
        Autoimmune hepatitis
    0
    0
        Primary biliary cirrhosis (PBC)
    0
    0
        Primary sclerotic cholangitis (PSC)
    0
    0
        Liver cirrhosis
    0
    0
        Hepatic steatosis
    24
    17
        None
    118
    97
    Previous surgery or therapy
    Baseline disease characteristics
    Units: Subjects
        Yes
    139
    110
        No
    9
    8
    Intake of medication 30 days before inclusion
    Baseline disease characteristics
    Units: Subjects
        Yes
    112
    91
        No
    36
    27
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    79.4 ± 16.6
    80.12 ± 15.58
    Height
    Units: cm
        arithmetic mean (standard deviation)
    171.2 ± 8.8
    171.56 ± 8.63

    End points

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    End points reporting groups
    Reporting group title
    LiMAx group
    Reporting group description
    		 Perioperative management of the patients according to the fast-track procedure (Novum) comprising pre- and postoperative measurement of the liver function by means of the LiMAx test. Therefore, the investigational medicinal product was administered twice. The postoperative LiMAx test was performed in the recovery room.

    Reporting group title
    Control group
    Reporting group description
    		 Perioperative management of the patients according to the clinical standard of care (standard transfer practice based on defined treatment and diagnostic algorithms)

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomized patients (n=148, LiMAx group: n=76, control group: n=72).

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The following patients were included in the modified Intention-to-treat population: 1. Randomised patients (control group). 2. Randomised patients with a postoperative LiMAx test (LiMAx group). 3. None of the following exceptions occurred: a. The planned liver resection was not done or was postponed for more than 72 hours. b. The required OPS code (5-502) was changed during surgery and/or surgery discontinued due to extended tumour progression. c. Death of patient during surgery. d. The planned liver resection had to be extended by an unplanned surgery concerning other solid organs. e. Leukocyte count was less than 1/nl before surgery (visit 4a). f. Elevated measures of ALT or AST, higher than 1000 units/l before surgery . (n=118, LiMAx group: n=58, control group: n=60)

    Primary: True positive subjects

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    End point title
    		 True positive subjects
    End point description
    Number of patients who were transferred to a general ward via the recovery room either due to positive result of the LiMAx test, or due to defined treatment or diagnostic criteria in the standard transfer practice, remained there and were able to be regularly discharged from the general ward at the latest on the 30th postoperative day.
    End point type
    Primary
    End point timeframe
    Visit 5 (Primary postoperative transfer): Destination after surgery (control group with preoperative ICU assignment) respectively transfer destination after recovery room (LiMAx group and control group with preoperative general ward assignment)
    End point values
    		 LiMAx group Control group mITT
    Number of subjects analysed
    58
    60
    118
    Units: Subjects
        True positive
    36
    1
    37
        Other
    22
    59
    81
    Statistical analysis title
    		 True positive subjects
    Comparison groups
    LiMAx group v Control group
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: False positive subjects

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    End point title
    		 False positive subjects
    End point description
    False positive patients were those patients who were transferred to a general ward either due to the positive result of the LiMAx test, or due to the defined treatment or diagnostic criteria in the standard transfer practice, but could not be regularly discharged from there (e.g. due to transfer to the INT, no regular discharge after less than 30 days postoperatively, or death of the patient). Patients for whom a positive test result was revised following the evaluation of extrahepatic criteria by a physician in the recovery room were also considered as false positives.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Primary postoperative transfer): Destination after surgery (control group with preoperative decision for ICU assignment) respectively transfer destination after recovery room (LiMAx group and control group with preoperative decision)
    End point values
    		 LiMAx group Control group mITT
    Number of subjects analysed
    58
    60
    118
    Units: Subjects
        False positive
    16
    2
    18
        Other
    42
    58
    100
    Statistical analysis title
    		 False positive subjects
    Comparison groups
    LiMAx group v Control group
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0002
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - It was expected, that the number of false positive subjects is higher in the LiMAx group, hence no superiority analysis was planned a-priori. The rates of both groups with their 95% confidence intervals were considered instead. For completeness, the CMH test was done.

