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    Clinical Trial Results:
    An International, Randomized, Double-Blind, Controlled Study of Rindopepimut/GM-CSF with Adjuvant Temozolomide in Patients with Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma (The “ACT IV” Study)

    Summary
    EudraCT number
    		 2011-006068-32
    Trial protocol
    		 HU   GR   GB   DE   AT   BE   ES   NL   IT   FR  
    Global end of trial date
    15 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Sep 2018
    First version publication date
    22 Sep 2018
    Other versions
    Summary report(s)
    		 ACT IV Abb CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    CDX110-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01480479
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celldex Therapeutics, Inc.
    Sponsor organisation address
    119 Fourth Ave, Needham, United States, 02494
    Public contact
    Celldex Therapeutics, Celldex Therapeutics. Inc. , info@celldex.com
    Scientific contact
    Celldex Therapeutics, Celldex Therapeutics. Inc., info@celldex.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
    29 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to confirm that the addition of rindopepimut/GM-CSF to adjuvant temozolomide improved overall survival in patients with newly diagnosed, resected, EGFRvIII positive glioblastoma who had undergone gross-total resection.
    Protection of trial subjects
    Safety assessments included monthly physical examination, vital signs, routine hematology, blood chemistry, urinalysis and evaluation of adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. An independent data monitoring committee (DMC) was convened for this study and acted in an advisory capacity to the sponsor with respect to safeguarding the interests of study patients, assessing interim safety and efficacy data, and for monitoring the overall conduct of the study.
    Background therapy
    		 Standard maintenance temozolomide administered orally at a dose of 150–200 mg/m2 on days 1–5 of 28-day cycles, for 6–12 cycles, or longer if consistent with the local standard of care.
    Evidence for comparator
    		 Keyhole limpet haemocyanin (KLH; 100 mcg ) was given as a control injection to produce a local reaction similar to that expected with rindopepimut to maintain the treatment blind.
    Actual start date of recruitment
    29 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    United States: 468
    Country: Number of subjects enrolled
    Canada: 70
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Switzerland: 17
    Country: Number of subjects enrolled
    Australia: 53
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    New Zealand: 12
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Peru: 1
    Worldwide total number of subjects
    745
    EEA total number of subjects
    92
    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)
    571
    From 65 to 84 years
    173
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patient screened in November 2011. In addition to the above countries listed, Colombia and Belgium screened patients.

    Pre-assignment
    Screening details
    		 Patients underwent tissue screening for EGFRvIII at the same time or ahead of screening for other eligibility criteria. EGFRvIII negativity was the largest reason for being ineligible for the trial.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Unblinded Pharmacists who were otherwise not involved in Study conduct, obtained a randomized treatment assignment and managed study treatment via interactive response technology. Prepared Study treatments were blinded prior to delivery to Study staff for administration. KLH was given as a control injection to produce a local reaction similar to what was expected for Rindopepimut. Humoral response was analyzed but only available to laboratory staff until database lock and unblinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active Study Drug
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rindopepimut
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intradermal use
    Dosage and administration details
    Rindopepimut (CDX-110): A vaccine consisting of a 14 amino-acid synthetic peptide (13 amino acids from EGFRvIII plus a cysteine residue; termed EGFRvIII peptide) covalently linked to the carrier protein Keyhole Limpet Hemocyanin (KLH); 0.8 mL containing approximately 500 mcg rindopepimut and 150 mcg GM-CSF administered via intradermal injections. Lots used include A1200126, B0011, B0013, P58605ARG.

    Investigational medicinal product name
    GM-CSF
    Investigational medicinal product code
    Other name
    Leukine, sargramostim
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intradermal use
    Dosage and administration details
    GM-CSF: Leukine® (sargramostim); yeast-derived, recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF); administered via intradermal injections. Lots used include B15195, B17684, B19739, B19946, B20641, B21696A.

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    TMZ, Temodar
    Pharmaceutical forms
    Tablet, Concentrate for concentrate for solution for infusion
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Temozolomide (TMZ): TEMODAR® (Merck); oral or intravenous administration according to the instructions in the product label and per standard practice; typical dose is 150 mg/m2 body surface area per day for the first cycle and may increase to 200 mg/m2 body surface area per day in subsequent cycles. Commercial supplies were used.

    Arm title
    		 Blinded Control
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Keyhole Limpet Hemocyanin
    Investigational medicinal product code
    Other name
    KLH, VACMUNE
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Keyhole Limpet Hemocyanin (KLH): VACMUNE® (Biosyn Corporation); a high purity, clinical grade, well-characterized aqueous formulation of a mixture of KLH 1 and KLH 2 immunocyanin subunits purified from native KLH, the high molecular mass hemocyanin of the giant keyhole limpet Megathura Crenulata, which has been reformulated and lyophilized by Celldex; 0.8 mL containing 100 mcg of KLH administered via intradermal injections. Lots used include 1-FIN-1145, 1-FIN-1646, 1-FIN-1947.

    Investigational medicinal product name
    Temozolomide
    Investigational medicinal product code
    Other name
    TMZ, Temodar
    Pharmaceutical forms
    Concentrate for concentrate for solution for infusion, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Temozolomide (TMZ): TEMODAR® (Merck); oral or intravenous administration according to the instructions in the product label and per standard practice; typical dose is 150 mg/m2 body surface area per day for the first cycle and may increase to 200 mg/m2 body surface area per day in subsequent cycles. Commercial supplies were used.

