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    Clinical Trial Results:
    Randomized crossover trial to assess the effects and quality of life in patients with locally advanced or metastatic pancreatic cancer treated with gemcitabine in combination with nab-paclitaxel: QOLINPAC

    Summary
    EudraCT number
    2013-004101-75
    Trial protocol
    BE  
    Global end of trial date
    29 Apr 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Aug 2019
    First version publication date
    08 Aug 2019
    Other versions
    Summary report(s)
    Consort diagram
    QOL analysis methodology
    Deaths on treatment
    Protocol deviations
    Selected references
    Publications
    Abbreviations

    Trial information

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    Trial identification
    Sponsor protocol code
    S56122-ML10190
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02106884
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Celgene internal number: AX-CL-PANC-PI-003568
    Sponsors
    Sponsor organisation name
    UZ Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Prof. Dr. Eric Van Cutsem, UZ Leuven, Digestive oncology, 0032 16344225, eric.vancutsem@uzleuven.be
    Scientific contact
    Prof. Dr. Eric Van Cutsem, UZ Leuven, Digestive oncology, 0032 16344225, eric.vancutsem@uzleuven.be
    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
    29 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare quality of life scores and times to definitive deterioration of the quality of life (QOL) scores in patients receiving nab-paclitaxel (n-P) + gemcitabine (G) versus gemcitabine (G) in monotherapy using the EORTC QLQ-C30 questionnaire.
    Protection of trial subjects
    Ethics review and approval, informed consent, prophylactic medication prior to infusions (to prevent chemotherapy known adverse events as per current practice and protocol recommendations), supportive care and routine monitoring.
    Background therapy
    /
    Evidence for comparator
    /
    Actual start date of recruitment
    09 May 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 146
    Worldwide total number of subjects
    146
    EEA total number of subjects
    146
    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)
    76
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    One hundred fourty-six patients were included. First patient enrolled: 08-May-2014. Last patient enrolled: 25-Nov-2015. End of trial notification was dated 15-May-2018 (last patient last visit) and submitted to EC and CA 10-Jul-2018. Last follow-up (FU) data collected 05-Feb-2019. The cut off date for final data was on 29-Apr-2019.

    Pre-assignment
    Screening details
    The study target population was represented by patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma, histologically or cytologically confirmed, eligible for treatment with gemcitabine and nab-paclitaxel in a first line setting. Patients were screened as per inclusion and exclusion criteria per protocol.

    Period 1
    Period 1 title
    Full study duration: baseline to FU (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A - nab-paclitaxel and gemcitabine
    Arm description
    Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine.
    Arm type
    Experimental

    Investigational medicinal product name
    Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane
    Pharmaceutical forms
    Concentrate for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per protocol dose was 125 mg/m2. Schedule: Infusions repeated for three weeks followed by a week of rest (4 week cycles). Nab-paclitaxel infusions were planned every 7 days on the same day of the week; deviations more than 2 days were not allowed.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Gemzar
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per protocol dose: 1000 mg/m2. Schedule: For patients in Arm A, gemcitabine was given the same day with and following nab-paclitaxel, i.e. once weekly for 3 weeks followed by a week of rest then repeat (4 week cycles). Gemcitabine infusions were planned every 7 days on the same day of the week; deviations more than 2 days were not allowed.

    Arm title
    Arm B - gemcitabine monotherapy
    Arm description
    Patients randomised to receive gemcitabine monotherapy.
    Arm type
    Standard of care - no comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Gemzar
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per protocol dose: 1000 mg/m2. Schedule: For patients in Arm B, gemcitabine was given in an initial sequence of seven weeks followed by a week of rest (first cycle is 8 weeks) then every week for three weeks followed by a week of rest (cycle 2 and subsequent cycles are of 4 weeks). Gemcitabine infusions were planned every 7 days on the same day of the week; deviations more than 2 days were not allowed. Patients in Arm B progressing on gemcitabine monotherapy and eligible to receive nab-paclitaxel and gemcitabine were allowed to switch to the combination.

    Number of subjects in period 1
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy
    Started
    72
    74
    Completed
    72
    73
    Not completed
    0
    1
         Change of diagnosis/exclusion criterion
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A - nab-paclitaxel and gemcitabine
    Reporting group description
    Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine.

    Reporting group title
    Arm B - gemcitabine monotherapy
    Reporting group description
    Patients randomised to receive gemcitabine monotherapy.

    Reporting group values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Total
    Number of subjects
    72 74 146
    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)
    39 37 76
        From 65-84 years
    33 37 70
        85 years and over
    0 0 0
    Gender categorical
    Units: Subjects
        Female
    31 32 63
        Male
    41 42 83
    ECOG performance status
    WHO EGOG performance status (PS) scale 0 Able to carry out all normal activity without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out light work 2 Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours. 3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
    Units: Subjects
        PS = 0
    27 23 50
        PS = 1
    42 49 91
        PS = 2
    3 2 5
    Site of pancreatic tumour
    Units: Subjects
        Head
    16 19 35
        Body
    37 34 71
        Tail
    19 21 40
    Locally advanced / metastatic
    Units: Subjects
        Locally advanced
    10 11 21
        Metastatic
    62 63 125
    Adjuvant treatment prior to inclusion
    Units: Subjects
        Yes
    5 6 11
        No
    67 68 135
    Subject analysis sets

    Subject analysis set title
    Intent to treat set (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients who consented to participate in the study and fulfilled all inclusion/exclusion criteria. One patient initially treated for pancreatic adenocarcinoma was excluded from the ITT set due to a subsequent change in diagnosis (neuroendocrine tumour).

