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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of Lenalidomide (Revlimid®) as Maintenance Therapy for Patients with B-Cell Chronic Lymphocytic Leukemia Following Second-Line Therapy (The Continuum Trial)

    Summary
    EudraCT number
    		 2007-001626-27
    Trial protocol
    		 GB   DE   BE   ES   HU   CZ   PT   AT   IT   DK   FR   SE   NL   IE   BG  
    Global end of trial date
    27 Oct 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 May 2023
    First version publication date
    12 Nov 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-5013-CLL-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@BMS.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@BMS.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
    09 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the efficacy of lenalidomide versus placebo maintenance therapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Feb 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
    France: 8
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    United States: 29
    Country: Number of subjects enrolled
    Czechia: 18
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Russian Federation: 62
    Country: Number of subjects enrolled
    United Kingdom: 21
    Worldwide total number of subjects
    317
    EEA total number of subjects
    142
    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)
    185
    From 65 to 84 years
    132
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 317 randomized and 315 treated

    Period 1
    Period 1 title
    Pre-treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Study was unblinded in 2016 after reaching the required number of progression events.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lenalidomide
    Arm description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg - 10mg QD PO (x 28-day cycle)

    Arm title
    		 Placebo
    Arm description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QD PO (x 28-day cycle)

    Number of subjects in period 1
    		Lenalidomide Placebo
    Started
    160
    157
    Completed
    158
    157
    Not completed
    2
    0
         Other reasons
    2
    -
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Study was unblinded in 2016 after reaching the required number of progression events.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lenalidomide
    Arm description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg - 10mg QD PO (x 28-day cycle)

    Arm title
    		 Placebo
    Arm description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    QD PO (x 28-day cycle)

    Number of subjects in period 2
    		Lenalidomide Placebo
    Started
    158
    157
    Subjects Escalated to 5mg
    129
    149
    Subjects Escalated to 10mg
    68
    88
    Completed
    0
    0
    Not completed
    158
    157
         PD with histologic transformation
    4
    2
         Adverse event, serious fatal
    4
    -
         Consent withdrawn by subject
    5
    2
         PD without histologic transformation
    51
    111
         Adverse event, non-fatal
    61
    15
         Other reasons
    32
    26
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR

    Reporting group title
    Placebo
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR

    Reporting group values
    		 Lenalidomide Placebo Total
    Number of subjects
    		 160 157 317
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 92 93 185
        From 65-84 years
    		 68 64 132
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.9 ( 8.08 ) 62.5 ( 8.85 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 45 44 89
        Male
    		 115 113 228
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 3 2 5
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 1 4 5
        White
    		 154 150 304
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 0 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 6 1 7
        Not Hispanic or Latino
    		 153 156 309
        Unknown or Not Reported
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Lenalidomide
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR

    Reporting group title
    Placebo
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR
    Reporting group title
    Lenalidomide
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR

    Reporting group title
    Placebo
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival (OS) is defined as the time from randomization to death from any cause. OS will be censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for participants who were lost to follow-up before death was documented.
    End point type
    Primary
    End point timeframe
    Up to 12 years
    End point values
    		 Lenalidomide Placebo
    Number of subjects analysed
    160
    157
    Units: Months
        median (confidence interval 95%)
    95.09 (70.35 to 103.52)
    73.28 (59.98 to 102.98)
    Statistical analysis title
    		 Overall Survival (OS)
    Comparison groups
    Lenalidomide v Placebo
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.276 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.15
    Notes
    [1] - The p-value is based on a stratified log-rank test.

    Secondary: Progression Free Survival 2 (PFS2)

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    End point title
    		 Progression Free Survival 2 (PFS2)
    End point description
    Progression Free Survival (PFS2) assessed by investigator is defined as the time from randomization to the second objective disease progression, or death from any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Up to 6 years
    End point values
    		 Lenalidomide Placebo
    Number of subjects analysed
    160
    154
    Units: Months
        median (confidence interval 95%)
    99999 (49.5 to 99999)
    35.9 (27.4 to 99999)
    No statistical analyses for this end point

    Secondary: Incidence of Participants with Adverse Events (AEs)

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    End point title
    		 Incidence of Participants with Adverse Events (AEs)
    End point description
    Incidence of participants with adverse events (AEs) that measure type, frequency and severity of AEs graded by National Cancer Institute Common Terminology Criteria (NCI CTCAE V 3.0) including any grade adverse events (AEs), Grade 3-4 AEs, AEs related to study drug, grade 3-4 AEs related to study drug.
    End point type
    Secondary
    End point timeframe
    From first dose to 30 days post last dose (up to 9 years)
    End point values
    		 Lenalidomide Placebo
    Number of subjects analysed
    158
    157
    Units: Participants
        Adverse Events (AEs)
    155
    149
        Grade 3-4 AEs
    136
    73
        AEs related to Study drugs
    143
    98
        Grade 3-4 AEs related to Study drugs
    117
    41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 9 years
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR

