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    Clinical Trial Results:
    “Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma”.

    Summary
    EudraCT number
    		 2009-016138-29
    Trial protocol
    		 FR   GB   ES   AT   NL   DE   BE   CZ   IT   GR   IE   PT   PL  
    Global end of trial date
    20 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2018
    First version publication date
    18 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APL-C-001-09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01102426
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharma Mar, S.A.
    Sponsor organisation address
    Avenida de los Reyes, 1 Polígono Industrial "La Mina", Colmenar Viejo, Madrid, Spain, 28770
    Public contact
    Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A. , 34 918466000, clinicaltrials@pharmamar.com
    Scientific contact
    Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit., Pharmamar, S.A., 34 918466000, clinicaltrials@pharmamar.com
    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
    08 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM).
    Protection of trial subjects
    The study was in compliance with ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 All the patients have to receive DXM with or without Plitidepsin. The administration of each study medication was as follows: Arm A: • DXM: 40 mg orally on Day 1, 8, 15 and 22 every four weeks (q4wk) at least one hour before plitidepsin infusion. • Plitidepsin: 5 mg/m2 i.v. diluted to a total volume of 250 mL in 0.9% saline (or 5% glucose) via a central venous catheter (suggested) or diluted to a total volume of 500 mL in 0.9% saline (or 5% glucose) via a peripheral line. Infusion was performed through a pump device over three hours (fixed rate) on Day 1 and 15 q4wk. Arm B: • DXM: 40 mg orally on Day 1, 8, 15 and 22 q4wk. A cycle was defined as a four-week period
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jun 2010
    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
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Austria: 28
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Czech Republic: 33
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Greece: 19
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    New Zealand: 8
    Country: Number of subjects enrolled
    Australia: 37
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Taiwan: 12
    Worldwide total number of subjects
    255
    EEA total number of subjects
    179
    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)
    124
    From 65 to 84 years
    129
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 255 patients were enrolled. 171 Group A (Plitidepsin in combination with DXM) and 84 Group B (DXM alone). Enrolled patients between 29Jun10 and 19May15 (Last randomization). The first dose of the first patient was given on 19May15 and the last dose of the last patient was given on 07Aug17.

    Pre-assignment
    Screening details
    		 IC Signed,Age ≥18,ECOG PS≤2,Life expectancy≥3 mo,Previously diagnosed MM,Relapsed or relapsed and refractory MM between 3&6,Previous bortezomib-containing and lenalidomide containing regimens,Measurable disease,At least 2week washout period since end last therapy,Adequate BM,renal, hepatic&metabolic,Normal LVEF by ECHO/MUGA,negative pregnancy test

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A (plitidepsin plus DXM)
    Arm description
    		 Arm A (plitidepsin plus DXM)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aplidin
    Investigational medicinal product code
    Other name
    Plitidepsin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg/m2 i.v. diluted to a total volume of 250 mL in 0.9% saline(or 5% glucose) via a central venous catheter (suggested) or diluted to a total volume of 500 mL in 0.9% saline (or 5% glucose) via a peripheral line. Infusion was performed through a pump device over three hours (fixed rate) on Day 1 and 15 q4wk.

    Investigational medicinal product name
    DXM
    Investigational medicinal product code
    Dexamethasone
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg orally on Day 1, 8, 15 and 22 every four weeks (q4wk) at least one hour before plitidepsin infusion.

    Arm title
    		 Arm B (DXM alone)
    Arm description
    		 Arm B (DXM alone)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    DXM
    Investigational medicinal product code
    Dexamethasone
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    DXM: 40 mg orally on Day 1, 8, 15 and 22 q4wk.