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients treated on trial (at least one dose of treatment).

    Subject analysis sets values
    Intent to treat set (ITT) Safety set
    Number of subjects
    145
    146
    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)
    76
    76
        From 65-84 years
    69
    70
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    63
    63
        Male
    82
    83
    ECOG performance status
    WHO EGOG performance status (PS) scale 0 Able to carry out all normal activity without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out light work 2 Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours. 3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair
    Units: Subjects
        PS = 0
    50
    50
        PS = 1
    90
    91
        PS = 2
    5
    5
    Site of pancreatic tumour
    Units: Subjects
        Head
    34
    35
        Body
    71
    71
        Tail
    40
    40
    Locally advanced / metastatic
    Units: Subjects
        Locally advanced
    20
    21
        Metastatic
    125
    125
    Adjuvant treatment prior to inclusion
    Units: Subjects
        Yes
    11
    11
        No
    134
    135

    End points

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    End points reporting groups
    Reporting group title
    Arm A - nab-paclitaxel and gemcitabine
    Reporting group description
    Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine.

    Reporting group title
    Arm B - gemcitabine monotherapy
    Reporting group description
    Patients randomised to receive gemcitabine monotherapy.

    Subject analysis set title
    Intent to treat set (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients who consented to participate in the study and fulfilled all inclusion/exclusion criteria. One patient initially treated for pancreatic adenocarcinoma was excluded from the ITT set due to a subsequent change in diagnosis (neuroendocrine tumour).

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All patients treated on trial (at least one dose of treatment).

    Primary: Deterioration-free survival rate of the QOL global health status at 3, 6 and 12 months

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    End point title
    Deterioration-free survival rate of the QOL global health status at 3, 6 and 12 months
    End point description
    1474 QOL questionnaires were completed (714 in arm A; 761 in arm B) The QOL global health status (GHS) is a functional parameter derived from the EORTC QLQ - C30 questionnaire, based on questions 29 "How would you rate your overall health during the past week?" and 30 "How would you rate your overall quality of life during the past week?". The deterioration free survival rate at 3 months is defined as the Kaplan-Meier estimate of the probability of being alive and free of deterioration of the QOL score at 3 months. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last FU.
    End point type
    Primary
    End point timeframe
    From date of randomisation to 3, 6 and 12 months respectively
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Percentage
        Rate at 3 months
    89
    73
    81
        Rate at 6 months
    74
    59
    66
        Rate at 12 months
    40
    35
    38
    Attachments
    GHS - TUDD
    Statistical analysis title
    Difference in GHS deterioration-free rates 3 mo
    Statistical analysis description
    Comparison of the deterioration-free survival rates based on definitive deterioration or death at 3, 6, 9, 12 months after randomisation. The comparisons are based on Z-tests after log-log transformations of the survival estimates. Deterioration-free survival rates at 3 months were respectively: Arm A (n-P+G) 88.89%, 95%CI [79.0-94.3] and Arm B (G monotherapy) 79.74%, 95%CI [60.7-81.3] with p=0.0166. Additional data is available upon request.
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.0166 [2]
    Method
    Z-test
    Confidence interval
    Notes
    [1] - The difference in the deterioration-free rate of the GHS at 3 months between the two arms was statistically significant.
    [2] - A stratification per centre was performed. 95% confidence intervals were based on a non-parametric bootstrap procedure. The difference was still significant with p<0.05.

    Primary: QOL global health status deterioration-free median survival

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    End point title
    QOL global health status deterioration-free median survival
    End point description
    The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score or death. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.
    End point type
    Primary
    End point timeframe
    From date of randomisation to end of follow up (max 3 years after database lock when applicable).
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Months
        median (confidence interval 95%)
    10.04 (7.16 to 12.02)
    8.02 (5.49 to 11.37)
    8.74 (6.67 to 10.84)
    Statistical analysis title
    Deterioration-free survival time Kaplan-Meier
    Statistical analysis description
    The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score (as defined above) or death. Median times to definitive deterioration or death with 95%CI are presented for the GHS QOL score per arm. A logrank comparison between arms was performed and the p-value is provided below. Additional data is available upon request.
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.378 [4]
    Method
    Logrank
    Confidence interval
    Notes
    [3] - Kaplan-Meier.
    [4] - The difference between arms of the median times to definitive deterioration of the GHS was not statistically significant.