    Reporting group title
    Lenalidomide
    Reporting group description
    		 2.5mg QD PO with escalation after 28 days to 5mg QD PO x 28 days, only if the 2.5mg dose was tolerated. Participants could be escalated to 10mg QD PO x 28 days, but only after 5 continuous cycles at 5mg and only if 5mg was well tolerated and if those participants had not achieved MRD-negative CR

    Serious adverse events
    		 Placebo Lenalidomide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 157 (31.21%)
    99 / 158 (62.66%)
         number of deaths (all causes)
    80
    78
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    8 / 157 (5.10%)
    9 / 158 (5.70%)
         occurrences causally related to treatment / all
    5 / 15
    6 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer stage III
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    4 / 157 (2.55%)
    8 / 158 (5.06%)
         occurrences causally related to treatment / all
    3 / 8
    3 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour flare
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         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
    Impaired healing
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue inflammation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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 / 157 (1.91%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    Acute respiratory failure
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchospasm
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 157 (0.64%)
    4 / 158 (2.53%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cranial nerve disorder
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Demyelination
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diplegia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual field defect
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia haemolytic autoimmune
         subjects affected / exposed
    2 / 157 (1.27%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune pancytopenia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         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
    0 / 157 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 157 (0.00%)
    7 / 158 (4.43%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    13 / 157 (8.28%)
    49 / 158 (31.01%)
         occurrences causally related to treatment / all
    16 / 18
    71 / 76
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye movement disorder
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuropathy
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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
    Erythema multiforme
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis herpetiformis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Mobility decreased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone tuberculosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr viraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster ophthalmic
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node abscess
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 157 (5.10%)
    7 / 158 (4.43%)
         occurrences causally related to treatment / all
    2 / 11
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia primary atypical
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 157 (0.00%)
    5 / 158 (3.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Salmonella sepsis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis bacterial
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (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 bacterial
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pericarditis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral labyrinthitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Lenalidomide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    140 / 157 (89.17%)
    152 / 158 (96.20%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour flare
         subjects affected / exposed
    9 / 157 (5.73%)
    12 / 158 (7.59%)
         occurrences all number
    14
    18
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 157 (7.64%)
    8 / 158 (5.06%)
         occurrences all number
    15
    10
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 157 (0.64%)
    10 / 158 (6.33%)
         occurrences all number
    1
    11
    Asthenia
         subjects affected / exposed
    2 / 157 (1.27%)
    10 / 158 (6.33%)
         occurrences all number
    2
    10
    Influenza like illness
         subjects affected / exposed
    2 / 157 (1.27%)
    11 / 158 (6.96%)
         occurrences all number
    2
    18
    Oedema peripheral
         subjects affected / exposed
    12 / 157 (7.64%)
    16 / 158 (10.13%)
         occurrences all number
    22
    20
    Fatigue
         subjects affected / exposed
    54 / 157 (34.39%)
    56 / 158 (35.44%)
         occurrences all number
    88
    121
    Pyrexia
         subjects affected / exposed
    17 / 157 (10.83%)
    28 / 158 (17.72%)
         occurrences all number
    26
    45
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    10 / 157 (6.37%)
    4 / 158 (2.53%)
         occurrences all number
    10
    6
    Oropharyngeal pain
         subjects affected / exposed
    16 / 157 (10.19%)
    15 / 158 (9.49%)
         occurrences all number
    19
    21
    Dyspnoea
         subjects affected / exposed
    11 / 157 (7.01%)
    16 / 158 (10.13%)
         occurrences all number
    15
    19
    Cough
         subjects affected / exposed
    32 / 157 (20.38%)
    46 / 158 (29.11%)
         occurrences all number
    44
    102
    Rhinorrhoea
         subjects affected / exposed
    4 / 157 (2.55%)
    10 / 158 (6.33%)
         occurrences all number
    6
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 157 (6.37%)
    10 / 158 (6.33%)
         occurrences all number
    13
    11
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    4 / 157 (2.55%)
    8 / 158 (5.06%)
         occurrences all number
