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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter Phase III study of RAD001 adjuvant therapy in high risk patients with Diffuse Large B-Cell Lymphoma (DLBCL) of RAD001 versus matching placebo after patients have achieved complete response with first-line rituximab-chemotherapy

    Summary
    EudraCT number
    		 2008-000498-40
    Trial protocol
    		 CZ   HU   SK   AT   IT   DE   GR   ES  
    Global end of trial date
    15 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2017
    First version publication date
    30 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001N2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00790036
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of everolimus versus matching placebo measured as disease free survival (DFS) in high risk patients with DLBCL after achieving complete response (CR) following first-line R-chemotherapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jul 2009
    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
    Argentina: 10
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    Austria: 16
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Canada: 48
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    China: 72
    Country: Number of subjects enrolled
    Colombia: 20
    Country: Number of subjects enrolled
    Czech Republic: 32
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Egypt: 16
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Italy: 54
    Country: Number of subjects enrolled
    Japan: 81
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Lebanon: 17
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Peru: 1
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    Saudi Arabia: 4
    Country: Number of subjects enrolled
    Singapore: 14
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Thailand: 16
    Country: Number of subjects enrolled
    Turkey: 18
    Country: Number of subjects enrolled
    United States: 86
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 1
    Worldwide total number of subjects
    742
    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)
    393
    From 65 to 84 years
    347
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Considering a recruitment period of 53 months and a final primary analysis performed after an anticipated duration of 69 months after study start, 727 patients had to be included. Actual enrolled: 742.

    Pre-assignment
    Screening details
    		 This was a randomized, double-blind, placebo-controlled, multicenter Phase III study in high risk patients (IPI 3-5) who achieved CR after first-line R-chemotherapy treatment.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RAD001 (Everolimus)
    Arm description
    		 RAD001 10 mg (two 5 mg tablets), daily for 12 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was formulated as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets. Everolimus was dispensed on Day 1 of each cycle until the end-of-treatment visit.

    Arm title
    		 Placebo
    Arm description
    		 Everolimus placebo 10 mg (two 5 mg tablets), daily for 12 months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo was formulated as tablets of 5 mg strength, blister-packed under aluminum foil in units of 10 tablets. Matching placebo was dispensed on Day 1 of each cycle until the end-of-treatment visit.

    Number of subjects in period 1
    		RAD001 (Everolimus) Placebo
    Started
    372
    370
    Untreated participants
    4 [1]
    6 [2]
    Completed
    177
    249
    Not completed
    195
    121
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    18
    7
         Disease progression
    24
    48
         Adverse event, non-fatal
    113
    44
         Administrative problems
    5
    9
         Abnormal lab values
    3
    2
         Lost to follow-up
    1
    2
         Subject/guardian decision
    20
    7
         Protocol deviation
    10
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These subjects, although randomized, were not treated with study drug due to administrative problems, protocol deviation and subject withdrawal of consent.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: These subjects, although randomized, were not treated with study drug due to administrative problems and subject withdrawal of consent.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RAD001 (Everolimus)
    Reporting group description
    		 RAD001 10 mg (two 5 mg tablets), daily for 12 months

    Reporting group title
    Placebo
    Reporting group description
    		 Everolimus placebo 10 mg (two 5 mg tablets), daily for 12 months

    Reporting group values
    		 RAD001 (Everolimus) Placebo Total
    Number of subjects
    		 372 370 742
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 192 201 393
        From 65-84 years
    		 180 167 347
        85 years and over
    		 0 2 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.6 ± 13.72 60.9 ± 13.61 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 204 166 370
        Male
    		 168 204 372

    End points

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    End points reporting groups
    Reporting group title
    RAD001 (Everolimus)
    Reporting group description
    		 RAD001 10 mg (two 5 mg tablets), daily for 12 months

    Reporting group title
    Placebo
    Reporting group description
    		 Everolimus placebo 10 mg (two 5 mg tablets), daily for 12 months

    Primary: Disease-free Survival (DFS)

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    End point title
    		 Disease-free Survival (DFS)
    End point description
    DFS was defined as the time from date of randomization to the date of event defined as the first documented relapse of the disease or death due to any cause. Relapse was based on investigator assessment and was assigned only if: It was documented according to Cheson guidelines by an objective radiological assessment method; It was documented by a biopsy proven lymphoma including new or recurrent bone marrow involvement; A new anticancer therapy for lymphoma started with subsequent confirmation of the relapse within 4 weeks of the start of this anticancer therapy
    End point type
    Primary
    End point timeframe
    From date of randomization to the date of event defined as the first documented recurrence of the disease, or death due to any cause and up to 6 years
    End point values
    		 RAD001 (Everolimus) Placebo
    Number of subjects analysed
    372
    370
    Units: Percentage of participants
        number (confidence interval 95%)
    77.8 (72.7 to 82.1)
    77 (72.1 to 81.1)
    Statistical analysis title
    		 DFS statistical analysis
    Comparison groups
    RAD001 (Everolimus) v Placebo
    Number of subjects included in analysis
    742
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.276 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.22
    Notes
    [1] - P-value was obtained from the one-sided unstratified log rank test.