    Secondary: Deterioration-free survival rate of the QOL functional scales at 3, 6 and 12 months

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    End point title
    Deterioration-free survival rate of the QOL functional scales at 3, 6 and 12 months
    End point description
    The QOL functional scales are derived from the EORTC QLQ - C30: Physical functioning (PF2)Q 1-5, Role functioning (RF2) Q6&7, Emotional functioning (EF) Q21-24, Cognitive functioning (CF) Q20&25, Social functioning (SF) Q26&27. The deterioration free survival rate at 3 months is defined as the Kaplan-Meier estimate of the probability of being alive and free of deterioration of the QOL score at 3 months. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to 3, 6 and 12 months respectively
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Percentage
        Physical functioning 3 months
    76
    67
    72
        Physical functioning 6 months
    65
    57
    61
        Physical functioning 12 months
    32
    31
    31
        Role functioning 3 months
    81
    68
    74
        Role functioning 6 months
    67
    53
    60
        Role functioning 12 months
    36
    32
    34
        Emotional functioning 3 months
    93
    79
    86
        Emotional functioning 6 months
    79
    68
    74
        Emotional functioning 12 months
    40
    43
    42
        Cognitive functioning 3 months
    89
    78
    83
        Cognitive functioning 6 months
    75
    66
    70
        Cognitive functioning 12 months
    40
    45
    42
        Social functioning 3 months
    86
    75
    81
        Social functioning 6 months
    69
    64
    67
        Social functioning 12 months
    36
    42
    39
    Statistical analysis title
    Difference in QOL deterioration-free rates at 3 mo
    Statistical analysis description
    Comparison of the deterioration-free survival rates of the QOL functional scales based on definitive deterioration or death at 3, 6, 9, 12 months after randomisation. The comparisons are based on Z-tests after log-log transformations of the survival estimates. Deterioration-free survival rates at 3 months difference between arms was significant for the Emotional functioning scale: Arm A (n-P+G) 93.1%, 95%CI [84.1-97.0] and Arm B (G monotherapy) 79.3%, 95%CI [68.1-87.0] with p=0.0238.
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.0238 [6]
    Method
    z-test
    Confidence interval
    Notes
    [5] - The difference in the deterioration-free rate at 3 months between the two arms was statistically significant for Emotional functioning. Additional data available upon request.
    [6] - Significant for Emotional functioning.

    Secondary: QOL functional scales deterioration-free median survival

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    End point title
    QOL functional scales deterioration-free median survival
    End point description
    The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score or death. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of follow up (max 3 years after database lock when applicable).
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Months
    median (confidence interval 95%)
        Physical functioning
    7.85 (6.51 to 10.38)
    6.64 (4.17 to 9.33)
    7.82 (6.31 to 9.07)
        Role functioning
    7.97 (6.51 to 10.58)
    6.51 (4.40 to 10.18)
    7.82 (6.11 to 9.00)
        Emotional functioning
    10.04 (8.25 to 12.02)
    11.04 (8.02 to 12.48)
    10.38 (8.74 to 11.96)
        Cognitive functioning
    8.87 (7.16 to 12.35)
    11.37 (6.64 to 12.55)
    9.92 (7.89 to 12.12)
        Social functioning
    9.05 (6.90 to 11.27)
    9.20 (6.11 to 12.48)
    9.13 (7.59 to 11.37)
    Statistical analysis title
    Deterioration-free survival time Kaplan-Meier
    Statistical analysis description
    The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score (as defined above) or death. Median times to definitive deterioration or death with 95%CI are presented for the functional QOL scales per arm. A logrank comparison between arms was performed for each scale. None of the comparisons was statistically significant. Additional data is available upon request.
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.8408 [8]
    Method
    Logrank
    Confidence interval
    Notes
    [7] - Kaplan-Meier.
    [8] - p-value of the inter-arm comparison of the median deterioration-free survival times for Physical functioning is provided. None of the comparisons of the Functional scales were statistically significant. Additional data is available upon request.

    Secondary: Deterioration-free survival rate of the QOL symptom scales at 3, 6 and 12 months

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    End point title
    Deterioration-free survival rate of the QOL symptom scales at 3, 6 and 12 months
    End point description
    The QOL symptom scales are derived from the EORTC QLQ - C30: Fatigue (FA) Q 10&12&18, Nausea and vomiting (NV) Q14&15, Pain (PA) Q9&19, Dyspnoea(DY) Q8, Insomnia (SL) Q11, Appetite loss (AP) Q13, Constipation (CO) Q16, Diarrhoea (DI) Q17, Financial difficulties (FI) Q28. The deterioration free survival rate at 3 months is defined as the Kaplan-Meier estimate of the probability of being alive and free of deterioration of the QOL score at 3 months. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to 3, 6 and 12 months respectively
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Percentage
        Fatigue 3 months
    92
    79
    85
        Fatigue 6 months
    76
    70
    73
        Fatigue 12 months
    47
    45
    46
        Nausea and vomiting 3 months
    88
    75
    81
        Nausea and vomiting 6 months
    75
    63
    69
        Nausea and vomiting 12 months
    44
    45
    44
        Pain 3 months
    85
    71
    78
        Pain 6 months
    76
    64
    70
        Pain 12 months
    39
    40
    40
        Dyspnoea 3 months
    89
    75
    82
        Dyspnoea 6 months
    74
    67
    70
        Dyspnoea 12 months
    43
    47
    45
        Insomnia 3 months
    75
    74
    74
        Insomnia 6 months
    60
    61
    61
        Insomnia 12 months
    38
    39
    38
        Appetite loss 3 months
    82
    70
    76
        Appetite loss 6 months
    64
    56
    60
        Appetite loss 12 months
    39
    35
    37
        Constipation 3 months
    82
    74
    78
        Constipation 6 months
    68
    63
    65
        Constipation 12 months
    33
    38
    35
        Diarrhoea 3 months
    88
    77
    82
        Diarrhoea 6 months
    72
    66
    69
        Diarrhoea 12 months
    38
    32
    40
        Financial difficulties 3 months
    92
    79
    85
        Financial difficulties 6 months
    78
    71
    74
        Financial difficulties 12 months
    43
    47
    45
    Statistical analysis title
    Difference in QOL deterioration-free rates at 3 mo
    Statistical analysis description
    Comparison of the deterioration-free survival rates of the QOL symptom scales based on definitive deterioration or death at 3, 6, 9, 12 months after randomisation. The comparisons are based on Z-tests after log-log transformations of the survival estimates. Deterioration-free survival rates at 3 months differences between arms were significant for Fatigue p=0.0433, Dyspnoea p=0.0381 and Financial difficulties p=0.0433. Additional data is available upon request.
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    [9]
    P-value
    = 0.0433 [10]
    Method
    z-test
    Confidence interval
    Notes
    [9] - Significant for Fatigue, Dyspnoea, Financial difficulties.
    [10] - p-value provided for Fatigue. Additional data available upon request.

