Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43857   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib in Combination with Bendamustine and Rituximab for Previously Untreated Chronic Lymphocytic Leukemia

    Summary
    EudraCT number
    		 2013-003313-17
    Trial protocol
    		 CZ   BE   HU   IT   ES   PL   HR  
    Global end of trial date
    16 Jun 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 May 2019
    First version publication date
    15 Apr 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Adding text to “Limitations and Caveats” section

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-312-0123
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01980888
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    16 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the progression-free survival in participants with previously untreated chronic lymphocytic leukemia (CLL) who would otherwise be suitable for bendamustine and rituximab treatment as standard of care.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 Bendamustine and rituximab
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Feb 2014
    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
    Poland: 33
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Hungary: 45
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    United States: 60
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Australia: 34
    Worldwide total number of subjects
    311
    EEA total number of subjects
    198
    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)
    153
    From 65 to 84 years
    158
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the North America, Australia, and Europe. The first participant was screened on 05 February 2014. The last study visit occurred on 16 June 2016.

    Pre-assignment
    Screening details
    		 392 participants were screened.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Idelalisib+Bendamustine+Rituximab
    Arm description
    		 Idelalisib + bendamustine + rituximab
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idelalisib
    Investigational medicinal product code
    Other name
    Zydelig®, GS-1101, CAL-101
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg administered twice daily

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Levact
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at a starting dose of 90 mg/m^2 for up to 6 total cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan, MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single-use vials administered weekly starting at 375 mg/m^2 on Day 1 (Week 0) and 500 mg/m^2 thereafter for a total of 6 cycles

    Arm title
    		 Placebo+Bendamustine+Rituximab
    Arm description
    		 Placebo + bendamustine + rituximab
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered twice daily

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Levact
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered at a starting dose of 90 mg/m^2 for up to 6 total cycles

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan, MabThera
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single-use vials administered weekly starting at 375 mg/m^2 on Day 1 (Week 0) and 500 mg/m^2 thereafter for a total of 6 cycles

    Number of subjects in period 1
    		Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Started
    157
    154
    Completed
    13
    21
    Not completed
    144
    133
         Withdrew Consent
    17
    6
         Non- Compliance with Study Drug
    3
    2
         Investigator's Discretion
    8
    3
         Study Terminated by Sponsor
    116
    122

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Idelalisib+Bendamustine+Rituximab
    Reporting group description
    		 Idelalisib + bendamustine + rituximab

    Reporting group title
    Placebo+Bendamustine+Rituximab
    Reporting group description
    		 Placebo + bendamustine + rituximab

    Reporting group values
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab Total
    Number of subjects
    		 157 154 311
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64 ( 8.7 ) 63 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 57 48 105
        Male
    		 100 106 206
    Race
    Units: Subjects
        Asian
    		 1 0 1
        Black or African American
    		 1 1 2
        White
    		 152 150 302
        Other
    		 3 1 4
        Not Permitted
    		 0 2 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 11 2 13
        Not Hispanic or Latino
    		 146 149 295
        Not Permitted
    		 0 3 3
    Rai Stage at Screening
    Rai staging is a way to categorize the disease progression of chronic lymphocytic leukemia (CLL) with higher stages reflecting increasing severity. Rai Stage 0: Lymphocytosis only, Rai Stage I: Lymphocytosis with lymphadenopathy, Rai Stage II: Lymphocytosis with hepatomegaly or splenomegaly, Rai Stage III: Lymphocytosis with anemia, Rai Stage IV: Lymphocytosis with thrombocytopenia.
    Units: Subjects
        Stage I
    		 28 30 58
        Stage II
    		 66 58 124
        Stage III
    		 25 32 57
        Stage IV
    		 38 34 72
    IgHV Mutation
    The mutation status of the unique immunoglobulin gene (IgHV) rearrangement in the monoclonal proliferation of B-cells in CLL can be used to predict aggressiveness of the disease. Participants with a mutated IgHV gene usually have a less aggressive and more indolent disease, with longer overall survival. Participants with an unmutated IgHV gene usually have a more aggressive disease and shorter overall survival.
    Units: Subjects
        Mutated
    		 54 54 108
        Unmutated
    		 102 100 202
        Missing
    		 1 0 1
    17p Deletion in CLL Cells
    Participants with CLL who have a 17p deletion lack a portion of the chromosome that acts to suppress cancer growth and is a recognized negative prognostic risk factor.
    Units: Subjects
        Absent
    		 146 145 291
        Present
    		 10 9 19
        Missing
    		 1 0 1

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Idelalisib+Bendamustine+Rituximab
    Reporting group description
    		 Idelalisib + bendamustine + rituximab

    Reporting group title
    Placebo+Bendamustine+Rituximab
    Reporting group description
    		 Placebo + bendamustine + rituximab

    Primary: Progression-Free Survival

    		 Close Top of page
    End point title
    		 Progression-Free Survival [1]
    End point description
    Progression-free survival (PFS) is defined as the interval from randomization to the first documentation of definitive disease progression or death from any cause. Definitive disease progression is CLL progression based on standard criteria, excluding lymphocytosis alone. PFS was to be assessed by an independent review committee (IRC). Due to the early termination of the study, efficacy data were not available for all subjects, and therefore the prespecified analyses were not conducted.
    End point type
    Primary
    End point timeframe
    Not applicable
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point values
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Not applicable
    Notes
    [2] - Analysis was not performed due to early study termination.
    [3] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Overall Response Rate

