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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multi-center study of BYM338 for treatment of cachexia in patients with stage IV non-small cell lung cancer or stage III/IV adenocarcinoma of the pancreas

    Summary
    EudraCT number
    		 2010-024342-30
    Trial protocol
    		 GB   LT  
    Global end of trial date
    24 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    16 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CBYM338X2202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01433263
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    24 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the preliminary efficacy of a single intravenous i.v. dose of BYM338 in increasing thigh muscle volume (TMV) as assessed by Magnetic Resonance Imaging (MRI) compared to placebo.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    Lithuania: 3
    Country: Number of subjects enrolled
    Romania: 13
    Worldwide total number of subjects
    57
    EEA total number of subjects
    23
    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)
    57
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Core Phase single dose BYM338 30mg/kg i.v. active or placebo with 8week followup. Followup phase started Week 8 & patients on placebo in the Core Phase were given BYM338 & patients on BYM338 in Core Phase continued to be followed for an additional 8 weeks. Late BYM338 are patients who received Placebo during Core Phase and then BYM338 after Week 8.

    Pre-assignment
    Screening details
    		 Core Phase single dose BYM338 30mg/kg i.v. active or placebo with 8week followup. Followup phase started Week 8 & patients on placebo in the Core Phase were given BYM338 & patients on BYM338 in Core Phase continued to be followed for an additional 8 weeks. Late BYM338 are patients who received Placebo during Core Phase and then BYM338 after Week 8.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 30mg/kg BYM338
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    BYM338
    Investigational medicinal product code
    BYM338
    Other name
    Bimagrumab
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    single dose BYM338 30 mg/kg i.v. lyophilized powder for injection

    Arm title
    		 Placebo / late 30mg/kg BYM338
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match BYM338
    Investigational medicinal product code
    BYM338
    Other name
    Placebo
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    single dose Placebo to match BYM338 i.v.

    Number of subjects in period 1
    		30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Started
    29
    28
    Completed
    10
    16
    Not completed
    19
    12
         Adverse event, serious fatal
    5
    3
         Consent withdrawn by subject
    10
    7
         Adverse event, non-fatal
    3
    1
         Protocol Deviation
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    30mg/kg BYM338
    Reporting group description
    		 -

    Reporting group title
    Placebo / late 30mg/kg BYM338
    Reporting group description
    		 -

    Reporting group values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338 Total
    Number of subjects
    		 29 28 57
    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)
    		 17 14 31
        From 65-84 years
    		 12 14 26
        85 years and over
    		 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 62.8 ( 10.17 ) 61.5 ( 10.74 ) -
    Gender, Male/Female
    Units: participants
        Male
    		 20 22 42
        Female
    		 9 6 15

    End points

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    End points reporting groups
    Reporting group title
    30mg/kg BYM338
    Reporting group description
    		 -

    Reporting group title
    Placebo / late 30mg/kg BYM338
    Reporting group description
    		 -

    Primary: Percentage Change from Baseline of Thigh Muscle Volume (TMV) by MRI Scan at week 8

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    End point title
    		 Percentage Change from Baseline of Thigh Muscle Volume (TMV) by MRI Scan at week 8
    End point description
    Thigh Muscle Volume (TMV) change was evaluated by a responder analysis. Patients whose loss of muscle TMV by MRI was no more than or equal to 2% at Week 8 was considered responders.
    End point type
    Primary
    End point timeframe
    Baseline, week 8
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    15
    22
    Units: Percentage Change of TMV
        arithmetic mean (standard deviation)
    2 ( 8.094 )
    0.65 ( 8.239 )
    Statistical analysis title
    		 % Change from Baseline of TMV by MRI Scan week 8
    Comparison groups
    30mg/kg BYM338 v Placebo / late 30mg/kg BYM338
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.541
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Percentage Change in body weight from baseline at week 7 and week 9

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    End point title
    		 Percentage Change in body weight from baseline at week 7 and week 9
    End point description
    Percentage Change in body weight from baseline in killograms (kg) at week 7 and week 9
    End point type
    Secondary
    End point timeframe
    Baseline, Week 7 and Week 9
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    29
    28
    Units: Percent Change of Weight (kg)
    arithmetic mean (standard deviation)
        Week 7 (n= 15, 17)
    -3.3 ( 5.035 )
    -0.68 ( 4.457 )
        Week 9 (n=14,16)
    -1.8 ( 7.131 )
    -0.32 ( 3.271 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax)