    Number of subjects in period 1
    		Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Started
    171
    84
    Completed
    0
    0
    Not completed
    171
    84
         Physician decision
    7
    4
         Consent withdrawn by subject
    24
    6
         Toxicity
    15
    3
         Randomized but not treated
    4
    1
         Death
    20
    5
         Other
    22
    10
         Progressive Disease
    79
    18
         Transferred to other arm/group
    -
    37

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (plitidepsin plus DXM)
    Reporting group description
    		 Arm A (plitidepsin plus DXM)

    Reporting group title
    Arm B (DXM alone)
    Reporting group description
    		 Arm B (DXM alone)

    Reporting group values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone) Total
    Number of subjects
    		 171 84 255
    Age categorical
    Years
    Units: Subjects
        Adults (18-64 years)
    		 88 36 124
        From 65-84 years
    		 82 47 129
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        median (full range (min-max))
    		 64.0 (36 to 85) 65.0 (42 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 74 49 123
        Male
    		 97 35 132
    ECOG PS
    PS Performance status
    Units: Subjects
        PS 0
    		 68 31 99
        PS 1
    		 74 42 116
        PS 2
    		 28 11 39
        PS 3
    		 1 0 1
    MM type at diagnosis
    Units: Subjects
        Non Secretory
    		 6 1 7
        Secretory IgA
    		 35 21 56
        Secretory IgD
    		 1 1 2
        Secretory IgG
    		 101 51 152
        Secretory IgM
    		 1 0 1
        Secretory Light chain disease
    		 27 10 37
    Durie-Salmon stage at diagnosis
    Units: Subjects
        Stage A
    		 0 1 1
        Stage IA
    		 21 9 30
        Stage IB
    		 0 2 2
        Stage II
    		 3 1 4
        Stage IIA
    		 44 20 64
        Stage IIB
    		 1 0 1
        Stage III
    		 2 1 3
        Stage IIIA
    		 85 43 128
        Stage IIIB
    		 14 7 21
        Not Durie-Salmon stage at diagnosis
    		 1 0 1
    ISS stage at diagnosis
    Units: Subjects
        Stage I
    		 72 33 105
        Stage II
    		 41 18 59
        Stage III
    		 23 15 38
        Not ISS stage at diagnosis
    		 35 18 53
    Cytogenetic risk group at diagnosis
    NA: not available; ND: not done; UK: unknown.
    Units: Subjects
        Standard risk
    		 34 21 55
        High risk
    		 38 16 54
        NA/ND/UK
    		 99 47 146
    Prior radiotherapy
    Units: Subjects
        Yes
    		 68 35 103
        No
    		 103 49 152
    Hb
    Units: g/dL
        median (full range (min-max))
    		 10.4 (7.0 to 14.6) 10.1 (7.4 to 14.6) -
    Platelets
    Units: 10^9/L
        median (full range (min-max))
    		 140 (11.0 to 517.0) 154 (24.0 to 452.0) -
    CrCL
    creatinine clearance
    Units: mL/min
        median (full range (min-max))
    		 72.9 (21.9 to 252.2) 69.4 (23.0 to 137.0) -
    Time from first diagnosis to randomization
    Units: months
        median (full range (min-max))
    		 71.8 (0.1 to 277.2) 70.0 (19.5 to 178.9) -
    Time from last PD/relapse to first study dose
    PD, Progressive disease
    Units: weeks
        median (full range (min-max))
    		 6.1 (-0.4 to 83.1) 6.4 (1.0 to 101.7) -
    Beta-2 microglobulin
    Units: mg/L
        median (full range (min-max))
    		 4.1 (0.0 to 27.3) 4.2 (0.2 to 65.0) -
    Number of lines of prior systemic therapy
    Units: Lines
        median (full range (min-max))
    		 4 (2 to 6) 4 (3 to 7) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A (plitidepsin plus DXM)
    Reporting group description
    		 Arm A (plitidepsin plus DXM)

    Reporting group title
    Arm B (DXM alone)
    Reporting group description
    		 Arm B (DXM alone)

    Primary: Progression-free Survival (Independent Review Committee)