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time from date of randomization to date of death due to any cause. If the patient was not known to have died, survival was censored at the date of the last contact.
    End point type
    Secondary
    End point timeframe
    From date of randomization to date of death due to any cause up to around 7 years
    End point values
    		 RAD001 (Everolimus) Placebo
    Number of subjects analysed
    372
    370
    Units: Percentage of participants
    number (confidence interval 95%)
        2 years
    90.7 (87 to 93.4)
    88.3 (84.4 to 91.3)
        3 years
    88 (83.8 to 91.1)
    83.7 (79.3 to 87.3)
        4 years
    85.4 (80.7 to 89.1)
    80.7 (75.8 to 84.7)
        5 years
    83.4 (78.1 to 87.5)
    77.4 (71.7 to 82)
        6 years
    80.3 (71.6 to 86.6)
    77.4 (71.7 to 82)
    Statistical analysis title
    		 OS Statistical analysis
    Comparison groups
    RAD001 (Everolimus) v Placebo
    Number of subjects included in analysis
    742
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.09

    Secondary: Lymphoma-specific survival (LSS)

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    End point title
    		 Lymphoma-specific survival (LSS)
    End point description
    LSS was defined as time from randomization to death as a result of lymphoma.
    End point type
    Secondary
    End point timeframe
    From randomization to death documented as a result of lymphoma up to 7 years
    End point values
    		 RAD001 (Everolimus) Placebo
    Number of subjects analysed
    372
    370
    Units: Percentage of participants
    number (confidence interval 95%)
        2 years
    94.9 (91.8 to 96.8)
    90.5 (86.9 to 93.2)
        3 years
    93.1 (89.6 to 95.5)
    88.8 (84.9 to 91.8)
        4 years
    91.6 (87.6 to 94.3)
    86.9 (82.6 to 90.3)
        5 years
    89.4 (84.6 to 92.8)
    85.4 (80.5 to 89.2)
        6 years
    89.4 (84.6 to 92.8)
    85.4 (80.5 to 89.2)
    Statistical analysis title
    		 LSS Statistical analysis
    Comparison groups
    RAD001 (Everolimus) v Placebo
    Number of subjects included in analysis
    742
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 1.07

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse Events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 Everolimus