    Secondary: QOL symptom scales deterioration-free median survival

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    End point title
    QOL symptom scales deterioration-free median survival
    End point description
    The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score or death. The definitive deterioration of the QOL score is a decrease of at least 10 points (minimal clinical important difference) as compared to the baseline score, with no further improvement of more than 10 points as compared to the score qualifying the deterioration or with no data after the deterioration was observed. Death was also considered as an event if the patient did not experience deterioration before death. Patients without event were censored at the time of last follow-up.
    End point type
    Secondary
    End point timeframe
    From date of randomisation to end of follow up (max 3 years after database lock when applicable).
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Months
    median (confidence interval 95%)
        Fatigue
    10.60 (8.25 to 14.55)
    11.04 (8.44 to 13.17)
    10.87 (8.97 to 12.71)
        Nausea and vomiting
    10.48 (8.97 to 14.55)
    10.87 (6.01 to 13.21)
    10.58 (8.64 to 12.35)
        Pain
    9.05 (6.97 to 11.27)
    9.72 (6.44 to 13.17)
    9.20 (7.82 to 11.37)
        Dyspnoea
    10.27 (7.59 to 12.88)
    11.43 (6.51 to 13.86)
    10.58 (8.25 to 12.48)
        Insomnia
    7.82 (5.55 to 10.61)
    8.97 (5.62 to 12.29)
    8.74 (6.28 to 10.61)
        Appetite loss
    8.44 (6.28 to 11.27)
    8.44 (4.63 to 11.37)
    8.44 (6.18 to 10.58)
        Constipation
    8.43 (6.51 to 10.38)
    9.17 (6.11 to 11.73)
    8.97 (6.90 to 10.58)
        Diarrhoea
    8.99 (7.66 to 11.04)
    9.20 (6.51 to 13.17)
    9.10 (7.85 to 11.04)
        Financial difficulties
    10.27 (7.66 to 12.35)
    11.43 (8.71 to 13.44)
    10.61 (8.71 to 12.35)
    Statistical analysis title
    Deterioration-free survival time Kaplan-Meier
    Statistical analysis description
    The deterioration-free survival is defined as the Kaplan-Meier estimate of median survival time to definitive deterioration of the QOL score (as defined above) or death. Median times to definitive deterioration or death with 95%CI are presented for the QOL symptom scales per arm. A logrank comparison between arms was performed for each scale. None of the comparisons was statistically significant. Additional data is available upon request.
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.5448 [12]
    Method
    Logrank
    Confidence interval
    Notes
    [11] - Kaplan-Meier survival analysis.
    [12] - p-value of the inter-arm comparison of the median deterioration-free survival times for Fatigue is provided. None of the comparisons of the Symptom scales were statistically significant. Additional data is available upon request.

    Secondary: Exposure to treatment

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    End point title
    Exposure to treatment
    End point description
    Total cumulative dose exposure is measured by dose intensity (total dose given/total dose planned*100) per drug. The "planned dose of nab-paclitaxel" refers, as per protocol, to a weekly administration of 125 mg/m² nab-paclitaxel for 3 weeks followed by a week of rest in 4-week cycles (Arm A only). The "planned dose of gemcitabine” refers to a weekly administration of 1000 mg/m2 gemcitabine following the same day nab-paclitaxel dose in Arm A (4-week cycles) and standard in Arm B (7 infusions + 1 week of rest for cycle 1 and 4-week cycles afterwards). Total doses are the sums of all theoretical "planned" and given doses, respectively.
    End point type
    Secondary
    End point timeframe
    From date of first infusion to date of last infusion. For patients in arm B who switched to the combination of n-P + G in second line dose exposure to n-P is given for this subset.
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Safety set
    Number of subjects analysed
    72
    74
    146 [13]
    Units: Percentage
        Nab-paclitaxel
    73
    74
    74
        Gemcitabine
    75
    70
    72
    Notes
    [13] - All patients received at least one dose of treatment (Safety set).
    No statistical analyses for this end point