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    End point title
    		 Maximum Observed Serum Concentration (Cmax)
    End point description
    Blood samples for pharmacokinetic (PK) evaluation were drawn on Day 1 30mg/kg BYM338 (Core)or week 8 Late 30mg/kg BYM338 (when placebo subjects were rolled over to active). PK parameters were calculated from plasma concentration-time data using non-compartmental methods.
    End point type
    Secondary
    End point timeframe
    Day 1 and Week 8
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    29
    14
    Units: ng/ml
        arithmetic mean (standard deviation)
    422 ( 142 )
    408 ( 78.4 )
    No statistical analyses for this end point

    Secondary: Time to Reach the Maximum Concentration After Drug Administration (Tmax)

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    End point title
    		 Time to Reach the Maximum Concentration After Drug Administration (Tmax)
    End point description
    Blood samples for pharmacokinetic (PK) evaluation were drawn on Day 1 30mg/kg BYM338 (Core)or week 8 Late 30mg/kg BYM338 (when placebo subjects were rolled over to active). Tmax was directly determined from the raw serum concentration-time data.
    End point type
    Secondary
    End point timeframe
    Day 1 and Week 8
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    29
    14
    Units: hr
        median (inter-quartile range (Q1-Q3))
    2.05 (1.83 to 3.92)
    2.22 (2 to 4)
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in total lean body mass (LBM) by Dual-Energy X-ray Absorptiometery (DXA) compared to placebo: at week 8

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    End point title
    		 Percentage Change from Baseline in total lean body mass (LBM) by Dual-Energy X-ray Absorptiometery (DXA) compared to placebo: at week 8
    End point description
    total lean body mass (LBM) is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(LBM at Visit - LBM at Baseline) / LBM at Baseline] * 100.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    19
    22
    Units: Percentage Change in LBM
        arithmetic mean (standard deviation)
    4.97 ( 7.537 )
    2.41 ( 4.625 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline of Bone Mineral Density (BMD) by Dual-Energy X-ray Absorptiometery (DXA) compared to placebo at week 8

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    End point title
    		 Percentage Change from Baseline of Bone Mineral Density (BMD) by Dual-Energy X-ray Absorptiometery (DXA) compared to placebo at week 8
    End point description
    Bone Mineral Density (BMD)is measured by dual energy x-ray absorptiometry (DXA).Percent Change = [(BMD at Visit - BMD at Baseline) / BMD at Baseline] * 100.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 8
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    19
    22
    Units: Percentage Change in BMD
        arithmetic mean (standard deviation)
    0.51 ( 3.712 )
    0.14 ( 4.14 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) number of steps taken compared to placebo at week 4 and 7

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    End point title
    		 Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) number of steps taken compared to placebo at week 4 and 7
    End point description
    Each patient was required to wear the ActivPal™ for a span of 6 days at Week 4 and Week 7 for patient home activity recording. The ActivPal™ was given to patients in clinic to wear for 6 consecutive days. The ActivPAL™ records periods spent sitting, standing and walking, sit-to-stand transitions, step count and rate of stepping (cadence) over a maximum period of 10 days with a fully charged new battery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 7
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    27
    28
    Units: percentage change in number of steps
    arithmetic mean (standard deviation)
        Week 4 (n=18, 23)
    917.78 ( 3720.491 )
    63.59 ( 130.913 )
        Week 7 (n=13, 22)
    -17.37 ( 80.35 )
    35.8 ( 119.486 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) Time Sedentary taken compared to placebo at week 4 and 7

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    End point title
    		 Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) Time Sedentary taken compared to placebo at week 4 and 7
    End point description
    Each patient was required to wear the ActivPal™ for a span of 6 days at Week 4 and Week 7 for patient home activity recording. The ActivPal™ was given to patients in clinic to wear for 6 consecutive days. The ActivPAL™ records periods spent sitting, standing and walking, sit-to-stand transitions, step count and rate of stepping (cadence) over a maximum period of 10 days with a fully charged new battery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 7
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    27
    28
    Units: percentage change in time (minutes)
    arithmetic mean (standard deviation)
        Week 4 (n=18, 23)
    -0.05 ( 10.049 )
    52.25 ( 207.403 )
        Week 7 (n=13, 22)
    107.85 ( 280.791 )
    60.25 ( 222.366 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) Time Standing compared to placebo at week 4 and 7

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    End point title
    		 Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) Time Standing compared to placebo at week 4 and 7
    End point description
    Each patient was required to wear the ActivPal™ for a span of 6 days at Week 4 and Week 7 for patient home activity recording. The ActivPal™ was given to patients in clinic to wear for 6 consecutive days. The ActivPAL™ records periods spent sitting, standing and walking, sit-to-stand transitions, step count and rate of stepping (cadence) over a maximum period of 10 days with a fully charged new battery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 7
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    27
    28
    Units: percentage change in time (minutes)
    arithmetic mean (standard deviation)
        Week 4 (n=18, 23)
    1.82 ( 78.364 )
    38.17 ( 111.361 )
        Week 7 (n=13, 22)
    41.9 ( 251.291 )
    23.76 ( 99.268 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) Time Stepping compared to placebo at week 4 and 7