    Secondary: Specificity

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    End point title
    		 Specificity
    End point description
    The specificity was estimated by calculation of the following ratio per group: number of true negatives/ (number of true negatives + number of false positives) (probability that the test result is negative given the patient is not appropriate for transfer to a general ward). Only true negative or false positive subjects of the mITT analysis set (53 subjects) are analysed.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Primary postoperative transfer): Destination after surgery (control group with preoperative decision for ICU assignment) respectively transfer destination after recovery room (LiMAx group and control group with preoperative decision)
    End point values
    		 LiMAx group Control group mITT
    Number of subjects analysed
    18
    35
    53
    Units: Subjects
        True negative
    2
    33
    35
        False positive
    16
    2
    18
    Statistical analysis title
    		 Specificity
    Comparison groups
    LiMAx group v Control group
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - It was expected, that the number of false positive subjects is higher in the LiMAx group, hence no superiority analysis was planned a-priori. The rates of both groups with their 95% confidence intervals were estimated according to Pearson-Clopper. For completeness, the CMH test was done.

    Secondary: Sensitivity

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    End point title
    		 Sensitivity
    End point description
    The sensitivity was estimated by calculation of the following ratio per group: number of true positives / (number of true positives + number of false negatives) (probability that the test result is positive given the patient really is appropriate for transfer to a general ward). Only true positive or false negative subjects of the mITT analysis set (65 subjects) are analysed.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Primary postoperative transfer): Destination after surgery (control group with preoperative ICU assignment) respectively transfer destination after recovery room (LiMAx group and control group with preoperative general ward assignment)
    End point values
    		 LiMAx group Control group mITT
    Number of subjects analysed
    40
    25
    65
    Units: Subjects
        True positive
    36
    1
    37
        False negative
    4
    24
    28
    Statistical analysis title
    		 Sensitivity
    Comparison groups
    LiMAx group v Control group
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Positive predictive value

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    End point title
    		 Positive predictive value
    End point description
    The positive predictive value of tests was estimated by calculation of the following ratio per group: number of true positives / (number of true positives + number of false positives) (probability that a patient is suitable for transfer to a general ward given that the test result is positive) Only true positive or false positive subjects of the mITT analysis set (55 subjects) are analysed.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Primary postoperative transfer): Destination after surgery (control group with preoperative ICU assignment) respectively transfer destination after recovery room (LiMAx group and control group with preoperative general ward assignment)
    End point values
    		 LiMAx group Control group mITT
    Number of subjects analysed
    52
    3
    55
    Units: Subjects
        True positive
    36
    1
    37
        False positive
    16
    2
    18
    Statistical analysis title
    		 Positive predictive value
    Comparison groups
    LiMAx group v Control group
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0253
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - It was expected, that the number of false positive subjects is higher in the LiMAx group, hence no superiority analysis was planned a-priori. The rates of both groups with their 95% confidence intervals were estimated according to Pearson-Clopper. For completeness, the CMH test was done.

    Secondary: Negative predictive value

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    End point title
    		 Negative predictive value
    End point description
    The negative predictive value of tests was estimated by calculation of the following ratio per group: number of true negatives/ (number of true negatives + number of false negatives) (probability that a patient is not appropriate for transfer to a general ward given that the result of the test is negative). Only true negative or false negative subjects of the mITT analysis set (63 subjects) are analysed.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Primary postoperative transfer): Destination after surgery (control group with preoperative ICU assignment) respectively transfer destination after recovery room (LiMAx group and control group with preoperative general ward assignment)
    End point values
    		 LiMAx group Control group mITT
    Number of subjects analysed
    6
    57
    63
    Units: Subjects
        True negative
    2
    33
    35
        False negative
    4
    24
    28
    Statistical analysis title
    		 Negative predictive value
    Comparison groups
    LiMAx group v Control group
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1108
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening up to the closing visit on post-operative day 30. Persisting subsequent diseases should be documented up until the completion of the trial.
    Adverse event reporting additional description
    Safety assessment is performed by ECGs, pulse, blood pressure measurement and laboratory parameters.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    LiMAx group
    Reporting group description
    		 Perioperative management of the patients according to the fast-track procedure (Novum) comprising pre- and postoperative measurement of the liver function by means of the LiMAx test. Therefore, the investigational medicinal product was administered twice. The postoperative LiMAx test was performed in the recovery room.