    Secondary: Overall response

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    End point title
    Overall response
    End point description
    Tumour response was assessed locally based on radiological assessments (CT/MRI) of target and non-target lesions and considering the occurrence of new lesions, as per RECIST criteria. Tumour response was defined at each evaluation as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Best response during treatment was selected for each patient. Overall response (OR) is defined as the best tumor response on treatment for each patient. Responders were considered CR + PR. Some patients were not evaluable for response (no scans available). Overall response rates (ORR) were calculated based on the ITT set.
    End point type
    Secondary
    End point timeframe
    Duration of treatment
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Counts of participants
        CR + PR
    31
    16
    47
        SD or PD
    39
    53
    92
        Not evaluable
    2
    4
    6
    Statistical analysis title
    Overall response counts and rates
    Statistical analysis description
    Descriptive. Rates of overall response (CR and PR) with 95%CI were calculated per arm: Arm A: ORR 44% 95%CI [32-56]; Arm B: ORR 23% 95%CI [13-33]. Percentages are based on evaluable patients only. A comparison between arms was performed (t-test) and the difference in response rates was statistically significant (p=0.008).
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    P-value
    = 0.008 [15]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [14] - T-test double sided.
    [15] - Difference between the 2 arms was statistically significant.

    Secondary: Duration of response (in responders)

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    End point title
    Duration of response (in responders)
    End point description
    Duration of response was calculated from the date of first documented response to the date of progression (including SD after PR) or date of start of new treatment in not progressed, when available. In 2 patients with CR, periods of PR are included. For those not documented as progressed before death, an unknown duration was kept and considered missing data.
    End point type
    Secondary
    End point timeframe
    Treatment
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    29 [16]
    15 [17]
    44
    Units: Months
        median (full range (min-max))
    6.3 (1.92 to 35)
    7.4 (1.50 to 20)
    6.83 (1.50 to 35)
    Notes
    [16] - 2 of 31 responders had an unknown duration of response thus not considered in this analysis
    [17] - 1 of 16 responders had an unknown duration of response thus not considered in this analysis
    No statistical analyses for this end point

    Secondary: Disease control

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    End point title
    Disease control
    End point description
    Tumour response was assessed locally based on radiological assessments (CT/MRI) of target and non-target lesions and considering the occurrence of new lesions, as per RECIST criteria. Tumour response was defined at each evaluation as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Best response during treatment was selected for each patient. Overall response is defined as the best tumor response on treatment for each patient. Disease control is defined as a best response on treatment of either CR, PR or SD (CR + PR + SD). Some patients were not evaluable for response (no scans available). Overall response rates were calculated based on the ITT set.
    End point type
    Secondary
    End point timeframe
    Duration of treatment
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Counts of participants
        CR + PR + SD
    58
    60
    118
        PD
    12
    9
    21
        Not evaluable
    2
    4
    6
    Statistical analysis title
    Disease control counts and rates
    Statistical analysis description
    Descriptive. Rates of disease control (CR, PR and SD) with 95%CI were calculated per arm: Arm A: DC rate 83% 95%CI [74-92]; Arm B: OR rate 87% 95%CI [79-95]. Percentages are based on evaluable patients only. A comparison between arms was performed (t-test) and the difference in response rates was statistically significant (p=0.503).
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [18]
    P-value
    = 0.503 [19]
    Method
    t-test, 2-sided
    Confidence interval
    Notes
    [18] - T-test double sided
    [19] - Not statistically significant

    Secondary: Progression rates at 1 year

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    End point title
    Progression rates at 1 year
    End point description
    Rate of progression of disease occuring within 1 year from date of randomisation are listed per arm. Details are provided in attached documents.
    End point type
    Secondary
    End point timeframe
    1 year from date of randomisation
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Percentage
        Progressed at 1 year
    71
    79
    75
        Not progressed at 1 year
    29
    21
    25
    No statistical analyses for this end point

    Secondary: Progression free survival

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    End point title
    Progression free survival
    End point description
    Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. All patients (ITT).
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Months
        median (confidence interval 95%)
    7.01 (5.45 to 8.05)
    5.06 (3.52 to 7.00)
    5.85 (5.06 to 7.13)
    Statistical analysis title
    Progression free survival median time Kaplan-Meier
    Statistical analysis description
    The median progression free survival is defined as the Kaplan-Meier estimate of median time from randomisation to first documented progression, date of last follow-up for non progressed patients or death. Median times with 95%CI are presented per arm. A logrank comparison between arms was performed and the P value is provided below. Additional data is available upon request.
    Comparison groups
    Arm B - gemcitabine monotherapy v Arm A - nab-paclitaxel and gemcitabine
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [20]
    P-value
    = 0.0295 [21]
    Method
    Logrank
    Confidence interval
    Notes
    [20] - Kaplan-Meier
    [21] - The difference between arms of the progression free survival time was statistically significant.

