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    Clinical Trial Results:
    Prospective Randomized Multicenter Phase II Trial to Investigate Intensified Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Cancer

    Summary
    EudraCT number
    		 2013-004796-12
    Trial protocol
    		 DE  
    Global end of trial date
    19 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Apr 2022
    First version publication date
    30 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AIO-PAK-0113
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02125136
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AIO-Studien-gGmbH
    Sponsor organisation address
    Kuno-Fischer-Str. 8, Berlin, Germany, 14057
    Public contact
    AIO-Studien-gGmbH, AIO-Studien-gGmbH, 0049 30322932931, info@aio-studien-ggmbh.de
    Scientific contact
    AIO-Studien-gGmbH, AIO-Studien-gGmbH, 0049 30322932931, info@aio-studien-ggmbh.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of intensified neoadjuvant chemotherapy on conversion rate to resetcability in LAPC.
    Protection of trial subjects
    This study was planned, analyzed and conducted according to the study protocol and in accordance with the International Conference on Harmonization (ICH) ‚Guideline for Good Clinical Practice E6(R1)‘, CPMP/ICH/135/95, based on the principles of the Declaration of Helsinki (1964) and its October 1996 amendment (Somerset West, South Africa). The study was duly conducted in compliance with the German Arzneimittelgesetz (AMG; German Drug Law), and the corresponding Directive 2001/20/EC. Subjects were fully informed regarding all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 168
    Worldwide total number of subjects
    168
    EEA total number of subjects
    168
    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)
    99
    From 65 to 84 years
    69
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment period of this clinical trial lasted from 18 November 2014 (first patient registered) to 27 April 2018 (last patient registered). Patients were recruited to 28 trial centres in Germany.

    Pre-assignment
    Screening details
    		 A total of 168 patients were screened for the clinical trial, 165 of whom received at least one dose of non-randomized neoadjuvant induction therapy.

    Period 1
    Period 1 title
    Non-randomized induction
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 nab-Pac/Gem induction treatment (non-randomized)
    Arm description
    		 Prior to randomization, all study participants received two cycles of induction treatment with nab-paclitaxel and gemcitabine.
    Arm type
    		 SoC induction treatment

    Investigational medicinal product name
    nab-Paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received 125 mg/m^2 on days 1, 8, and 15 of a 28-day cycle as intravenous infusion over 30 minutes.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered at a dose of 1000 mg/m^2 on days 1, 8, and 15 of a 28-day cycle as intravenous infusion over a period of 30 minutes.

    Number of subjects in period 1
    		nab-Pac/Gem induction treatment (non-randomized)
    Started
    168
    Completed
    130
    Not completed
    38
         Consent withdrawn by subject
    3
         Patient's wish
    3
         Adverse event
    4
         Progressive disease
    22
         Protocol deviation
    5
         not specified
    1
    Period 2
    Period 2 title
    Randomized treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A - nab-Pac/Gem
    Arm description
    		 Patients randomized to Arm A received two additional cycles of induction treatment with nab-paclitaxel and gemcitabine. Cycle length of 28 days was maintained.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    nab-paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received 125 mg/m^2 on days 1, 8, and 15 of a 28-day cycle as intravenous infusion over 30 minutes.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered at a dose of 1000 mg/m^2 on days 1, 8, and 15 of a 28-day cycle as intravenous infusion over a period of 30 minutes.

    Arm title
    		 Arm B - FOLFIRINOX
    Arm description
    		 Patients randomized to Arm B switched their induction treatment after two cycles of nab-paclitaxel plus gemcitabine to FOLFIRINOX. The latter was administered for four cycles of 14 days. 66 patients were randomized to Arm B. Of these, 61 received randomized treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin was given at 85 mg/m^2 as a 2-hour i.v. infusion.

    Investigational medicinal product name
    Folinic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Folinic acid was given at 400 mg/m^2 as a 2-hour i.v. infusion.

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Irinotecan was given at 180 mg/m^2 as a 90-minute i.v. infusion (application through a Y-connector parallel to infusion of folinic acid and 30 minutes after start of folinic acid was possible).

    Investigational medicinal product name
    5-Fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-Fluorouracil 400 mg/m^2 was administered as i.v. bolus, followed by a continuous i.v. infusion of fluorouracil at 2400 mg/m^2 over 46 hours starting on Day 1.