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    End point title
    		 Progression-free Survival (Independent Review Committee)
    End point description
    The primary study analysis was based on externally assessed PFS data (An external IRC, blinded to treatment arm, assigned a progression or censoring date for each patient based on laboratory data and radiological and bone marrow assessments when required, and evaluation of all relevant clinical information, according to a predefined algorithm) in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD (IMWG criteria) or death due to any cause. If the patient received further antitumor therapy before PD, PFS was censored on the date of the last disease assessment prior to the administration. If the patient was lost to follow-up , the PFS was censored at the date of last valid tumor assessment before the missing evaluations. Event was assigned as the first time a PD is reported without the necessity of its confirmation.
    End point type
    Primary
    End point timeframe
    Overall period - IRC-All Randomized Patients
    End point values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Number of subjects analysed
    171
    84
    Units: months
        median (confidence interval 95%)
    2.6 (1.9 to 3.0)
    1.7 (1.1 to 2.0)
    Statistical analysis title
    		 Arm A compared to Arm B
    Comparison groups
    Arm B (DXM alone) v Arm A (plitidepsin plus DXM)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0054 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.477
         upper limit
    		 0.885
    Notes
    [1] - PFS at 6 months (95% CI): Arm A: 20.0% (13.1-26.9%) vs Arm B: 10.0% (2.0-18.0%); p=0.0618
    [2] - Cox regression: HR p=0.0062

    Secondary: Progression-free Survival (Investigator assessment)

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    End point title
    		 Progression-free Survival (Investigator assessment)
    End point description
    The secondary study analysis was based on Investigator’s assessment PFS data in the ITT efficacy population, defined as all patients randomized to either treatment arm. PFS was calculated from randomization to the first evidence of PD (IMWG criteria) or death due to any cause. If the patient received further antitumor therapy before PD and within the timeframe expected for first follow-up, PFS was censored on the date of the last disease assessment prior to the administration of this antitumor therapy. If the patient was lost to follow-up for the assessment of progression, or had more than one missing follow-up between the date of last tumor assessment and the date of progression, death or further antitumor therapy, the PFS was censored at the date of last valid tumor assessment before the missing evaluations. Event was assigned as the first time a PD is reported without the necessity of its confirmation.
    End point type
    Secondary
    End point timeframe
    Overall period - IA - All Randomized Patients
    End point values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Number of subjects analysed
    171
    84
    Units: months
        median (confidence interval 95%)
    2.9 (2.1 to 3.7)
    1.1 (1.0 to 1.9)
    Statistical analysis title
    		 Arm A compared to Arm B
    Comparison groups
    Arm A (plitidepsin plus DXM) v Arm B (DXM alone)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.512
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.382
         upper limit
    		 0.686
    Notes
    [3] - PFS at 6 months (95% CI): Arm A: 26.4% (19.1-33.7%) vs Arm B: 8.1% (1.9-14.3%); p=0.0002
    [4] - Cox regression HR: p<0.0001

    Secondary: Best Overall Response (Independent Review Committee)

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    End point title
    		 Best Overall Response (Independent Review Committee)
    End point description
    CR; complete response; DXM, dexamethasone; MR; minor response; NE, not evaluable; ORR, overall response rate; P, plitidepsin; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD; stable disease; VGPR, very good partial response.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Number of subjects analysed
    171
    84
    Units: subjects
        VGPR
    2
    0
        PR
    15
    1
        MR
    22
    2
        SD
    43
    21
        PD
    41
    35
        NE
    48
    25
    Statistical analysis title
    		 Overall response rate
    Comparison groups
    Arm A (plitidepsin plus DXM) v Arm B (DXM alone)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [5] - ORR (95% CI): Arm A: 22.8% (16.8-29.8%) vs Arm B: 3.6% (0.7-10.1%); p<0.0001 ORR (excluding MR) (95% CI): Arm A: 9.9% (5.9-15.4%) vs Arm B: 1.2% (0.03-6.5%); p=0.0085

    Secondary: Duration of Response (Independent Review Committee)