    9
    8
    Weight increased
         subjects affected / exposed
    9 / 157 (5.73%)
    5 / 158 (3.16%)
         occurrences all number
    10
    7
    Weight decreased
         subjects affected / exposed
    14 / 157 (8.92%)
    22 / 158 (13.92%)
         occurrences all number
    18
    42
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 157 (5.73%)
    16 / 158 (10.13%)
         occurrences all number
    12
    21
    Headache
         subjects affected / exposed
    14 / 157 (8.92%)
    17 / 158 (10.76%)
         occurrences all number
    38
    20
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    44 / 157 (28.03%)
    106 / 158 (67.09%)
         occurrences all number
    80
    479
    Leukopenia
         subjects affected / exposed
    2 / 157 (1.27%)
    12 / 158 (7.59%)
         occurrences all number
    2
    21
    Anaemia
         subjects affected / exposed
    7 / 157 (4.46%)
    9 / 158 (5.70%)
         occurrences all number
    17
    13
    Thrombocytopenia
         subjects affected / exposed
    19 / 157 (12.10%)
    44 / 158 (27.85%)
         occurrences all number
    29
    103
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 157 (5.73%)
    18 / 158 (11.39%)
         occurrences all number
    12
    21
    Diarrhoea
         subjects affected / exposed
    26 / 157 (16.56%)
    65 / 158 (41.14%)
         occurrences all number
    45
    165
    Dyspepsia
         subjects affected / exposed
    8 / 157 (5.10%)
    12 / 158 (7.59%)
         occurrences all number
    10
    12
    Constipation
         subjects affected / exposed
    8 / 157 (5.10%)
    27 / 158 (17.09%)
         occurrences all number
    14
    42
    Abdominal pain upper
         subjects affected / exposed
    4 / 157 (2.55%)
    9 / 158 (5.70%)
         occurrences all number
    9
    12
    Nausea
         subjects affected / exposed
    27 / 157 (17.20%)
    26 / 158 (16.46%)
         occurrences all number
    39
    36
    Vomiting
         subjects affected / exposed
    13 / 157 (8.28%)
    12 / 158 (7.59%)
         occurrences all number
    22
    15
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 157 (1.27%)
    8 / 158 (5.06%)
         occurrences all number
    4
    9
    Hyperhidrosis
         subjects affected / exposed
    5 / 157 (3.18%)
    11 / 158 (6.96%)
         occurrences all number
    5
    11
    Pruritus
         subjects affected / exposed
    9 / 157 (5.73%)
    20 / 158 (12.66%)
         occurrences all number
    10
    32
    Rash
         subjects affected / exposed
    13 / 157 (8.28%)
    42 / 158 (26.58%)
         occurrences all number
    20
    71
    Night sweats
         subjects affected / exposed
    31 / 157 (19.75%)
    30 / 158 (18.99%)
         occurrences all number
    58
    50
    Actinic keratosis
         subjects affected / exposed
    3 / 157 (1.91%)
    10 / 158 (6.33%)
         occurrences all number
    6
    20
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    20 / 157 (12.74%)
    18 / 158 (11.39%)
         occurrences all number
    43
    21
    Arthralgia
         subjects affected / exposed
    10 / 157 (6.37%)
    23 / 158 (14.56%)
         occurrences all number
    19
    35
    Musculoskeletal pain
         subjects affected / exposed
    7 / 157 (4.46%)
    11 / 158 (6.96%)
         occurrences all number
    10
    19
    Muscle spasms
         subjects affected / exposed
    10 / 157 (6.37%)
    22 / 158 (13.92%)
         occurrences all number
    18
    34
    Myalgia
         subjects affected / exposed
    8 / 157 (5.10%)
    4 / 158 (2.53%)
         occurrences all number
    8
    4
    Pain in extremity
         subjects affected / exposed
    6 / 157 (3.82%)
    13 / 158 (8.23%)
         occurrences all number
    18
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    12 / 157 (7.64%)
    22 / 158 (13.92%)
         occurrences all number
    21
    33
    Herpes zoster
         subjects affected / exposed
    9 / 157 (5.73%)
    9 / 158 (5.70%)
         occurrences all number
    12
    10
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 157 (4.46%)
    12 / 158 (7.59%)
         occurrences all number
    9
    16
    Influenza
         subjects affected / exposed
    3 / 157 (1.91%)
    14 / 158 (8.86%)
         occurrences all number
    4
    17
    Nasopharyngitis
         subjects affected / exposed
    18 / 157 (11.46%)
    16 / 158 (10.13%)
         occurrences all number
    29
    34
    Respiratory tract infection
         subjects affected / exposed
    10 / 157 (6.37%)
    14 / 158 (8.86%)
         occurrences all number
    19
    20
    Oral herpes
         subjects affected / exposed
    7 / 157 (4.46%)
    10 / 158 (6.33%)
         occurrences all number
    8
    13
    Pharyngitis
         subjects affected / exposed
    7 / 157 (4.46%)
    10 / 158 (6.33%)
         occurrences all number
    8
    11
    Sinusitis
         subjects affected / exposed
    5 / 157 (3.18%)
    16 / 158 (10.13%)
         occurrences all number
    8
    23
    Pneumonia
         subjects affected / exposed
    2 / 157 (1.27%)
    10 / 158 (6.33%)
         occurrences all number
    2
    15
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 157 (17.83%)
    31 / 158 (19.62%)
         occurrences all number
    68
    53
    Viral infection
         subjects affected / exposed
    5 / 157 (3.18%)
    8 / 158 (5.06%)
         occurrences all number
    6
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    9 / 157 (5.73%)
    15 / 158 (9.49%)
         occurrences all number
    10
    19
    Hypokalaemia
         subjects affected / exposed
    3 / 157 (1.91%)
    10 / 158 (6.33%)
         occurrences all number
    3
    32

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2008
    Inclusion and Exclusion Criteria Update
    24 Apr 2015
    Study Endpoints Update
    13 May 2016
    Study Design Update
    16 Mar 2018
    Study Design Update

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

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