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    End point title
    		 Percentage Change from Baseline of physical activity levels (using the ActivPAL™ device) Time Stepping compared to placebo at week 4 and 7
    End point description
    Each patient was required to wear the ActivPal™ for a span of 6 days at Week 4 and Week 7 for patient home activity recording. The ActivPal™ was given to patients in clinic to wear for 6 consecutive days. The ActivPAL™ records periods spent sitting, standing and walking, sit-to-stand transitions, step count and rate of stepping (cadence) over a maximum period of 10 days with a fully charged new battery.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 7
    End point values
    		 30mg/kg BYM338 Placebo / late 30mg/kg BYM338
    Number of subjects analysed
    27
    28
    Units: percentage change in time (minutes)
    arithmetic mean (standard deviation)
        Week 4 (n=18, 22)
    1446.69 ( 6011.324 )
    85.3 ( 159.949 )
        Week 7 (n=13, 21)
    -31.64 ( 67.18 )
    33.39 ( 129.218 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Core - 30 mg/kg BYM338
    Reporting group description
    		 Core - 30 mg/kg BYM338

    Reporting group title
    Core - Placebo
    Reporting group description
    		 Core - Placebo

    Reporting group title
    Follow-up - 30 mg/kg BYM338
    Reporting group description
    		 Follow-up - 30 mg/kg BYM338

    Reporting group title
    Follow-up - Placebo
    Reporting group description
    		 Follow-up - Placebo

    Reporting group title
    Follow-up - 30mg/kg BYM338 Late
    Reporting group description
    		 Follow-up - 30mg/kg BYM338 Late