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    End point title
    		 Duration of Response (Independent Review Committee)
    End point description
    DR was calculated from the date of first documentation of response to the date of disease progression or death. The same censoring rules described above for PFS calculation were also considered for DR.
    End point type
    Secondary
    End point timeframe
    Overall period - IRC- All Responder Patients
    End point values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Number of subjects analysed
    39 [6]
    3 [7]
    Units: months
        median (confidence interval 95%)
    3.7 (2.7 to 10.5)
    1.8 (1.8 to 5.5)
    Notes
    [6] - Responder Patients
    [7] - Responder Patients
    Statistical analysis title
    		 Arm A compared to Arm B
    Comparison groups
    Arm A (plitidepsin plus DXM) v Arm B (DXM alone)
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.1015 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.384
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.113
         upper limit
    		 1.303
    Notes
    [8] - DR at 6 months (95% CI): Arm A: 41.2% (24.6-57.7%) vs 0.0% (0.0-.%)
    [9] - Cox regression HR: 0.1247

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    OS was defined as the time from the date of randomization to the date of death or last contact
    End point type
    Secondary
    End point timeframe
    Overall period - All Randomized Patients
    End point values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Number of subjects analysed
    171
    84
    Units: months
        median (confidence interval 95%)
    11.6 (9.2 to 16.1)
    8.9 (6.0 to 15.4)
    Statistical analysis title
    		 Arm A compared to Arm B
    Comparison groups
    Arm A (plitidepsin plus DXM) v Arm B (DXM alone)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.1261 [11]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.797
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.596
         upper limit
    		 1.067
    Notes
    [10] - OS at 12 months (95% CI): Arm A: 48.3% (40.4-56.2%) vs Arm B: 42.1% (31.3-52.9%); p=0.3625 OS at 24 months (95% CI): Arm A: 30.8% (23.3-38.3%) vs Arm B: 21.0% (12.0-30.1%); p=0.1037
    [11] - Cox regression HR: p=0.1273

    Secondary: Best Overall Response (Investigator assessment)

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    End point title
    		 Best Overall Response (Investigator assessment)
    End point description
    CR; complete response; DXM, dexamethasone; MR; minor response; NE, not evaluable; ORR, overall response rate; P, plitidepsin; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD; stable disease; VGPR, very good partial resp
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Number of subjects analysed
    171
    84
    Units: subjects
        VGPR
    4
    0
        PR
    16
    1
        MR
    31
    0
        SD
    61
    31
        PD
    37
    39
        NE
    22
    13
    Statistical analysis title
    		 Overall response rate
    Comparison groups
    Arm A (plitidepsin plus DXM) v Arm B (DXM alone)
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [12] - ORR (95% CI): Arm A: 29.8% (23.1-37.3%) vs Arm B: 1.2% (0.03-6.5%); p<0.0001 ORR (excluding MR) (95% CI): Arm A: 11.7% (7.3-17.5%) vs Arm B: 1.2% (0.03-6.5%); p=0.0029

    Secondary: Duration of Response (Investigator assessment)

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    End point title
    		 Duration of Response (Investigator assessment)
    End point description
    DR was calculated from the date of first documentation of response to the date of disease progression or death. The same censoring rules described above for PFS calculation were also considered for DR.
    End point type
    Secondary
    End point timeframe
    Overall period
    End point values
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Number of subjects analysed
    51 [13]
    1 [14]
    Units: months
        median (confidence interval 95%)
    5.1 (3.2 to 6.2)
    0.9 (-999 to 999)
    Notes
    [13] - Responder Patients
    [14] - Responder Patients -999,999 = Interval could not be calculated
    Statistical analysis title
    		 Arm A compared to Arm B
    Comparison groups
    Arm B (DXM alone) v Arm A (plitidepsin plus DXM)
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0001 [16]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.004
         upper limit
    		 0.479
    Notes
    [15] - DR at 6 months (95% CI): Arm A: 38.2% (23.7-52.8%) vs 0.0% (0.0-.%)
    [16] - Cox regression HR: 0.0105