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Serious adverse events
    		 Everolimus Placebo All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    105 / 368 (28.53%)
    62 / 364 (17.03%)
    167 / 732 (22.81%)
         number of deaths (all causes)
    5
    2
    7
         number of deaths resulting from adverse events
    2
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 368 (0.00%)
    2 / 364 (0.55%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythromelalgia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose ulceration
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vein disorder
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 368 (0.82%)
    2 / 364 (0.55%)
    5 / 732 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular swelling
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 368 (0.82%)
    2 / 364 (0.55%)
    5 / 732 (0.68%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Granulomatous pneumonitis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 368 (1.09%)
    1 / 364 (0.27%)
    5 / 732 (0.68%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 368 (0.82%)
    0 / 364 (0.00%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinitis allergic
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device difficult to use
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 368 (0.27%)
    1 / 364 (0.27%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biopsy lung
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CD4 lymphocytes decreased
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 368 (0.82%)
    0 / 364 (0.00%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 368 (0.27%)
    3 / 364 (0.82%)
    4 / 732 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 368 (0.00%)
    2 / 364 (0.55%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital haematoma
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 368 (0.27%)
    2 / 364 (0.55%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 368 (1.09%)
    2 / 364 (0.55%)
    6 / 732 (0.82%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    5 / 368 (1.36%)
    1 / 364 (0.27%)
    6 / 732 (0.82%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 368 (0.27%)
    1 / 364 (0.27%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brachial plexopathy
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral artery occlusion
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalomalacia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IVth nerve paresis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    0 / 368 (0.00%)
    2 / 364 (0.55%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular dementia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paresis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    8 / 368 (2.17%)
    5 / 364 (1.37%)
    13 / 732 (1.78%)
         occurrences causally related to treatment / all
    8 / 8
    3 / 5
    11 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 368 (1.90%)
    4 / 364 (1.10%)
    11 / 732 (1.50%)
         occurrences causally related to treatment / all
    6 / 7
    4 / 4
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 368 (0.00%)
    3 / 364 (0.82%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ophthalmoplegia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 368 (0.27%)
    1 / 364 (0.27%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pityriasis rosea
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 368 (0.27%)
    1 / 364 (0.27%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 368 (0.27%)
    1 / 364 (0.27%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    1 / 368 (0.27%)
    2 / 364 (0.55%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Herpes zoster
         subjects affected / exposed
    1 / 368 (0.27%)
    1 / 364 (0.27%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Moraxella infection
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    3 / 368 (0.82%)
    1 / 364 (0.27%)
    4 / 732 (0.55%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 368 (1.90%)
    3 / 364 (0.82%)
    10 / 732 (1.37%)
         occurrences causally related to treatment / all
    6 / 7
    2 / 3
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia cryptococcal
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyonephrosis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 368 (0.54%)
    0 / 364 (0.00%)
    2 / 732 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tinea pedis
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 368 (0.27%)
    3 / 364 (0.82%)
    4 / 732 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 368 (0.54%)
    1 / 364 (0.27%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 368 (0.00%)
    1 / 364 (0.27%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperlipidaemia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 368 (0.82%)
    0 / 364 (0.00%)
    3 / 732 (0.41%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 368 (0.27%)
    0 / 364 (0.00%)
    1 / 732 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus Placebo All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    348 / 368 (94.57%)
    276 / 364 (75.82%)
    624 / 732 (85.25%)
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    21 / 368 (5.71%)
    5 / 364 (1.37%)
    26 / 732 (3.55%)
         occurrences all number
    26
    7
    33
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    33 / 368 (8.97%)
    5 / 364 (1.37%)
    38 / 732 (5.19%)
         occurrences all number
    41
    6
    47
    CD4 lymphocytes decreased
         subjects affected / exposed
    37 / 368 (10.05%)
    18 / 364 (4.95%)
    55 / 732 (7.51%)
         occurrences all number
    41
    21
    62
    Weight decreased
         subjects affected / exposed
    28 / 368 (7.61%)
    6 / 364 (1.65%)
    34 / 732 (4.64%)
         occurrences all number
    30
    6
    36
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 368 (5.16%)
    13 / 364 (3.57%)
    32 / 732 (4.37%)
         occurrences all number
    20
    15
    35
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 368 (5.71%)
    27 / 364 (7.42%)
    48 / 732 (6.56%)
         occurrences all number
    22
    32
    54
    Dysgeusia
         subjects affected / exposed
    25 / 368 (6.79%)
    7 / 364 (1.92%)
    32 / 732 (4.37%)
         occurrences all number
    28
    7
    35
    Headache
         subjects affected / exposed