    Secondary: Death rates at 30 days from last treatment

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    End point title
    Death rates at 30 days from last treatment
    End point description
    Deaths of all causes occuring between the signature of consent and the date of last infusion + 30 days for each patient are listed per arm. Only one of these fatalities was deemed possibly related to the investigational drug. Details are provided in attached documents.
    End point type
    Secondary
    End point timeframe
    From signature of informed consent to last infusion + 30 days for each patient
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Percentage
        Deceased at 30 days from last treatment
    7
    15
    11
        Alive at 30 days from last treatment
    93
    85
    89
    No statistical analyses for this end point

    Secondary: Death rates at 1 year

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    End point title
    Death rates at 1 year
    End point description
    Rate of deaths of all causes occuring within 1 year from date of randomisation are listed per arm. Details are provided in attached documents.
    End point type
    Secondary
    End point timeframe
    1 year from the date of randomisation
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Percentage
        Deceased at 1 year
    51
    51
    51
        Alive at 1 year
    49
    49
    49
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    Overall survival
    End point description
    Overall survival was considered from start of treatment to death. All patients (ITT)
    End point type
    Secondary
    End point timeframe
    Treatment + follow-up
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Intent to treat set (ITT)
    Number of subjects analysed
    72
    73
    145
    Units: Months
        median (confidence interval 95%)
    10.94 (8.97 to 15.18)
    11.73 (8.74 to 13.44)
    11.43 (9.13 to 13.21)
    Statistical analysis title
    Overall survival median time Kaplan-Meier
    Statistical analysis description
    The median overall survival is defined as the Kaplan-Meier estimate of median time from randomisation to death or last follow-up. Median times to death with 95%CI are presented per arm. A logrank comparison between arms was performed and the P value is provided below. Additional data is available upon request.
    Comparison groups
    Arm A - nab-paclitaxel and gemcitabine v Arm B - gemcitabine monotherapy
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    other [22]
    P-value
    = 0.7005 [23]
    Method
    Logrank
    Confidence interval
    Notes
    [22] - Kaplan-Meier
    [23] - The difference between arms of the median survival time was not statistically significant.

    Secondary: Laboratory safety assessment

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    End point title
    Laboratory safety assessment
    End point description
    Severe laboratory abnormalities (hematology and biochemistry grade 3 and higher). Worst grade per patient. All patients treated (Safety set).
    End point type
    Secondary
    End point timeframe
    From signature of informed consent to end of treatment visit plus 30 days.
    End point values
    Arm A - nab-paclitaxel and gemcitabine Arm B - gemcitabine monotherapy Safety set
    Number of subjects analysed
    72
    74 [24]
    146
    Units: Counts of participants
        Hemoglobin decreased
    10
    8
    18
        Neutrophils decreased
    31
    31
    62
        White blood cell count decreased
    22
    11
    33
        Platelet count decreased
    12
    11
    23
        Hyperglycemia
    6
    10
    16
        Serum creatinine increased
    0
    2
    2
        Bilirubin increased
    3
    8
    11
        ALT increased
    13
    8
    21
        AST increased
    7
    8
    15
        ALP increased
    9
    11
    20
        Albumin decreased
    4
    4
    8
        Magnesium decreased
    4
    9
    13
        Sodium decreased
    8
    13
    21
        Potassium decreased
    8
    6
    14
        Potassium increased
    1
    0
    1
        Calcium decreased
    3
    2
    5
    Notes
    [24] - Safety set - all patients.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAE) and adverse events (AE) occurring from the signature of informed consent to the end of treatment visit plus 30 days.
    Adverse event reporting additional description
    All SAEs occurring between the signature of informed consent and the end of treatment visit + 30 days are listed. Severe adverse events (grade 3-5, worst grade per patient) are listed in the non-serious AE table, SAEs are included. A summary of the severe laboratory abnormalities is provided in section "End points".
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NCI -CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Arm A - nab-paclitaxel and gemcitabine
    Reporting group description
    Patients were randomised to receive a combination regimen of nab-paclitaxel and gemcitabine

    Reporting group title
    ARM B - gemcitabine monotherapy
    Reporting group description
    Patients randomised to receive gemcitabine in monotherapy. Some patients within this Arm switched to the combination regimen and received nab-paclitaxel with gemcitabine after the first progression on gemcitabine monotherapy. Safety set. All patients included.

    Reporting group title
    Total (Safety set)
    Reporting group description
    Safety set. All patients included. ??? 16 deaths on trt due to all causes within 30 days from last trt ----->>> this entered here

    Reporting group title
    Subset nab-paclitaxel + gemcitabine in 2nd line
    Reporting group description
    A separate additional analysis is performed for the population subset that received the combination of nab-paclitaxel and gemcitabine in second line, after the initial progression on gemcitabine monotherapy (cross-over group).