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Arm A (plitidepsin plus DXM)
    Reporting group description
    		 Arm A (plitidepsin plus DXM)

    Reporting group title
    Arm B (DXM alone)
    Reporting group description
    		 Arm B (DXM alone)

    Serious adverse events
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 167 (59.28%)
    26 / 83 (31.33%)
         number of deaths (all causes)
    126
    74
         number of deaths resulting from adverse events
    23
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmablastic lymphoma
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 167 (2.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 167 (1.80%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 167 (4.79%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 167 (1.20%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 167 (4.19%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 167 (3.59%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    12 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    6 / 167 (3.59%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    3 / 167 (1.80%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cells increased
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Drug administration error
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 167 (1.80%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systolic dysfunction
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 167 (1.80%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperviscosity syndrome
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 167 (1.80%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 167 (2.40%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 167 (3.59%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    3 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 167 (1.80%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 167 (2.40%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal failure acute
         subjects affected / exposed
    2 / 167 (1.20%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Calculus urinary
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 167 (1.80%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myopathy toxic
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 167 (0.60%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    15 / 167 (8.98%)
    3 / 83 (3.61%)
         occurrences causally related to treatment / all
    9 / 18
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    2 / 167 (1.20%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 167 (1.80%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sepsis
         subjects affected / exposed
    9 / 167 (5.39%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    3 / 9
    2 / 2
         deaths causally related to treatment / all
    0 / 5
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 167 (2.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 167 (2.40%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium colitis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Clostridium difficile infection
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 167 (1.80%)
    1 / 83 (1.20%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    6 / 167 (3.59%)
    2 / 83 (2.41%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    4 / 167 (2.40%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 83 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A (plitidepsin plus DXM) Arm B (DXM alone)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    161 / 167 (96.41%)
    80 / 83 (96.39%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    22 / 167 (13.17%)
    0 / 83 (0.00%)
         occurrences all number
    48
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 167 (6.59%)
    0 / 83 (0.00%)
         occurrences all number
    20
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    28 / 167 (16.77%)
    0 / 83 (0.00%)
         occurrences all number
    41
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    15 / 167 (8.98%)
    1 / 83 (1.20%)
         occurrences all number
    34
    1
    Weight decreased
         subjects affected / exposed
    12 / 167 (7.19%)
    1 / 83 (1.20%)
         occurrences all number
    13
    1
    Platelet count decreased
         subjects affected / exposed
    7 / 167 (4.19%)
    5 / 83 (6.02%)
         occurrences all number
    67
    21
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 167 (8.38%)
    5 / 83 (6.02%)
         occurrences all number
    17
    6
    Hypotension
         subjects affected / exposed
    16 / 167 (9.58%)
    1 / 83 (1.20%)
         occurrences all number
    17
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 167 (10.78%)
    5 / 83 (6.02%)
         occurrences all number
    18
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    69 / 167 (41.32%)