    42 / 368 (11.41%)
    31 / 364 (8.52%)
    73 / 732 (9.97%)
         occurrences all number
    50
    34
    84
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    61 / 368 (16.58%)
    18 / 364 (4.95%)
    79 / 732 (10.79%)
         occurrences all number
    70
    23
    93
    Leukopenia
         subjects affected / exposed
    29 / 368 (7.88%)
    23 / 364 (6.32%)
    52 / 732 (7.10%)
         occurrences all number
    50
    27
    77
    Lymphopenia
         subjects affected / exposed
    22 / 368 (5.98%)
    13 / 364 (3.57%)
    35 / 732 (4.78%)
         occurrences all number
    31
    13
    44
    Neutropenia
         subjects affected / exposed
    89 / 368 (24.18%)
    57 / 364 (15.66%)
    146 / 732 (19.95%)
         occurrences all number
    146
    76
    222
    Thrombocytopenia
         subjects affected / exposed
    55 / 368 (14.95%)
    9 / 364 (2.47%)
    64 / 732 (8.74%)
         occurrences all number
    81
    11
    92
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    37 / 368 (10.05%)
    28 / 364 (7.69%)
    65 / 732 (8.88%)
         occurrences all number
    45
    33
    78
    Fatigue
         subjects affected / exposed
    66 / 368 (17.93%)
    55 / 364 (15.11%)
    121 / 732 (16.53%)
         occurrences all number
    81
    76
    157
    Oedema peripheral
         subjects affected / exposed
    69 / 368 (18.75%)
    25 / 364 (6.87%)
    94 / 732 (12.84%)
         occurrences all number
    94
    26
    120
    Pyrexia
         subjects affected / exposed
    62 / 368 (16.85%)
    32 / 364 (8.79%)
    94 / 732 (12.84%)
         occurrences all number
    73
    38
    111
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    25 / 368 (6.79%)
    21 / 364 (5.77%)
    46 / 732 (6.28%)
         occurrences all number
    31
    25
    56
    Aphthous ulcer
         subjects affected / exposed
    21 / 368 (5.71%)
    4 / 364 (1.10%)
    25 / 732 (3.42%)
         occurrences all number
    32
    5
    37
    Constipation
         subjects affected / exposed
    19 / 368 (5.16%)
    25 / 364 (6.87%)
    44 / 732 (6.01%)
         occurrences all number
    24
    34
    58
    Diarrhoea
         subjects affected / exposed
    99 / 368 (26.90%)
    49 / 364 (13.46%)
    148 / 732 (20.22%)
         occurrences all number
    143
    66
    209
    Dry mouth
         subjects affected / exposed
    23 / 368 (6.25%)
    5 / 364 (1.37%)
    28 / 732 (3.83%)
         occurrences all number
    23
    5
    28
    Mouth ulceration
         subjects affected / exposed
    57 / 368 (15.49%)
    13 / 364 (3.57%)
    70 / 732 (9.56%)
         occurrences all number
    104
    24
    128
    Nausea
         subjects affected / exposed
    51 / 368 (13.86%)
    37 / 364 (10.16%)
    88 / 732 (12.02%)
         occurrences all number
    68
    41
    109
    Stomatitis
         subjects affected / exposed
    166 / 368 (45.11%)
    28 / 364 (7.69%)
    194 / 732 (26.50%)
         occurrences all number
    263
    32
    295
    Vomiting
         subjects affected / exposed
    34 / 368 (9.24%)
    30 / 364 (8.24%)
    64 / 732 (8.74%)
         occurrences all number
    44
    35
    79
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    65 / 368 (17.66%)
    40 / 364 (10.99%)
    105 / 732 (14.34%)
         occurrences all number
    78
    49
    127
    Dyspnoea
         subjects affected / exposed
    32 / 368 (8.70%)
    11 / 364 (3.02%)
    43 / 732 (5.87%)
         occurrences all number
    38
    11
    49
    Epistaxis
         subjects affected / exposed
    34 / 368 (9.24%)
    2 / 364 (0.55%)
    36 / 732 (4.92%)
         occurrences all number
    37
    2
    39
    Pneumonitis
         subjects affected / exposed
    24 / 368 (6.52%)
    1 / 364 (0.27%)
    25 / 732 (3.42%)
         occurrences all number
    24
    1
    25
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    36 / 368 (9.78%)
    22 / 364 (6.04%)
    58 / 732 (7.92%)
         occurrences all number
    40
    25
    65
    Rash
         subjects affected / exposed
    70 / 368 (19.02%)
    31 / 364 (8.52%)
    101 / 732 (13.80%)
         occurrences all number
    95
    35
    130
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    25 / 368 (6.79%)
    16 / 364 (4.40%)
    41 / 732 (5.60%)
         occurrences all number
    31
    18
    49
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 368 (8.15%)
    31 / 364 (8.52%)
    61 / 732 (8.33%)
         occurrences all number
    41
    35
    76
    Back pain
         subjects affected / exposed
    22 / 368 (5.98%)
    33 / 364 (9.07%)
    55 / 732 (7.51%)
         occurrences all number
    26
    34
    60
    Pain in extremity
         subjects affected / exposed
    25 / 368 (6.79%)
    28 / 364 (7.69%)
    53 / 732 (7.24%)
         occurrences all number
    26
    32
    58
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    42 / 368 (11.41%)
    32 / 364 (8.79%)
    74 / 732 (10.11%)
         occurrences all number
    51
    40
    91
    Pneumonia
         subjects affected / exposed
    23 / 368 (6.25%)
    3 / 364 (0.82%)
    26 / 732 (3.55%)
         occurrences all number
    23
    3
    26
    Sinusitis
         subjects affected / exposed
    21 / 368 (5.71%)
    11 / 364 (3.02%)
    32 / 732 (4.37%)
         occurrences all number
    23
    13
    36
    Upper respiratory tract infection
         subjects affected / exposed
    42 / 368 (11.41%)
    27 / 364 (7.42%)
    69 / 732 (9.43%)
         occurrences all number
    56
    32
    88
    Urinary tract infection
         subjects affected / exposed
    20 / 368 (5.43%)
    18 / 364 (4.95%)
    38 / 732 (5.19%)
         occurrences all number
    25
    29
    54
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    43 / 368 (11.68%)
    19 / 364 (5.22%)
    62 / 732 (8.47%)
         occurrences all number
    48
    20
    68
    Hypercholesterolaemia
         subjects affected / exposed
    42 / 368 (11.41%)
    13 / 364 (3.57%)
    55 / 732 (7.51%)
         occurrences all number
    45
    13
    58
    Hyperglycaemia
         subjects affected / exposed
    40 / 368 (10.87%)
    26 / 364 (7.14%)
    66 / 732 (9.02%)
         occurrences all number
    50
    33
    83
    Hypertriglyceridaemia
         subjects affected / exposed
    32 / 368 (8.70%)
    16 / 364 (4.40%)
    48 / 732 (6.56%)
         occurrences all number
    48
    21
    69

