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    Clinical Trial Results:
    An International, Multicenter, Randomized, Double-Blind Study of Vorinostat (MK-0683) or Placebo in Combination with Bortezomib in Patients with Multiple Myeloma

    Summary
    EudraCT number
    		 2008-003752-30
    Trial protocol
    		 ES   DE   BE   FR   AT   CZ   PT   HU   IT   BG   GB   GR  
    Global end of trial date
    30 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2016
    First version publication date
    24 Jun 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    0683-088
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00773747
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Registration Number: MK-0683-088
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    30 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Sep 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a multi-site, randomized, double-blind study to determine the safety and efficacy of vorinostat (MK-0683/Zolinza®) and bortezomib compared with placebo and bortezomib in participants with relapsed or refractory multiple myeloma. The primary measurement of efficacy was the duration of progression-free survival.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. Study-specific patient protections include implementation of a stopping rule for futility, stopping rule for overwhelming efficacy, and dose modification based on worst severity toxicities experienced by participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2008
    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: 29
    Country: Number of subjects enrolled
    Australia: 38
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Brazil: 29
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    China: 81
    Country: Number of subjects enrolled
    Croatia: 13
    Country: Number of subjects enrolled
    Czech Republic: 33
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Greece: 23
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    India: 48
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 38
    Country: Number of subjects enrolled
    Malaysia: 8
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    New Zealand: 35
    Country: Number of subjects enrolled
    Philippines: 28
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    South Africa: 19
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Thailand: 14
    Country: Number of subjects enrolled
    United Kingdom: 11
    Worldwide total number of subjects
    637
    EEA total number of subjects
    224
    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)
    381
    From 65 to 84 years
    253
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study enrolled participants with an established diagnosis of multiple myeloma based on standard criteria that have received at least 1 but not more than 3 prior anti-myeloma regimens and have demonstrated progressive disease after the most recent treatment regimen. Additional inclusion and exclusion criteria applied.

    Pre-assignment
    Screening details
    		 637 participants were randomized to treatment and 635 participants received at least 1 dose of MK-0683 or placebo: 315 participants were treated with vorinostat + bortezomib and 320 participants were treated with placebo + bortezomib.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vorinostat + Bortezomib
    Arm description
    		 Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vorinostat 400 mg
    Investigational medicinal product code
    Other name
    ZOLINZA®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Vorinostat 400 mg orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle

    Investigational medicinal product name
    Bortezomib 1.3 mg/m^2
    Investigational medicinal product code
    Other name
    VELCADE®
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 0f a 21-day treatment cycle

    Arm title
    		 Placebo + Bortezomib
    Arm description
    		 Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 0f a 21-day treatment cycle.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Bortezomib 1.3 mg/m^2
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 0f a 21-day treatment cycle

    Investigational medicinal product name
    Matching Placebo for Vorinostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle

    Number of subjects in period 1
    		Vorinostat + Bortezomib Placebo + Bortezomib
    Started
    317
    320
    Completed
    22
    24
    Not completed
    295
    296
         Adverse event, serious fatal
    5
    8
         Consent withdrawn by subject
    89
    61
         Physician decision
    26
    18
         Adverse event, non-fatal
    61
    62
         Lost to follow-up
    -
    1
         Lack of efficacy
    112
    144
         Protocol deviation
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vorinostat + Bortezomib
    Reporting group description
    		 Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

    Reporting group title
    Placebo + Bortezomib
    Reporting group description
    		 Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 0f a 21-day treatment cycle.

    Reporting group values
    		 Vorinostat + Bortezomib Placebo + Bortezomib Total
    Number of subjects
    		 317 320 637
    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)
    		 200 181 381
        From 65-84 years
    		 116 137 253
        85 years and over
    		 1 2 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.9 ± 10 62.7 ± 10 -
    Gender Categorical
    Units: Subjects
        Female
    		 126 134 260
        Male
    		 191 186 377

    End points

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    End points reporting groups
    Reporting group title
    Vorinostat + Bortezomib
    Reporting group description
    		 Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