    Reporting group title
    Control group
    Reporting group description
    		 Perioperative management of the patients according to the clinical standard of care (standard transfer practice based on defined treatment and diagnostic algorithms)

    Serious adverse events
    		 LiMAx group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 76 (10.53%)
    14 / 72 (19.44%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Investigations
    PT: General physical condition abnormal
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Liver function test abnormal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    PT: Abdominal wound dehiscence
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Wound dehiscence
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Post procedural bile leak
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    PT: Hypertension
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Hypertensive crisis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    PT: Cardiac arrest
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Acute myocardial infarction
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    PT: Bile duct stent removal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    PT: Syncope
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PT: Asthenia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Pyrexia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Multi-organ failure
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    PT: Abdominal pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PT: Pleural effusion
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Pulmonary embolism
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    PT: Renal failure
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    PT: Pain in extremity
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    PT: Haematoma infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Wound infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PT: Abdominal abscess
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 LiMAx group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 76 (81.58%)
    58 / 72 (80.56%)
    Vascular disorders
    PT: Hypertension
         subjects affected / exposed
    4 / 76 (5.26%)
    3 / 72 (4.17%)
         occurrences all number
    4
    3
    PT: Hypotension
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 72 (5.56%)
         occurrences all number
    5
    4
    PT: Circulatory collapse
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    General disorders and administration site conditions
    PT: Oedema peripheral
         subjects affected / exposed
    4 / 76 (5.26%)
    3 / 72 (4.17%)
         occurrences all number
    4
    3
    PT: Impaired healing
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 72 (5.56%)
         occurrences all number
    3
    4
    PT: Pyrexia
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 72 (5.56%)
         occurrences all number
    7
    4
    PT: Pain
         subjects affected / exposed
    7 / 76 (9.21%)
    9 / 72 (12.50%)
         occurrences all number
    10
    9
    PT: Fatigue
         subjects affected / exposed
    1 / 76 (1.32%)
    3 / 72 (4.17%)
         occurrences all number
    1
    5
    Respiratory, thoracic and mediastinal disorders
    PT: Pleural effusion
         subjects affected / exposed
    6 / 76 (7.89%)
    4 / 72 (5.56%)
         occurrences all number
    6
    4
    PT: Dyspnoea
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    PT: Cough
         subjects affected / exposed
    2 / 76 (2.63%)
    5 / 72 (6.94%)
         occurrences all number
    2
    5
    PT: Pneumothorax
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 72 (2.78%)
         occurrences all number
    1
    3
    PT: Respiratory failure
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    3
    Psychiatric disorders
    PT: Sleep disorder
         subjects affected / exposed
    8 / 76 (10.53%)
    6 / 72 (8.33%)
         occurrences all number
    8
    7
    Investigations
    PT: C-reactive protein increased
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    PT: Body temperature increased
         subjects affected / exposed
    4 / 76 (5.26%)
    5 / 72 (6.94%)
         occurrences all number
    4
    5
    PT: Blood bilirubin increased
         subjects affected / exposed
    1 / 76 (1.32%)
    3 / 72 (4.17%)
         occurrences all number
    1
    3
    PT: Haemoglobin decreased
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    PT: Procedural nausea
         subjects affected / exposed
    9 / 76 (11.84%)
    5 / 72 (6.94%)
         occurrences all number
    9
    6
    PT: Post procedural constipation
         subjects affected / exposed
    5 / 76 (6.58%)
    5 / 72 (6.94%)
         occurrences all number
    5
    5
    PT: Wound complication
         subjects affected / exposed
    26 / 76 (34.21%)
    21 / 72 (29.17%)
         occurrences all number
    26
    21
    PT: Procedural pain
         subjects affected / exposed
    25 / 76 (32.89%)
    24 / 72 (33.33%)