    34 / 83 (40.96%)
         occurrences all number
    203
    97
    Neutropenia
         subjects affected / exposed
    12 / 167 (7.19%)
    2 / 83 (2.41%)
         occurrences all number
    26
    3
    Thrombocytopenia
         subjects affected / exposed
    15 / 167 (8.98%)
    8 / 83 (9.64%)
         occurrences all number
    47
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    32 / 167 (19.16%)
    9 / 83 (10.84%)
         occurrences all number
    60
    11
    Chest pain
         subjects affected / exposed
    9 / 167 (5.39%)
    2 / 83 (2.41%)
         occurrences all number
    12
    2
    Fatigue
         subjects affected / exposed
    55 / 167 (32.93%)
    18 / 83 (21.69%)
         occurrences all number
    95
    22
    Oedema peripheral
         subjects affected / exposed
    31 / 167 (18.56%)
    5 / 83 (6.02%)
         occurrences all number
    45
    6
    Pyrexia
         subjects affected / exposed
    32 / 167 (19.16%)
    11 / 83 (13.25%)
         occurrences all number
    50
    14
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    16 / 167 (9.58%)
    1 / 83 (1.20%)
         occurrences all number
    16
    1
    Constipation
         subjects affected / exposed
    21 / 167 (12.57%)
    5 / 83 (6.02%)
         occurrences all number
    23
    7
    Diarrhoea
         subjects affected / exposed
    57 / 167 (34.13%)
    8 / 83 (9.64%)
         occurrences all number
    80
    10
    Dyspepsia
         subjects affected / exposed
    9 / 167 (5.39%)
    4 / 83 (4.82%)
         occurrences all number
    12
    5
    Nausea
         subjects affected / exposed
    76 / 167 (45.51%)
    17 / 83 (20.48%)
         occurrences all number
    122
    19
    Vomiting
         subjects affected / exposed
    41 / 167 (24.55%)
    3 / 83 (3.61%)
         occurrences all number
    57
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 167 (18.56%)
    9 / 83 (10.84%)
         occurrences all number
    42
    10
    Dyspnoea
         subjects affected / exposed
    23 / 167 (13.77%)
    3 / 83 (3.61%)
         occurrences all number
    36
    3
    Epistaxis
         subjects affected / exposed
    10 / 167 (5.99%)
    6 / 83 (7.23%)
         occurrences all number
    11
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    18 / 167 (10.78%)
    10 / 83 (12.05%)
         occurrences all number
    23
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 167 (4.79%)
    6 / 83 (7.23%)
         occurrences all number
    8
    6
    Back pain
         subjects affected / exposed
    16 / 167 (9.58%)
    15 / 83 (18.07%)
         occurrences all number
    18
    22
    Bone pain
         subjects affected / exposed
    12 / 167 (7.19%)
    15 / 83 (18.07%)
         occurrences all number
    13
    17
    Muscular weakness
         subjects affected / exposed
    21 / 167 (12.57%)
    3 / 83 (3.61%)
         occurrences all number
    27
    5
    Musculoskeletal pain
         subjects affected / exposed
    12 / 167 (7.19%)
    1 / 83 (1.20%)
         occurrences all number
    14
    1
    Myalgia
         subjects affected / exposed
    30 / 167 (17.96%)
    3 / 83 (3.61%)
         occurrences all number
    47
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 167 (2.99%)
    5 / 83 (6.02%)
         occurrences all number
    5
    5
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 167 (8.38%)
    5 / 83 (6.02%)
         occurrences all number
    19
    5
    Urinary tract infection
         subjects affected / exposed
    12 / 167 (7.19%)
    2 / 83 (2.41%)
         occurrences all number
    13
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    34 / 167 (20.36%)
    5 / 83 (6.02%)
         occurrences all number
    40
    5
    Hypercalcaemia
         subjects affected / exposed
    8 / 167 (4.79%)
    7 / 83 (8.43%)
         occurrences all number
    9
    11
    Hyperglycaemia
         subjects affected / exposed
    11 / 167 (6.59%)
    3 / 83 (3.61%)
         occurrences all number
    16
    3
    Hypokalaemia
         subjects affected / exposed
    19 / 167 (11.38%)
    5 / 83 (6.02%)
         occurrences all number
    23
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Dec 2010