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2010
    The changes in this amendment were based on feedback from Investigators and institutional review boards/ethics committees, everolimus project-level updates and guidelines and clarifications and changes on study procedures and inclusion/exclusion criteria: Changes to criteria included: Bone marrow biopsy result prior to study start must be negative, Evidence of current CNS involvement with lymphoma; Changes to study procedures included: Hepatitis testing, pregnancy testing, and CNS involvement with lymphoma screening, end of treatment visit ≤ 7 days after stopping study drug, definition of relapse disease, additional biomarker assessment, study drug dosing and interruption, and concomitant medications.
    08 Nov 2010
    Several inclusion and exclusion criteria had been revised based on the feedback received from Investigators related to standard of care. As a consequence, the study design, the randomization and the analysis of the primary endpoint were revised: the minimum number of prior R-CHOP treatment cycles was reduced from 6 (in original protocol) to 5 cycles; the enrollment of patients who had received prior R-EPOCH treatment was allowed. Additionally, the randomization scheme was modified to stratify patients according to the type of prior rituximab-chemotherapy they received (R-CHOP vs. R-EPOCH). Patients enrolled in the original protocol were assigned to R-CHOP stratum; the analysis of the primary endpoint (disease-free survival) was modified to now use a stratified log-rank test to account for the new randomization scheme instead of an unstratified log-rank test as planned in the original protocol. This amendment also contained changes to ensure consistency across the everolimus clinical development program.
    15 Dec 2011
    The reason for this amendment was slow enrollment rate. Enrollment in this study had not met the expected rate as per the original assumptions, despite implementing practical and feasible approaches to increase the enrollment rate. The feasibility of the study within reasonable timelines was questionable with the current sample size. Therefore, in order not to jeopardize the feasibility of conducting the study within reasonable timelines, the sample size was modified to ensure completion of the study in a timely manner. The power of the study was reduced from 90% to 80%. Therefore the required number of DFS events was reduced from 374 to 279, resulting in sample size reduction 915 to 687 patients.
    15 Feb 2013
    The reason for this amendment was to include revised definition of relapsed disease, update protocol based on Investigator Brochure Edition 11, include Novartis guidance on prevention of pregnancy in clinical trials, and clarify and make changes on study procedures.
    02 Sep 2013
    The reason for this amendment was to increase the sample size, provide additional information on the unblinding and communication of interim OS results, and to include some clarifications related to study procedures. As the study remained blinded at the time of this amendment, this amendment did not affect the integrity of the study.
    10 Sep 2014
    The reason for the protocol amendment was to modify the censoring rule in the primary endpoint analysis for patients starting a new anticancer therapy; modify the follow-up of tumor assessment for patients starting a new anticancer therapy; and modify the definition of imaging modality change. As the study remained blinded at the time of this amendment, this amendment did not affect the integrity of the study.
    29 Jul 2015
    Globally there was one site that did not receive Amendment 7 approval by Last Patient Last Visit on 15-Jun-2016 (approval received 24-Jun-2016). This amendment was done for the following reasons: to remove the second IA and to conduct the final DFS analysis using a pre-defined fixed cut-off date of 31-Dec-2015 and the number of actual DFS events observed by that date, considering the long median study follow-up of 50 months (and at least 24 months follow-up for all patients by end of December 2015). Since there were fewer DFS events for the final DFS analysis, the power for primary endpoint was also amended; to maintain the interim overall survival (OS) analysis at the final DFS analysis (i.e., one IA for OS was removed) and perform the final OS analysis using a pre-defined fixed cutoff date of 31-Dec-2018 (5 years after randomization of the last patient) and the number of actual OS events observed by that date. Based on the number and timing of deaths observed in this study as of 22-Jun-2015 on pooled (i.e., blinded) data, the current projections suggested that it was highly unlikely that the originally targeted 338 OS events will ever be reached. Since there would be fewer death events at final OS analysis, the power for OS was also amended.

    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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