    Number of subjects in period 2
    		Arm A - nab-Pac/Gem Arm B - FOLFIRINOX
    Started
    64
    66
    Neoadjuvant chemotherapy
    60
    51
    Explorative laparotomy
    40
    42
    Resection in curative intent
    23
    29
    Adjuvant chemotherapy
    16
    21
    Completed
    12
    18
    Not completed
    52
    48
         Physician decision
    9
    5
         Screening failure
    -
    1
         Consent withdrawn/patient's wish
    9
    11
         Death
    1
    1
         Other
    1
    -
         Adverse event
    6
    10
         Suspected progression
    -
    1
         Progressive disease
    10
    6
         No resectability/no resection
    15
    13
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Non-randomized induction
    Reporting group description
    		 This reporting group contains all enrolled patients. All but 3 of these received non-randomized induction treatment.

    Reporting group values
    		 Non-randomized induction Total
    Number of subjects
    		 168 168
    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)
    		 0 0
        From 65-84 years
    		 99 99
        85 years and over
    		 69 69
    Gender categorical
    Units: Subjects
        Female
    		 81 81
        Male
    		 87 87

    End points

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    End points reporting groups
    Reporting group title
    nab-Pac/Gem induction treatment (non-randomized)
    Reporting group description
    		 Prior to randomization, all study participants received two cycles of induction treatment with nab-paclitaxel and gemcitabine.
    Reporting group title
    Arm A - nab-Pac/Gem
    Reporting group description
    		 Patients randomized to Arm A received two additional cycles of induction treatment with nab-paclitaxel and gemcitabine. Cycle length of 28 days was maintained.

    Reporting group title
    Arm B - FOLFIRINOX
    Reporting group description
    		 Patients randomized to Arm B switched their induction treatment after two cycles of nab-paclitaxel plus gemcitabine to FOLFIRINOX. The latter was administered for four cycles of 14 days. 66 patients were randomized to Arm B. Of these, 61 received randomized treatment.

    Subject analysis set title
    EFF-res
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The EFF analysis set contains all subjects who received at least one dose of randomized study treatment. The EFF-res set contains all subjects of the EFF set who underwent tumor resection.

    Primary: Resection rate

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    End point title
    		 Resection rate
    End point description
    End point type
    Primary
    End point timeframe
    The primary endpoint was the rate of patients who underwent pancreatic resection in curative intention based on the evaluation during exploratory laparotomy after intensified neoadjuvant chemotherapy.
    End point values
    		 Arm A - nab-Pac/Gem Arm B - FOLFIRINOX
    Number of subjects analysed
    64
    66
    Units: Resected patients
    23
    29
    Statistical analysis title
    		 Resection rate
    Statistical analysis description
    With regard to the conversion to resectability, patients in whom (after randomization) resectability with curative intent was not achieved were evaluated as unresectable.
    Comparison groups
    Arm B - FOLFIRINOX v Arm A - nab-Pac/Gem
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3757
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.716
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.354
         upper limit
    		 1.448

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    For each patient who was not known to have had a progression or death as of the data extract date, the PFS time was censored at the date of the patient’s last recorded study visit or follow-up. Patients were observed for a median duration of 13.8 months (mean 16.0 ± 10.9 months, minimum 0.3, maximum 55.2 months).
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) is the time from the first day of the first cycle of neoadjuvant chemotherapy to the date of objective disease progression or to death of any cause.
    End point values
    		 Arm A - nab-Pac/Gem Arm B - FOLFIRINOX
    Number of subjects analysed
    64
    66
    Units: months
        number (confidence interval 95%)
    10.2 (8.4 to 11.8)
    12.3 (9.6 to 13.8)
    Statistical analysis title
    		 Progression-free survival
    Comparison groups
    Arm A - nab-Pac/Gem v Arm B - FOLFIRINOX
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.145
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.745
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.501
         upper limit
    		 1.109

    Secondary: Relapse-free survival

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    End point title
    		 Relapse-free survival
    End point description
    For each patient who was not known to have had a relapse as of the data extract cut-off date, the time to relapse was censored at the date of the patient’s last recorded study visit or follow-up.
    End point type
    Secondary
    End point timeframe
    Relapse-free survival (RFS) is the time from the first day after pancreatic resection to the date of relapse, defined as either local relapse of pancreatic cancer or occurrence of distant metastases, during or after adjuvant chemotherapy.
    End point values
    		 Arm A - nab-Pac/Gem Arm B - FOLFIRINOX EFF-res
    Number of subjects analysed
    23
    29
    52
    Units: months
        median (confidence interval 95%)
    7.4 (5.9 to 12.2)
    9.9 (7.9 to 10.8)
    8.2 (7.4 to 10.6)
    Statistical analysis title
    		 Relapse-free survival
    Comparison groups
    Arm B - FOLFIRINOX v Arm A - nab-Pac/Gem
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.696
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.883
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.473
         upper limit
    		 1.696