         occurrences all number
    25
    24
    PT: Wound dehiscence
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    PT: Procedural dizziness
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    PT: Post procedural bile leak
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 72 (1.39%)
         occurrences all number
    2
    1
    PT: Wound secretion
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 72 (5.56%)
         occurrences all number
    0
    4
    Cardiac disorders
    PT: Tachycardia
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 72 (5.56%)
         occurrences all number
    1
    4
    PT: Bradycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    3
    Nervous system disorders
    PT: Dizziness
         subjects affected / exposed
    7 / 76 (9.21%)
    11 / 72 (15.28%)
         occurrences all number
    9
    11
    PT: Hypoaesthesia
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 72 (2.78%)
         occurrences all number
    4
    2
    Blood and lymphatic system disorders
    PT: Anaemia
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 72 (6.94%)
         occurrences all number
    3
    5
    PT: Leukocytosis
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    PT: Thrombocytopenia
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 72 (5.56%)
         occurrences all number
    1
    4
    Gastrointestinal disorders
    PT: Vomiting
         subjects affected / exposed
    12 / 76 (15.79%)
    10 / 72 (13.89%)
         occurrences all number
    15
    11
    PT: Nausea
         subjects affected / exposed
    17 / 76 (22.37%)
    21 / 72 (29.17%)
         occurrences all number
    18
    23
    PT: Constipation
         subjects affected / exposed
    12 / 76 (15.79%)
    9 / 72 (12.50%)
         occurrences all number
    13
    9
    PT: Abdominal pain
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 72 (5.56%)
         occurrences all number
    3
    6
    PT: Abdominal distension
         subjects affected / exposed
    6 / 76 (7.89%)
    6 / 72 (8.33%)
         occurrences all number
    6
    6
    PT: Diarrhoea
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 72 (4.17%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    PT: Hyperhidrosis
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    PT: Pruritus
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 72 (5.56%)
         occurrences all number
    0
    4
    PT: Erythema
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    PT: Musculoskeletal pain
         subjects affected / exposed
    6 / 76 (7.89%)
    5 / 72 (6.94%)
         occurrences all number
    6
    6
    PT: Back pain
         subjects affected / exposed
    6 / 76 (7.89%)
    6 / 72 (8.33%)
         occurrences all number
    6
    6
    Infections and infestations
    PT: Urinary tract infection
         subjects affected / exposed
    4 / 76 (5.26%)
    4 / 72 (5.56%)
         occurrences all number
    4
    4
    Metabolism and nutrition disorders
    PT: Hypoalbuminaemia
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 72 (4.17%)
         occurrences all number
    2
    3
    PT: Hypokalaemia
         subjects affected / exposed
    12 / 76 (15.79%)
    8 / 72 (11.11%)
         occurrences all number
    12
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2013
    Substantial Amendment submitted 23 August 2013 due to the suggested amendments between study protocol Version 04 dated November 05, 2012, and study protocol Version 05, dated August 15, 2013. The protocol was amended for the following reasons: - Prolongation of study recruitment time line - Rewording of inclusion/exclusion criteria for clarification - Update on participating investigators/study sites - Changes related to revised scheduling of visit 4 (separated with protocol version 05 into visit 4a and 4b). Due to the separation into steps 4a and 4b it was ensured that the safety blood draw 12 – 24 hours after the last application of the investigational medicinal product was still conducted (4a) within this time frame, whereas the volumetry of the resectate was able to be conducted at the day of the surgery (4b) even if the surgery takes place 72 hours later. - Adjustment of the time frame for conduct of the postoperative LiMAx test up to 6 hours after skin suturing. - Premature withdrawal: Clarification which type of organs that might have been affected by an expansion of the surgery might result in a premature drop out of the patient. Clarification was focusing on organ types potentially increasing the postoperative risks.
    20 Mar 2014
    Substantial Amendment submitted 11 March 2014 due to the suggested amendments between study protocol Version 05 dated August 15, 2013, and study protocol Version 06, dated March 03, 2014. The protocol was amended for the following reasons: - Prolongation of study recruitment time line - Rewording of inclusion/exclusion criteria for clarification - Update on participating investigators/study sites

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

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