    Serious adverse events
    Arm A - nab-paclitaxel and gemcitabine ARM B - gemcitabine monotherapy Total (Safety set) Subset nab-paclitaxel + gemcitabine in 2nd line
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 72 (69.44%)
    48 / 74 (64.86%)
    98 / 146 (67.12%)
    15 / 37 (40.54%)
         number of deaths (all causes)
    5
    11
    16
    4
         number of deaths resulting from adverse events
    2
    3
    5
    0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 74 (5.41%)
    7 / 146 (4.79%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
    1 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 72 (4.17%)
    5 / 74 (6.76%)
    8 / 146 (5.48%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 5
    5 / 8
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    9 / 72 (12.50%)
    9 / 74 (12.16%)
    18 / 146 (12.33%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    7 / 10
    3 / 10
    10 / 20
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flu like symptoms
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 74 (1.35%)
    4 / 146 (2.74%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Alteration of general condition
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug misuse
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalized edema
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemoptysis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary edema
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 74 (4.05%)
    5 / 146 (3.42%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemolytic Uremic Syndrome
         subjects affected / exposed
    3 / 72 (4.17%)
    2 / 74 (2.70%)
    5 / 146 (3.42%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischemia cerebrovascular
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasovagal reaction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 74 (5.41%)
    5 / 146 (3.42%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic perforation
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal and galbladder obstruction on stent
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric hemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
    3 / 146 (2.05%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastro-enteritis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sigmoiditis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic duct stenosis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 74 (2.70%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 74 (1.35%)
    4 / 146 (2.74%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomach pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 74 (4.05%)
    5 / 146 (3.42%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 74 (4.05%)
    3 / 146 (2.05%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 74 (4.05%)
    4 / 146 (2.74%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 74 (2.70%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Galbladder obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
    3 / 146 (2.05%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 72 (4.17%)
    0 / 74 (0.00%)
    3 / 146 (2.05%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 74 (4.05%)
    5 / 146 (3.42%)
    2 / 37 (5.41%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 4
    2 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major denutrition
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    3 / 72 (4.17%)
    3 / 74 (4.05%)
    6 / 146 (4.11%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    7 / 72 (9.72%)
    2 / 74 (2.70%)
    9 / 146 (6.16%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 2
    4 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious syndrome with mastoiditis/synovitis/positive hemocultures
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic thromboflebitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 72 (5.56%)
    0 / 74 (0.00%)
    4 / 146 (2.74%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Arm A - nab-paclitaxel and gemcitabine ARM B - gemcitabine monotherapy Total (Safety set) Subset nab-paclitaxel + gemcitabine in 2nd line
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 72 (100.00%)
    74 / 74 (100.00%)
    146 / 146 (100.00%)
    37 / 37 (100.00%)
    Vascular disorders
    Capillary leak syndrome
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hematoma
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hypertension
         subjects affected / exposed
    8 / 72 (11.11%)
    7 / 74 (9.46%)
    15 / 146 (10.27%)
    1 / 37 (2.70%)
         occurrences all number
    12
    11
    23
    1
    Thromboembolic event
         subjects affected / exposed
    5 / 72 (6.94%)
    6 / 74 (8.11%)
    11 / 146 (7.53%)
    0 / 37 (0.00%)
         occurrences all number
    6
    8
    14
    0
    Hypotension
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    3
    1
    Fatigue
         subjects affected / exposed
    16 / 72 (22.22%)
    21 / 74 (28.38%)
    37 / 146 (25.34%)
    10 / 37 (27.03%)
         occurrences all number
    26
    38
    64
    21
    Fever
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Multi-organ failure
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    General status alteration
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 74 (4.05%)
    4 / 146 (2.74%)
    1 / 37 (2.70%)
         occurrences all number
    1
    3
    4
    1
    Pain
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 74 (6.76%)
    6 / 146 (4.11%)
    2 / 37 (5.41%)
         occurrences all number
    2
    5
    7
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Anxiety
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    1
    Depression
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Investigations
    Weight loss
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 74 (2.70%)
    4 / 146 (2.74%)
    2 / 37 (5.41%)
         occurrences all number
    2
    2
    4
    2
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Myocardial infarction
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 74 (4.05%)
    3 / 146 (2.05%)
    0 / 37 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dyspnea
         subjects affected / exposed
    6 / 72 (8.33%)
    4 / 74 (5.41%)
    10 / 146 (6.85%)
    0 / 37 (0.00%)
         occurrences all number
    9
    5
    14
    0
    Epistaxis
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1
    2
    1
    Hypoxia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    COPD
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Pumonary edema
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    2
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    7 / 72 (9.72%)
    11 / 74 (14.86%)
    18 / 146 (12.33%)
    2 / 37 (5.41%)
         occurrences all number
    9
    18
    27
    2
    Febrile neutropenia
         subjects affected / exposed
    3 / 72 (4.17%)
    0 / 74 (0.00%)
    3 / 146 (2.05%)
    0 / 37 (0.00%)
         occurrences all number
    4
    0
    4
    0
    Hemolytic uremic syndrome
         subjects affected / exposed
    3 / 72 (4.17%)
    3 / 74 (4.05%)
    6 / 146 (4.11%)
    0 / 37 (0.00%)
         occurrences all number
    3
    3
    6
    0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hemiparesis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 74 (2.70%)
    7 / 146 (4.79%)
    2 / 37 (5.41%)
         occurrences all number
    6
    3
    9
    3
    Somnolence
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Syncope
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 74 (4.05%)
    5 / 146 (3.42%)
    1 / 37 (2.70%)
         occurrences all number
    2
    3
    5
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 72 (4.17%)
    8 / 74 (10.81%)
    11 / 146 (7.53%)
    2 / 37 (5.41%)
         occurrences all number
    5
    9
    14
    2
    Ascites
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    2
    1
    Colitis
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1
    2
    1
    Colonic obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Constipation
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    2
    1
    Diarrhea
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 74 (2.70%)
    7 / 146 (4.79%)
    2 / 37 (5.41%)
         occurrences all number
    5
    2
    7
    2
    Gastric ulcer
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    1
    Gastroparesis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Ileus
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Mucositis oral
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Nausea
         subjects affected / exposed
    5 / 72 (6.94%)
    6 / 74 (8.11%)
    11 / 146 (7.53%)
    2 / 37 (5.41%)
         occurrences all number
    5
    6
    11
    2
    Obstruction gastric
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    3
    1
    Diverticulitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    1
    Intrapancreatic obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    1
    Hematemesis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hernia inguinalis with obstruction
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pancreatitis
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 74 (2.70%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    3
    1
    Small intestinal obstruction
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 74 (2.70%)
    4 / 146 (2.74%)
    0 / 37 (0.00%)
         occurrences all number
    2
    3
    5
    0
    Stomach pain
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    6 / 72 (8.33%)
    4 / 74 (5.41%)
    10 / 146 (6.85%)
    0 / 37 (0.00%)
         occurrences all number
    6
    4
    10
    0
    Colonic perforation
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 74 (4.05%)
    3 / 146 (2.05%)
    0 / 37 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    2 / 72 (2.78%)
    6 / 74 (8.11%)
    8 / 146 (5.48%)
    1 / 37 (2.70%)
         occurrences all number
    2
    6
    8
    1
    Cholecystitis
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 74 (5.41%)
    5 / 146 (3.42%)
    2 / 37 (5.41%)
         occurrences all number
    1
    6
    7
    3
    Gallbladder obstruction
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Hepatic failure
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Cholestasis
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    0
    3
    3
    1
    Dilated bile ducts
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Jaundice
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 74 (0.00%)
    2 / 146 (1.37%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 74 (2.70%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences all number
    1
    2
    3
    1
    Bone pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    7 / 72 (9.72%)
    14 / 74 (18.92%)
    21 / 146 (14.38%)
    9 / 37 (24.32%)
         occurrences all number
    8
    18
    26
    10
    Dehydration
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 74 (2.70%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    0
    2
    2
    1
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    3
    1
    Appendicitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Biliary tract infection
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 74 (1.35%)
    3 / 146 (2.05%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    3
    1
    Bladder infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Bronchial infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Catheter related infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    1
    1
    Gallbladder infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Hepatic infection
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 74 (1.35%)
    2 / 146 (1.37%)
    1 / 37 (2.70%)
         occurrences all number
    2
    2
    4
    1
    Lung infection
         subjects affected / exposed
    6 / 72 (8.33%)
    3 / 74 (4.05%)
    9 / 146 (6.16%)
    1 / 37 (2.70%)
         occurrences all number
    7
    3
    10
    1
    Infection without neutropenia NOS
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Paronychia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pleural infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 74 (0.00%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Sepsis
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 74 (2.70%)
    4 / 146 (2.74%)
    1 / 37 (2.70%)
         occurrences all number
    2
    2
    4
    1
    Tooth infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 74 (1.35%)
    1 / 146 (0.68%)
    0 / 37 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 72 (5.56%)
    0 / 74 (0.00%)
    4 / 146 (2.74%)
    0 / 37 (0.00%)
         occurrences all number
    4
    0
    4
    0