    Reporting group title
    Placebo + Bortezomib
    Reporting group description
    		 Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 0f a 21-day treatment cycle.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron’s likelihood approximation to account for ties in event times.
    End point type
    Primary
    End point timeframe
    From randomization to event of disease progression or death assessed up to 32 months (final study analysis)
    End point values
    		 Vorinostat + Bortezomib Placebo + Bortezomib
    Number of subjects analysed
    317 [1]
    320 [2]
    Units: Months
        median (confidence interval 95%)
    7.63 (6.87 to 8.4)
    6.83 (5.67 to 7.73)
    Notes
    [1] - Intention to treat (ITT) population including all randomized participants.
    [2] - ITT population including all randomized participants.
    Statistical analysis title
    		 Ratio of Hazard Rates Assessed up to 32 Months
    Comparison groups
    Vorinostat + Bortezomib v Placebo + Bortezomib
    Number of subjects included in analysis
    637
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.774
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.636
         upper limit
    		 0.941

    Secondary: Number of Participants with Clinical and Laboratory Adverse Events (AEs)

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    End point title
    		 Number of Participants with Clinical and Laboratory Adverse Events (AEs)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after the last dose of study drug
    End point values
    		 Vorinostat + Bortezomib Placebo + Bortezomib
    Number of subjects analysed
    315 [3]
    320 [4]
    Units: Participants
    312
    315
    Notes
    [3] - All Patients as Treated population: all randomized participants who received ≥1 dose of study drug
    [4] - All Patients as Treated population: all randomized participants who received ≥1 dose of study drug
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was measured from the start of the treatment to death due to any cause. Overall Survival is represented as the number of deaths per 100-person- months and was computed by dividing the number of participants with an event of death that occurred during the study follow-up period by the total duration of follow-up (in 100 months) for all the participants in each cohort since participants had different lengths of follow-up.
    End point type
    Secondary
    End point timeframe
    From randomization up to 32 months (final study analysis)
    End point values
    		 Vorinostat + Bortezomib Placebo + Bortezomib
    Number of subjects analysed
    317 [5]
    320 [6]
    Units: Events/100-person Months
        number (confidence interval 95%)
    1.7 (1.56 to 1.84)
    1.9 (1.75 to 2.05)
    Notes
    [5] - ITT population including all randomized participants.
    [6] - ITT population including all randomized participants.
    Statistical analysis title
    		 Ratio of Hazard Rates Assessed up to 32 Months
    Comparison groups
    Vorinostat + Bortezomib v Placebo + Bortezomib
    Number of subjects included in analysis
    637
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.858
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.622
         upper limit
    		 1.184

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    Time to progression was measured from the start of the treatment to the time when the criteria for progression was met or death due to myeloma (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron’s likelihood approximation to account for ties in event times.
    End point type
    Secondary
    End point timeframe
    Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
    End point values
    		 Vorinostat + Bortezomib Placebo + Bortezomib
    Number of subjects analysed
    317 [7]
    320 [8]
    Units: Months
        median (confidence interval 95%)
    7.73 (7 to 8.53)
    7.03 (6.33 to 7.73)
    Notes
    [7] - ITT population including all randomized participants.
    [8] - ITT population including all randomized participants.
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective response rate was measured as the proportion of patients who achieved a confirmed partial response or better during the course of the study. Response to study therapy was assessed using EBMT Criteria and confirmed by Independent Adjudication Review.
    End point type
    Secondary
    End point timeframe
    Baseline and at the end of each 21-day Cycle assessed up to 32 months (final study analysis)
    End point values
    		 Vorinostat + Bortezomib Placebo + Bortezomib
    Number of subjects analysed
    315 [9]
    320 [10]
    Units: Percentage of Participants
        number (confidence interval 95%)
    56.2 (50.5 to 61.7)
    40.6 (35.2 to 46.2)
    Notes
    [9] - Full Analysis Set: all randomized patient who received ≥1 dose of study treatment
    [10] - Full Analysis Set: all randomized patient who received ≥1 dose of study treatment
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to 30 days after the last dose of study drug
    Adverse event reporting additional description
    AEs were reported for the All Patients as Treated Population that included all randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo + Bortezomib
    Reporting group description
    		 Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 0f a 21-day treatment cycle.