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Restaging 2 was performed at the end of randomized neoadjuvant chemotherapy treatment: Cycle 2 Day 24± 3 days for nab-Pac/Gem or Cycle 4 Day 10 ± 3 days for FOLFIRINOX.
    End point type
    Secondary
    End point timeframe
    The objective response rate (ORR) is defined as the rate of patients achieving partial response (PR) or complete response (CR) according to RECIST version 1.1 criteria at restaging 2.
    End point values
    		 Arm A - nab-Pac/Gem Arm B - FOLFIRINOX
    Number of subjects analysed
    64
    66
    Units: Number of patients with CR or PR
    14
    11
    Statistical analysis title
    		 Objective response rate
    Comparison groups
    Arm B - FOLFIRINOX v Arm A - nab-Pac/Gem
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5087
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.582
         upper limit
    		 3.367

    Secondary: Disease control rate

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    End point title
    		 Disease control rate
    End point description
    Restaging 2 was performed at the end of randomized neoadjuvant chemotherapy treatment: Cycle 2 Day 24± 3 days for nab-Pac/Gem or Cycle 4 Day 10 ± 3 days for FOLFIRINOX.
    End point type
    Secondary
    End point timeframe
    The disease control rate (DCR) is defined as the rate of patients achieving partial response (PR) or complete response (CR) according to RECIST version 1.1 criteria at restaging 2.
    End point values
    		 Arm A - nab-Pac/Gem Arm B - FOLFIRINOX
    Number of subjects analysed
    64
    66
    Units: Patients with CR, PR or SD
    52
    47
    Statistical analysis title
    		 Disease control rate
    Comparison groups
    Arm A - nab-Pac/Gem v Arm B - FOLFIRINOX
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2187
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.752
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.769
         upper limit
    		 3.991

    Secondary: Rate of R0/R1 resection according to CRM concept

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    End point title
    		 Rate of R0/R1 resection according to CRM concept
    End point description
    End point type
    Secondary
    End point timeframe
    Rates of R0/R1 resections according to the circumferential resection margin (CRM) concept
    End point values
    		 Arm A - nab-Pac/Gem Arm B - FOLFIRINOX EFF-res
    Number of subjects analysed
    23
    29
    52
    Units: Resected patients
        R0 wide
    6
    13
    19
        R0 narrow
    10
    7
    17
        R0
    1
    0
    1
        R1
    6
    9
    15
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    For each patient for whom it was not known whether he/she was still alive at the data extract date, the time to death of any cause was censored at the date of the patient’s last recorded study visit or follow-up.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) is the time from the first day of the first cycle of neoadjuvant chemotherapy to the date of death of any cause.
    End point values
    		 Arm A - nab-Pac/Gem Arm B - FOLFIRINOX
    Number of subjects analysed
    64
    66
    Units: months
        median (confidence interval 95%)
    18.8 (16.0 to 22.2)
    20.7 (13.8 to 27.4)
    Statistical analysis title
    		 Overall survival
    Comparison groups
    Arm A - nab-Pac/Gem v Arm B - FOLFIRINOX
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6213
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from first administration of any IMP to 28 days after the last dose of any IMP. The time interval from date of exploratory laparotomy / pancreatic resection until 14 days before first administration of adjuvant chemotherapy was excluded from reporting.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Pts. with non-randomized induction treatment only
    Reporting group description
    		 This group reports on patients who received only non-randomized induction treatment with nab-paclitaxel/gemcitabine and did not proceed to the randomized phase of induction treatment.

    Reporting group title
    Treatment Arm A
    Reporting group description
    		 -

    Reporting group title
    Treatment Arm B
    Reporting group description
    		 -