    Number of subjects in period 1
    		Active Study Drug Blinded Control
    Started
    371
    374
    Completed
    362
    361
    Not completed
    9
    13
         Consent withdrawn by subject
    5
    7
         other, not specified
    1
    3
         Lost to follow-up
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active Study Drug
    Reporting group description
    		 -

    Reporting group title
    Blinded Control
    Reporting group description
    		 -

    Reporting group values
    		 Active Study Drug Blinded Control Total
    Number of subjects
    		 371 374 745
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 59 (25 to 80) 58 (19 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 119 146 265
        Male
    		 252 228 480
    Subject analysis sets

    Subject analysis set title
    MRD Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients with minimal residual disease.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment.

    Subject analysis sets values
    		 MRD Population ITT Safety Population
    Number of subjects
    405
    745
    741
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    58 (19 to 85)
    58 (19 to 85)
    58 (19 to 85)
    Gender categorical
    Units: Subjects
        Female
    151
    265
    261
        Male
    254
    480
    480

    End points

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    End points reporting groups
    Reporting group title
    Active Study Drug
    Reporting group description
    		 -

    Reporting group title
    Blinded Control
    Reporting group description
    		 -

    Subject analysis set title
    MRD Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Patients with minimal residual disease.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of study treatment.

    Primary: Overall survival in the MRD population

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    End point title
    		 Overall survival in the MRD population
    End point description
    End point type
    Primary
    End point timeframe
    From randomization until death or study closure.
    End point values
    		 Active Study Drug Blinded Control
    Number of subjects analysed
    195
    210
    Units: months
        median (confidence interval 95%)
    20.1 (18.5 to 22.1)
    20.0 (18.1 to 21.9)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Active Study Drug v Blinded Control
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.025
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time the patient had taken at least one dose of double-blind vaccine through (whichever occurs first) either a) 28 calendar days after the last administration of double-blind vaccine, or b) initiation of alternative anticancer therapy.
    Adverse event reporting additional description
    Adverse events and serious adverse events were to be recorded on the CRF. Assessments included monthly physical exams, vital signs, routine hematology, blood chemistry, and urinalysis as well as quality of life questionnaires, MDASI-BT, QLQ-C#) and BN20.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Active Study Drug
    Reporting group description
    		 -

    Reporting group title
    Blinded Control
    Reporting group description
    		 -

    Serious adverse events
    		 Active Study Drug Blinded Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    96 / 369 (26.02%)
    102 / 372 (27.42%)
         number of deaths (all causes)
    254
    269
         number of deaths resulting from adverse events
    7
    6
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Borderline mucinous tumour of ovary
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm benign
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    4 / 369 (1.08%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hypotension
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         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
    3 / 369 (0.81%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    3 / 369 (0.81%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    0 / 369 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 369 (1.90%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    7 / 369 (1.90%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    3 / 369 (0.81%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         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
    Fall
         subjects affected / exposed
    4 / 369 (1.08%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoradionecrosis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomeningocele
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    2 / 369 (0.54%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    1 / 369 (0.27%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tachycardia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    3 / 369 (0.81%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    7 / 369 (1.90%)
    12 / 372 (3.23%)
         occurrences causally related to treatment / all
    4 / 7
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 369 (0.27%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 369 (0.27%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 369 (0.27%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    3 / 369 (0.81%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    2 / 369 (0.54%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    4 / 369 (1.08%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    5 / 369 (1.36%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Movement disorder
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    2 / 369 (0.54%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    18 / 369 (4.88%)
    22 / 372 (5.91%)
         occurrences causally related to treatment / all
    2 / 18
    1 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 369 (0.27%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    5 / 369 (1.36%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasogenic cerebral oedema
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    5 / 369 (1.36%)
    3 / 372 (0.81%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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 distension
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 369 (0.27%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal fissure
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    1 / 369 (0.27%)
    5 / 372 (1.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site erythema
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    Acne
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         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
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 369 (0.54%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    3 / 369 (0.81%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes insipidus
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    Back pain
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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 / 369 (0.00%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    3 / 369 (0.81%)
    4 / 372 (1.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 369 (0.54%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tooth infection
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (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
    7 / 369 (1.90%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    West Nile viral infection
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 369 (0.81%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 369 (0.27%)
    2 / 372 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 372 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 372 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    		 Active Study Drug Blinded Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    362 / 369 (98.10%)
    353 / 372 (94.89%)
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    261 / 369 (70.73%)
    118 / 372 (31.72%)
         occurrences all number
    71
    32
    Injection site oedema
         subjects affected / exposed
    35 / 369 (9.49%)
    13 / 372 (3.49%)
         occurrences all number
    10
    4
    Injection site pruritus
         subjects affected / exposed
    146 / 369 (39.57%)
    29 / 372 (7.80%)
         occurrences all number
    40
    8
    Injection site rash
         subjects affected / exposed
    55 / 369 (14.91%)
    13 / 372 (3.49%)
         occurrences all number
    15
    4
    Injection site swelling
         subjects affected / exposed
    42 / 369 (11.38%)
    7 / 372 (1.88%)
         occurrences all number
    11
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    43 / 369 (11.65%)
    64 / 372 (17.20%)
         occurrences all number
    12
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28844499
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