    Reporting group title
    Vorinostat + Bortezomib
    Reporting group description
    		 Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

    Serious adverse events
    		 Placebo + Bortezomib Vorinostat + Bortezomib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    138 / 320 (43.13%)
    130 / 315 (41.27%)
         number of deaths (all causes)
    17
    11
         number of deaths resulting from adverse events
    2
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    13 / 320 (4.06%)
    10 / 315 (3.17%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 10
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 320 (0.94%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 320 (0.63%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 320 (0.00%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 320 (0.31%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 320 (0.63%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    Fatigue
         subjects affected / exposed
    5 / 320 (1.56%)
    3 / 315 (0.95%)
         occurrences causally related to treatment / all
    6 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pelvic mass
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    9 / 320 (2.81%)
    6 / 315 (1.90%)
         occurrences causally related to treatment / all
    4 / 12
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 320 (0.63%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    27 / 320 (8.44%)
    32 / 315 (10.16%)
         occurrences causally related to treatment / all
    0 / 43
    0 / 52
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 320 (0.63%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic coma
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (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
    4 / 320 (1.25%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 320 (0.31%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 320 (0.63%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Febrile neutropenia
         subjects affected / exposed
    0 / 320 (0.00%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 320 (0.31%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 320 (0.94%)
    9 / 315 (2.86%)
         occurrences causally related to treatment / all
    1 / 3
    11 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    10 / 320 (3.13%)
    9 / 315 (2.86%)
         occurrences causally related to treatment / all
    9 / 10
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (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
    3 / 320 (0.94%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 320 (2.19%)
    8 / 315 (2.54%)
         occurrences causally related to treatment / all
    6 / 8
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic necrosis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 320 (1.25%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 320 (0.63%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism primary
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 320 (0.94%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis pneumococcal
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 320 (0.31%)
    4 / 315 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 320 (0.00%)
    6 / 315 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (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
    6 / 320 (1.88%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster ophthalmic
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (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
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 320 (0.63%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 320 (4.06%)
    14 / 315 (4.44%)
         occurrences causally related to treatment / all
    4 / 13
    5 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 320 (1.56%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 320 (0.94%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 320 (0.94%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (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 / 320 (1.25%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 320 (1.56%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 320 (0.63%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 320 (0.00%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 320 (0.31%)
    1 / 315 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 320 (0.00%)
    2 / 315 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 320 (0.31%)
    0 / 315 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Placebo + Bortezomib Vorinostat + Bortezomib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    306 / 320 (95.63%)
    312 / 315 (99.05%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    11 / 320 (3.44%)
    17 / 315 (5.40%)
         occurrences all number
    14
    26
    Weight decreased
         subjects affected / exposed
    22 / 320 (6.88%)
    22 / 315 (6.98%)
         occurrences all number
    30
    36
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 320 (4.06%)
    29 / 315 (9.21%)
         occurrences all number
    16
    37
    Hypotension
         subjects affected / exposed
    12 / 320 (3.75%)
    19 / 315 (6.03%)
         occurrences all number
    15
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 320 (8.44%)
    36 / 315 (11.43%)
         occurrences all number
    37
    56
    Dysgeusia
         subjects affected / exposed
    6 / 320 (1.88%)
    23 / 315 (7.30%)
         occurrences all number
    8
    28
    Headache
         subjects affected / exposed
    34 / 320 (10.63%)
    35 / 315 (11.11%)
         occurrences all number
    45
    45
    Hypoaesthesia
         subjects affected / exposed
    18 / 320 (5.63%)
    10 / 315 (3.17%)
         occurrences all number
    26
    12
    Neuralgia
         subjects affected / exposed
    86 / 320 (26.88%)
    82 / 315 (26.03%)
         occurrences all number
    125
    124