    Serious adverse events
    		 Pts. with non-randomized induction treatment only Treatment Arm A Treatment Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 35 (68.57%)
    28 / 64 (43.75%)
    33 / 66 (50.00%)
         number of deaths (all causes)
    0
    1
    2
         number of deaths resulting from adverse events
    0
    1
    2
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 64 (3.13%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 64 (1.56%)
    4 / 66 (6.06%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 64 (4.69%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Complex regional pain syndrome
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical haemolytic uraemic syndrome
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 64 (3.13%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 64 (1.56%)
    5 / 66 (7.58%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 64 (1.56%)
    4 / 66 (6.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    6 / 35 (17.14%)
    6 / 64 (9.38%)
    8 / 66 (12.12%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 8
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    4 / 35 (11.43%)
    4 / 64 (6.25%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 64 (3.13%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 64 (3.13%)
    2 / 66 (3.03%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 64 (3.13%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 64 (3.13%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pts. with non-randomized induction treatment only Treatment Arm A Treatment Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 35 (97.14%)
    64 / 64 (100.00%)
    61 / 66 (92.42%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 64 (4.69%)
    8 / 66 (12.12%)
         occurrences all number
    3
    7
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 64 (3.13%)
    7 / 66 (10.61%)
         occurrences all number
    3
    3
    11
    C-reactive protein increased
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 64 (4.69%)
    4 / 66 (6.06%)
         occurrences all number
    1
    3
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 35 (8.57%)
    5 / 64 (7.81%)
    6 / 66 (9.09%)
         occurrences all number
    3
    5
    7
    Neutrophil count decreased
         subjects affected / exposed
    1 / 35 (2.86%)
    7 / 64 (10.94%)
    9 / 66 (13.64%)
         occurrences all number
    1
    16
    16
    Platelet count decreased
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 64 (6.25%)
    5 / 66 (7.58%)
         occurrences all number
    6
    4
    8
    Weight decreased
         subjects affected / exposed
    8 / 35 (22.86%)
    15 / 64 (23.44%)
    14 / 66 (21.21%)
         occurrences all number
    8
    15
    17
    White blood cell count decreased
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 64 (3.13%)
    6 / 66 (9.09%)
         occurrences all number
    0
    5
    12
    Nervous system disorders
    Cholinergic syndrome
         subjects affected / exposed
    0 / 35 (0.00%)
    0 / 64 (0.00%)
    5 / 66 (7.58%)
         occurrences all number
    0
    0
    6
    Dizziness
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 64 (4.69%)
    2 / 66 (3.03%)
         occurrences all number
    0
    5
    3
    Dysgeusia
         subjects affected / exposed
    2 / 35 (5.71%)
    12 / 64 (18.75%)
    17 / 66 (25.76%)
         occurrences all number
    2
    12
    20
    Headache
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 64 (4.69%)
    5 / 66 (7.58%)
         occurrences all number
    0
    3
    6
    Neuropathy peripheral
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    4 / 66 (6.06%)
         occurrences all number
    0
    1
    6
    Paraesthesia
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 64 (6.25%)
    10 / 66 (15.15%)
         occurrences all number
    0
    4
    11
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    4 / 66 (6.06%)
         occurrences all number
    0
    1
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 64 (6.25%)
    5 / 66 (7.58%)
         occurrences all number
    0
    5
    6
    Polyneuropathy
         subjects affected / exposed
    2 / 35 (5.71%)
    19 / 64 (29.69%)
    17 / 66 (25.76%)
         occurrences all number
    2
    26
    18
    Sleep disorder
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 64 (6.25%)
    2 / 66 (3.03%)
         occurrences all number
    0
    4
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 35 (28.57%)
    16 / 64 (25.00%)
    10 / 66 (15.15%)
         occurrences all number
    11
    29
    16
    Leukopenia
         subjects affected / exposed
    5 / 35 (14.29%)
    27 / 64 (42.19%)
    16 / 66 (24.24%)
         occurrences all number
    6
    53
    29
    Neutropenia
         subjects affected / exposed
    6 / 35 (17.14%)
    32 / 64 (50.00%)
    25 / 66 (37.88%)
         occurrences all number
    7
    56
    46
    Thrombocytopenia
         subjects affected / exposed
    5 / 35 (14.29%)
    17 / 64 (26.56%)
    16 / 66 (24.24%)
         occurrences all number
    5
    28
    30
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 35 (25.71%)
    31 / 64 (48.44%)
    33 / 66 (50.00%)
         occurrences all number
    14
    50
    58
    Influenza like illness
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 64 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    0
    5
    0
    Mucosal inflammation
         subjects affected / exposed
    2 / 35 (5.71%)
    13 / 64 (20.31%)
    12 / 66 (18.18%)
         occurrences all number
    3
    16
    18
    Oedema
         subjects affected / exposed
    1 / 35 (2.86%)
    7 / 64 (10.94%)
    6 / 66 (9.09%)
         occurrences all number
    1
    8