    Serious adverse events
    		 Core - 30 mg/kg BYM338 Core - Placebo Follow-up - 30 mg/kg BYM338 Follow-up - Placebo Follow-up - 30mg/kg BYM338 Late
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 29 (62.07%)
    4 / 28 (14.29%)
    7 / 19 (36.84%)
    1 / 3 (33.33%)
    7 / 21 (33.33%)
         number of deaths (all causes)
    6
    1
    4
    0
    3
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    6 / 29 (20.69%)
    0 / 28 (0.00%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Tumour pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angiopathy
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dilatation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Core - 30 mg/kg BYM338 Core - Placebo Follow-up - 30 mg/kg BYM338 Follow-up - Placebo Follow-up - 30mg/kg BYM338 Late
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 29 (65.52%)
    19 / 28 (67.86%)
    12 / 19 (63.16%)
    2 / 3 (66.67%)
    13 / 21 (61.90%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    2
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 28 (10.71%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    7
    1
    0
    1
    Fatigue
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 28 (10.71%)
    4 / 19 (21.05%)
    1 / 3 (33.33%)
    1 / 21 (4.76%)
         occurrences all number
    6
    4
    4
    1
    1
    Asthenia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haemoptysis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    0
    1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rales
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    0
    0
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    1
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    2
    0
    0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Laceration
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    0
    1
    1
    Headache
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    0
    0
    2
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Myoclonus
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    0
    0
    3
    Tremor
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 29 (13.79%)
    6 / 28 (21.43%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    3 / 21 (14.29%)
         occurrences all number
    4
    6
    2
    1
    4
    Neutropenia
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 28 (10.71%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    6
    2
    0
    3
    Leukopenia
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    4
    2
    1
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    2
    1
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 28 (10.71%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    3
    0
    0
    1
    Ascites
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    1 / 19 (5.26%)
    1 / 3 (33.33%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    1
    1
    1
    Dysphagia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 28 (10.71%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    5
    3
    1
    0
    7
    Constipation
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    3
    0
    Nausea
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    5
    1
    0
    0
    2
    Stomatitis
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 28 (10.71%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    3
    2
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    1
    0
    0
    3
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 28 (7.14%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    0
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Bladder irritation
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Infections and infestations
    Gingival infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 28 (7.14%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Septic shock
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 28 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    0
    0
    0
    1
    Dehydration
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 28 (7.14%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 28 (3.57%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Lactic acidosis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Malnutrition
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 28 (3.57%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2011
    Amendment 1 : Revision of Study Design: The study will consist of a Core period, an Open Label Follow-up period, and a Vital Status follow-up period. The Core period will be unchanged with a single dose of BYM338 or placebo at Visit 3. Total duration of the Core period will be 8 weeks. The open-label Extension period will be removed. An eight week open-label treatment/Follow up period will be added: At Visit 8, week 11 a single dose of BYM338 will be offered to all patients who received placebo at Visit 3. Patients who received active drug at Visit 3 will be followed for an additional 8 weeks (total of 16 weeks), but will NOT receive any additional doses of BYM338. Revision of the following Inclusion #3 & 4 and Exclusion #2, 3, 4, 6 Criteria Inclusion #3: Eliminate requirement for 4 weeks of stable 2nd line chemotherapy for pancreatic cancer. Patients must be tolerating chemotherapy with respect to nausea/vomiting and dietary intake before starting study drug, without specifying a time frame. Inclusion #4: Define “simple starvation.” Add a provision to include: In patients with 2+ or greater pitting edema of the legs, documented weight loss > 2% over 4 weeks, not due to diuretic therapy, is acceptable for inclusion. Exclusion #2: Clarify radiation that is excluded for 4 weeks refers only to radiation of the soft tissues of the chest, abdomen, or brain. Exclusion #3: Add “uncontrolled pain” after steatorrhea. Exclusion #4: Add “uncontrolled” in front of exocrine pancreas dysfunction. Exclusion #6: Delete including major depression. Delete Food Frequency Questionnaire (FFQ) and food diary; replace with 2-day Food Record. Delete requirement of MRI of primary tumor. CT will be allowed for primary tumor progression imaging. MRI will remain the method used for measuring TMV. Add: Tumor progression will be followed using RECIST criteria. Safety labs (hematology, coagulations, chemistry) will be measured by local laboratories,
    25 Jul 2011
    Amendment 2 : The protocol is being amended to address comments from a Health Authority in addition to updating the text for a serious adverse event, provide clarifications and correct minor issues. Revision of Serious Adverse Event text: The text in amendment 1 stated the SAE occurred 4 weeks after dosing. The text has been updated after the investigator updated the SAE report. The Human Pharmacokinetic data was updated to reflect data from a recent Pharmacokinetic an alysis. Inclusion of “maintenance therapy” was added to inclusion criteria #3. At some centers, patients are maintained on a chemotherapeutic regimen if they demonstrate partial response or stable disease; to allow such patients to participate in this study, we are amending the protocol to include this approach as "maintenance (chemo) therapy".Inclusion criteria #5, “unintentional” added before weight loss Visit window for week 8 post dose is +/- 7 days to allow for more flexibility.
    06 Dec 2011
    Amendment 3: The purpose of this amendment is to: 1. Incorporate additional monitoring measures based on Adverse events observed with a compound with a related mechanism of action (supine and standing blood pressure and more specific physical examination) 2. Extend the timeframe for required use of highly effective contraception for women of child-bearing potential to 14 weeks from the previously mandated 8 weeks after stopping treatment, based on a new half-life calculation 3. Correct minor inconsistencies in the document and update information, i.e. serious adverse event information updated.
    07 Mar 2012
    Amendment 4: The purpose of this amendment is to: To provide clarity on inclusion criteria for lines of chemotherapy for NSCLC and pancreatic patients, based on feedback from active investigators. Available chemotherapeutic agents have been used in different combination and in varying orders depending on the judgement of treating oncologist and tumor response. As a result of longer survival of cancer patients there is a need for a more prolonged and aggressive use of chemtherapeutic agents occasionally known as 3rd or 4th line of therapy In addition, cancer cachexia has been usually manifested in advanced cases with 3rd or 4th line of therapies. In order to capture the appropriate population for this study with the proper weight loss and expected survival, related inclusion criteria have been revised. Correct the timeframe for capturing Serious Adverse Events (SAE’s) from 60 days post dose to 30 days post End of Study (EOS) visit. Remove the blood draw for pharmacogenomics at screening. Clarify windows for the study visits to allow for increased flexibility for the sites. Correct inconsistencies in the document and update information, i.e. Serious Adverse Event information updated.
    25 Sep 2012
    Amendment 5: The primary purpose of this amendment is to introduce an internal Data Monitoring Committee (DMC) separate from the BYM338 project team, which is being implemented in all new and ongoing phase 1 and 2a studies with BYM338. This DMC is being introduced at the request of the US FDA because of the new mode of action of BYM338, for which the safety profile is not fully characterized, and because of safety concerns observed by FDA with a non-Novartis molecule with a similar mode of action.
    30 Jul 2013
    Amendment 6: The purpose of this amendment is to address the administrative inconsistencies and to allow for additional interim analyses for decision-making purposes if needed.
    10 Mar 2014
    Amendment 7: In the original protocol, the review of previous concomitant medications was limited to 8 weeks prior to the start of the study. However, it has been recognized that knowledge of concomitant medication administration (e.g., chemotherapy) given > 8 weeks prior to study start provides a fuller context from which to interpret responses to treatment in this study. Therefore the protocol is being amended to allow for collection of information on concomitant medications from the time of diagnosis of the current disease stage.

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

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