    This protocol amendment included the following changes: -A retrospective analysis performed in all adult patients treated with single-agent plitidepsin in phase I (at the recommended dose) and phase II clinical trials showed plitidepsin administration through a peripheral vein safe enough to be considered in this q3wk schedule whenever a central venous line was deemed unsuitable for any reason (e.g., coagulation problems, technical difficulties, patient’s refusal, etc.). Therefore, central venous catheter administration was suggested, but peripheral lines were also accepted. -The exact binomial 95% CI for RR was provided to clarify futility analysis rules, as requested by the IDMC. -Patient eligibility criteria were modified to allow inclusion of patients with stable atrial fibrillation, or patients with controlled infection on antibiotics. -Some assessment and procedures were modified: 1 To allow determination of direct bilirubin only if total bilirubin was above ULN. 2 To extend from 14 to 28 days the timeframe for some baseline disease evaluation assessments (bone marrow, serum and urinary protein determinations, and radiological assessment in case of plasmacytomas); to clarify X-ray as the myeloma skeletal evaluation method; 3 Following a request by the French Health Authorities as to be consistent with the information reported in the Investigator’s Brochure of plitidepsin regarding coagulation tests monitoring, the sentence "close monitoring of patients taking oral anticoagulants is required" was added into the footnotes of the "Schedule of Assessments and Procedures" table and to the section "Concomitant Medication". 4 Corrected in this amendment: IVRS system was used always in this trial, but due to a mistake during writing, v 1.0 of the protocol referred in the Patient Registration Section to a manual model (fast fact sheet). -A clarification regarding the extraction of PK blood samples was made.
    12 Apr 2013
    This protocol amendment included the following changes: -An update of study contact details and study timelines. -The implementation of the determination of direct bilirubin only if total bilirubin was above the ULN. -An update of the instructions for the preparation (dilution) of plitidepsin, in order to make them consistent with the preparation guidelines and other related documents that allow dilution with 5% glucose. -The removal of the need for assessing the creatinine clearance (measured) at baseline and end of treatment, leaving just the calculated creatinine clearance included in Biochemistry A. -To allow skeletal evaluation at baseline and end of treatment or whenever required, by X-ray or CT-scan, as long as the same procedure is used throughout the study. -To allow phone contacts for patients during survival follow-up whenever the patient’s disease was so serious that he/she was unable to attend the clinic. This only applied to patients who were followed up after discontinuing treatment due to PD. -The conduct of the QTc substudy to assess the potential effects of plitidepsin on the heart activity of patients enrolled in this clinical trial. In particular the QTc interval, based on electrocardiogram evaluation, was to be recorded and studied. -An update of the PK section of the protocol. -An update of the Safety section in accordance with current regulations. -An update of the telephone number used for reporting SAEs to the PV Service out of office hours. -The IMWG uniform criteria for MM were initially used to document disease progression or response to treatment. In the second study stage, this protocol amendment implemented the use of the updated IMWG criteria only, and to remove the Durie et al. IMWG version shown in App. 5. Therefore, the decision taken at that time was to not confirm PD in two assessments. Due to this reason, the analysis of the primary endpoint was to identify the first PD reported with no further confirmation

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Dec 2012
    An early futility analysis was performed when information from 40 patients in Arm A were evaluable for response. A response rate (IMWG criteria) of at least 30% (12 or more responses by IRC review) was taken as threshold for continuation of the study. A minimum response rate of 30% was considered as clinically significant in this setting. This result ensured that the lower limit of the exact binomial 95% CI for RR would be greater than 15% (95% CI in case of 12 responses would be 16.6%-46.5%). However, the information from all randomized patients in both arms at that time was used by the IDMC to evaluate the safety profile and to provide the Sponsor with a recommendation for the further study conduct. No claim for superiority in efficacy was to be formulated in this interim analysis and no alpha-spending for the analysis of PFS was foreseen. Accrual was to be on-hold while data for the futility analysis was assessed. For futility analysis based on objective RR, the All Evaluable Patients analysis dataset was used. On 9 December 2012, the evaluation by the IDMC of efficacy and safety data from the first 60 evaluable patients included in this study resulted in the recommendation to continue the trial unmodified, as the study met the established efficacy threshold of 30% response rate according to IMWG criteria pre-specified in the protocol (RR in Arm A, plitidepsin plus DXM, was 37.8%). No safety issues were reported. Therefore, patient accrual was resumed.
    09 Dec 2012

    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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