    8
    Oedema peripheral
         subjects affected / exposed
    4 / 35 (11.43%)
    16 / 64 (25.00%)
    11 / 66 (16.67%)
         occurrences all number
    4
    18
    13
    Pain
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 64 (3.13%)
    6 / 66 (9.09%)
         occurrences all number
    0
    2
    6
    Pyrexia
         subjects affected / exposed
    5 / 35 (14.29%)
    17 / 64 (26.56%)
    13 / 66 (19.70%)
         occurrences all number
    5
    22
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 35 (5.71%)
    9 / 64 (14.06%)
    7 / 66 (10.61%)
         occurrences all number
    4
    9
    9
    Abdominal pain upper
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 64 (6.25%)
    5 / 66 (7.58%)
         occurrences all number
    3
    4
    7
    Constipation
         subjects affected / exposed
    5 / 35 (14.29%)
    20 / 64 (31.25%)
    16 / 66 (24.24%)
         occurrences all number
    6
    26
    22
    Diarrhoea
         subjects affected / exposed
    12 / 35 (34.29%)
    30 / 64 (46.88%)
    27 / 66 (40.91%)
         occurrences all number
    15
    45
    46
    Dyspepsia
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 64 (4.69%)
    5 / 66 (7.58%)
         occurrences all number
    0
    3
    5
    Nausea
         subjects affected / exposed
    12 / 35 (34.29%)
    34 / 64 (53.13%)
    39 / 66 (59.09%)
         occurrences all number
    13
    51
    71
    Stomatitis
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 64 (6.25%)
    7 / 66 (10.61%)
         occurrences all number
    2
    4
    8
    Vomiting
         subjects affected / exposed
    6 / 35 (17.14%)
    14 / 64 (21.88%)
    21 / 66 (31.82%)
         occurrences all number
    7
    20
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    5 / 66 (7.58%)
         occurrences all number
    0
    1
    5
    Dyspnoea
         subjects affected / exposed
    1 / 35 (2.86%)
    5 / 64 (7.81%)
    2 / 66 (3.03%)
         occurrences all number
    1
    5
    3
    Epistaxis
         subjects affected / exposed
    1 / 35 (2.86%)
    8 / 64 (12.50%)
    7 / 66 (10.61%)
         occurrences all number
    1
    10
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    8 / 35 (22.86%)
    29 / 64 (45.31%)
    36 / 66 (54.55%)
         occurrences all number
    8
    32
    40
    Dry skin
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 64 (6.25%)
    4 / 66 (6.06%)
         occurrences all number
    3
    4
    5
    Pruritus
         subjects affected / exposed
    3 / 35 (8.57%)
    0 / 64 (0.00%)
    4 / 66 (6.06%)
         occurrences all number
    3
    0
    4
    Rash
         subjects affected / exposed
    6 / 35 (17.14%)
    10 / 64 (15.63%)
    12 / 66 (18.18%)
         occurrences all number
    7
    11
    19
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences all number
    2
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 64 (3.13%)
    3 / 66 (4.55%)
         occurrences all number
    0
    2
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    3 / 66 (4.55%)
         occurrences all number
    0
    1
    5
    Back pain
         subjects affected / exposed
    0 / 35 (0.00%)
    6 / 64 (9.38%)
    4 / 66 (6.06%)
         occurrences all number
    0
    7
    5
    Bone pain
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 64 (6.25%)
    1 / 66 (1.52%)
         occurrences all number
    0
    4
    1
    Myalgia
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 64 (6.25%)
    0 / 66 (0.00%)
         occurrences all number
    0
    5
    0
    Pain in extremity
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 64 (6.25%)
    2 / 66 (3.03%)
         occurrences all number
    0
    4
    3
    Infections and infestations
    Infection
         subjects affected / exposed
    2 / 35 (5.71%)
    7 / 64 (10.94%)
    2 / 66 (3.03%)
         occurrences all number
    2
    8
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 64 (1.56%)
    7 / 66 (10.61%)
         occurrences all number
    0
    2
    9
    Skin infection
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 64 (0.00%)
    0 / 66 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 35 (28.57%)
    14 / 64 (21.88%)
    19 / 66 (28.79%)
         occurrences all number
    12
    15
    24
    Hypokalaemia
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 64 (4.69%)
    6 / 66 (9.09%)
         occurrences all number
    6
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2015
    New findings in the main effecting frequency of reported adverse events as well as adverse effects (e. g. Sepsis, interstitial pneumonitis, Stevens-Johnson Syndrome, HUS) were adapted to new findings respectively included in the protocol. Furthermore, some modifications in inclusion criteria, screening procedures mainly regarding CT examination (a three-phase contrast-enhanced spiral CT is recommended) and requirements for starting a new cycle of chemotherapy were made. Procedures during Follow-up were amended. More detailed information for management of dose omissions is given. In addition a new way for preparation and administration of nab-paclitaxel is described: due to a comparatively small volume of the nab-paclitaxel infusion, the infusion tube should be rinsed after application. NCCN-Guidelines Pancreatic Adenocarcinoma version 1.2015 is included.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The dropout rate during induction chemotherapy and the surgical conversion rate in the nab-paclitaxel plus gemcitabine group were higher than expected, which probably resulted in an underpowered study.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33338442
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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