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2014
    Amendment to the ICF due to changes to the safety language in the ICF.
    26 Nov 2014
    Amendment to add four additional participating institutions.
    20 Jul 2015
    Amendment of the protocol to adjust the timing of study procedures, to clarify inclusion/exclusion criteria and increase sample size from 110 to 143 due to observed patient compliance in providing QOL data.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Jun 2015
    Temporary interuption of recruitment at the completion of initial sample size on 18-Jun-2015. The protocol amendment to adjust the timing of study procedures, to clarify inclusion/exclusion criteria and increase sample size from 110 to 143 due to observed patient compliance in providing QOL data was approved on 17-Jul-2015 by the Belgian Health Authority (FAGG) and 20-Jul-2015 by the designated central ethics committee. Recruitment was restarted after all regulatory approvals on 24-Jul-2015.
    24 Jul 2015

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Quality of life endpoints are sensitive to confounding factors such as age, intercurrent disease, time from last completed questionnaire to the last follow-up or death. Tumour response and AE relationship to treatment were locally assessed.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/8433390
    http://www.ncbi.nlm.nih.gov/pubmed/25436122
    http://www.ncbi.nlm.nih.gov/pubmed/20724140
    http://www.ncbi.nlm.nih.gov/pubmed/26185420
    http://www.ncbi.nlm.nih.gov/pubmed/18599286
    http://www.ncbi.nlm.nih.gov/pubmed/21561347
    http://www.ncbi.nlm.nih.gov/pubmed/25638248
    http://www.ncbi.nlm.nih.gov/pubmed/23213101
    http://www.ncbi.nlm.nih.gov/pubmed/20886240
    http://www.ncbi.nlm.nih.gov/pubmed/20030832
    http://www.ncbi.nlm.nih.gov/pubmed/27914467
    http://www.ncbi.nlm.nih.gov/pubmed/19695956
    http://www.ncbi.nlm.nih.gov/pubmed/24127333
    http://www.ncbi.nlm.nih.gov/pubmed/25207767
    http://www.ncbi.nlm.nih.gov/pubmed/27247222
    http://www.ncbi.nlm.nih.gov/pubmed/28399388
    http://www.ncbi.nlm.nih.gov/pubmed/21969517
    http://www.ncbi.nlm.nih.gov/pubmed/24131140
    http://www.ncbi.nlm.nih.gov/pubmed/29791286
    http://www.ncbi.nlm.nih.gov/pubmed/25311306
    http://www.ncbi.nlm.nih.gov/pubmed/24902940
    http://www.ncbi.nlm.nih.gov/pubmed/23341367
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