    Neuropathy peripheral
         subjects affected / exposed
    64 / 320 (20.00%)
    62 / 315 (19.68%)
         occurrences all number
    97
    94
    Paraesthesia
         subjects affected / exposed
    12 / 320 (3.75%)
    20 / 315 (6.35%)
         occurrences all number
    14
    27
    Peripheral sensory neuropathy
         subjects affected / exposed
    27 / 320 (8.44%)
    33 / 315 (10.48%)
         occurrences all number
    39
    58
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    79 / 320 (24.69%)
    91 / 315 (28.89%)
         occurrences all number
    164
    198
    Leukopenia
         subjects affected / exposed
    32 / 320 (10.00%)
    42 / 315 (13.33%)
         occurrences all number
    122
    121
    Neutropenia
         subjects affected / exposed
    95 / 320 (29.69%)
    112 / 315 (35.56%)
         occurrences all number
    300
    406
    Thrombocytopenia
         subjects affected / exposed
    106 / 320 (33.13%)
    172 / 315 (54.60%)
         occurrences all number
    384
    749
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    40 / 320 (12.50%)
    46 / 315 (14.60%)
         occurrences all number
    80
    89
    Fatigue
         subjects affected / exposed
    96 / 320 (30.00%)
    125 / 315 (39.68%)
         occurrences all number
    176
    350
    Oedema peripheral
         subjects affected / exposed
    24 / 320 (7.50%)
    24 / 315 (7.62%)
         occurrences all number
    27
    28
    Pyrexia
         subjects affected / exposed
    70 / 320 (21.88%)
    66 / 315 (20.95%)
         occurrences all number
    130
    114
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    17 / 320 (5.31%)
    8 / 315 (2.54%)
         occurrences all number
    21
    11
    Abdominal pain
         subjects affected / exposed
    27 / 320 (8.44%)
    22 / 315 (6.98%)
         occurrences all number
    40
    37
    Abdominal pain upper
         subjects affected / exposed
    13 / 320 (4.06%)
    26 / 315 (8.25%)
         occurrences all number
    20
    42
    Constipation
         subjects affected / exposed
    86 / 320 (26.88%)
    64 / 315 (20.32%)
         occurrences all number
    132
    91
    Diarrhoea
         subjects affected / exposed
    133 / 320 (41.56%)
    194 / 315 (61.59%)
         occurrences all number
    275
    604
    Dyspepsia
         subjects affected / exposed
    26 / 320 (8.13%)
    24 / 315 (7.62%)
         occurrences all number
    40
    38
    Nausea
         subjects affected / exposed
    126 / 320 (39.38%)
    193 / 315 (61.27%)
         occurrences all number
    247
    457
    Vomiting
         subjects affected / exposed
    80 / 320 (25.00%)
    140 / 315 (44.44%)
         occurrences all number
    127
    280
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    48 / 320 (15.00%)
    52 / 315 (16.51%)
         occurrences all number
    61
    71
    Dyspnoea
         subjects affected / exposed
    28 / 320 (8.75%)
    26 / 315 (8.25%)
         occurrences all number
    35
    36
    Oropharyngeal pain
         subjects affected / exposed
    13 / 320 (4.06%)
    16 / 315 (5.08%)
         occurrences all number
    16
    17
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 320 (0.94%)
    24 / 315 (7.62%)
         occurrences all number
    3
    26
    Rash
         subjects affected / exposed
    40 / 320 (12.50%)
    31 / 315 (9.84%)
         occurrences all number
    61
    43
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    29 / 320 (9.06%)
    28 / 315 (8.89%)
         occurrences all number
    36
    32
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    27 / 320 (8.44%)
    26 / 315 (8.25%)
         occurrences all number
    40
    34
    Back pain
         subjects affected / exposed
    47 / 320 (14.69%)
    49 / 315 (15.56%)
         occurrences all number
    69
    67
    Bone pain
         subjects affected / exposed
    24 / 320 (7.50%)
    15 / 315 (4.76%)
         occurrences all number
    39
    27
    Muscle spasms
         subjects affected / exposed
    15 / 320 (4.69%)
    21 / 315 (6.67%)
         occurrences all number
    17
    25
    Pain in extremity
         subjects affected / exposed
    38 / 320 (11.88%)
    16 / 315 (5.08%)
         occurrences all number
    52
    21
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    19 / 320 (5.94%)
    22 / 315 (6.98%)
         occurrences all number
    21
    26
    Nasopharyngitis
         subjects affected / exposed
    18 / 320 (5.63%)
    16 / 315 (5.08%)
         occurrences all number
    20
    22
    Upper respiratory tract infection
         subjects affected / exposed
    38 / 320 (11.88%)
    55 / 315 (17.46%)
         occurrences all number
    58
    76
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    85 / 320 (26.56%)
    75 / 315 (23.81%)
         occurrences all number
    139
    123
    Hypokalaemia
         subjects affected / exposed
    25 / 320 (7.81%)
    35 / 315 (11.11%)
         occurrences all number
    40
    57

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2009
    Global substantial Amendment 1 revised the study flow chart and reduced the eligibility criteria for minimal acceptable renal function at study entry.
    06 Jan 2010
    Global substantial Amendment 2 added a dose modification summary table and updated dose modification guidelines to clarify the sequence of drug modifications and whether modification was required or optional for each agent. Supportive care recommendations were also added.
    05 Nov 2010
    Global substantial Amendment 3 revised the study design to delete the second interim analysis, increase the efficacy target at final analysis, and to move the final analysis to an earlier date.
    17 Mar 2011
    Global substantial Amendment 4 incorporated end of study procedures and added an extension phase for the study.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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