    		 Close Top of page
    End point title
    		 Overall Response Rate
    End point description
    Overall response rate (ORR) is defined as the proportion of participants who achieve a confirmed complete or partial response. ORR was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Not applicable
    Notes
    [4] - Analysis was not performed due to early study termination.
    [5] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Nodal Response Rate

    		 Close Top of page
    End point title
    		 Nodal Response Rate
    End point description
    Nodal response rate is defined as the proportion of participants who achieve a 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Nodal response rate was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Not applicable
    Notes
    [6] - Analysis was not performed due to early study termination.
    [7] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Complete Response Rate

    		 Close Top of page
    End point title
    		 Complete Response Rate
    End point description
    Complete response rate is defined as the proportion of participants who achieve a confirmed complete response. Complete response rate was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Not applicable
    Notes
    [8] - Analysis was not performed due to early study termination.
    [9] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Overall Survival

    		 Close Top of page
    End point title
    		 Overall Survival
    End point description
    Overall survival is defined as the interval from randomization to death from any cause. Due to the early termination of the study, efficacy data were not mature for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Not applicable
    Notes
    [10] - Analysis was not performed due to early study termination.
    [11] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Secondary: Minimal Residual Disease Negativity Rate at Week 36

    		 Close Top of page
    End point title
    		 Minimal Residual Disease Negativity Rate at Week 36
    End point description
    Minimal residual disease (MRD) negativity rate is defined as the proportion of participants with MRD < 10^-4 assessed by flow cytometry in bone marrow at Week 36 after therapy initiation or at least 12 weeks after the last dose of rituximab or bendamustine (whichever is later) for participants receiving the final dose of rituximab after the original scheduled date. MRD negativity rate was to be assessed by an IRC. Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    End point type
    Secondary
    End point timeframe
    Not applicable
    End point values
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Not applicable
    Notes
    [12] - Analysis was not performed due to early study termination.
    [13] - Analysis was not performed due to early study termination.
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Up to 22 months plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set: participants who received at least 1 dose of study treatment, with treatment assignments designated according to the actual treatment received. NOTE: Serious adverse events and deaths causally related to “treatment” refers to events deemed related to idelalisib/placebo/rituximab treatment per investigator assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Idelalisib+Bendamustine+Rituximab
    Reporting group description
    		 Idelalisib + bendamustine + rituximab

    Reporting group title
    Placebo+Bendamustine+Rituximab
    Reporting group description
    		 Placebo + bendamustine + rituximab

    Serious adverse events
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    113 / 156 (72.44%)
    68 / 154 (44.16%)
         number of deaths (all causes)
    13
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant ascites
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (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
    26 / 156 (16.67%)
    19 / 154 (12.34%)
         occurrences causally related to treatment / all
    24 / 35
    18 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 156 (0.00%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serum sickness
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         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 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 156 (3.21%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    6 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    3 / 156 (1.92%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 156 (2.56%)
    3 / 154 (1.95%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 156 (0.64%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         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
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dysarthria
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 156 (5.13%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    11 / 11
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    29 / 156 (18.59%)
    16 / 154 (10.39%)
         occurrences causally related to treatment / all
    29 / 33
    19 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 156 (4.49%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 156 (1.28%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    6 / 156 (3.85%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised erythema
         subjects affected / exposed
    2 / 156 (1.28%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    4 / 156 (2.56%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular acidosis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         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
    Compartment syndrome
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic amyotrophy
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus gastritis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 156 (1.92%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 156 (1.28%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis infectious
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    5 / 156 (3.21%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    11 / 156 (7.05%)
    6 / 154 (3.90%)
         occurrences causally related to treatment / all
    4 / 11
    4 / 9
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 156 (1.92%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    9 / 156 (5.77%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 2
         deaths causally related to treatment / all
    1 / 4
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strongyloidiasis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tonsillitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 156 (2.56%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 156 (1.92%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    5 / 156 (3.21%)
    4 / 154 (2.60%)
         occurrences causally related to treatment / all
    5 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Idelalisib+Bendamustine+Rituximab Placebo+Bendamustine+Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    154 / 156 (98.72%)
    150 / 154 (97.40%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    11 / 156 (7.05%)
    10 / 154 (6.49%)
         occurrences all number
    13
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    21 / 156 (13.46%)
    9 / 154 (5.84%)
         occurrences all number
    25
    10
    Chills
         subjects affected / exposed
    21 / 156 (13.46%)
    14 / 154 (9.09%)
         occurrences all number
    28
    14
    Fatigue
         subjects affected / exposed
    43 / 156 (27.56%)
    44 / 154 (28.57%)
         occurrences all number
    52
    60
    Mucosal inflammation
         subjects affected / exposed
    14 / 156 (8.97%)
    1 / 154 (0.65%)
         occurrences all number
    15
    2
    Oedema peripheral
         subjects affected / exposed
    19 / 156 (12.18%)
    16 / 154 (10.39%)
         occurrences all number
    21
    19
    Pyrexia
         subjects affected / exposed
    71 / 156 (45.51%)
    38 / 154 (24.68%)
         occurrences all number
    116
    61
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    8 / 156 (5.13%)
    2 / 154 (1.30%)
         occurrences all number
    10
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 156 (21.79%)
    29 / 154 (18.83%)
         occurrences all number
    47
    36
    Dyspnoea
         subjects affected / exposed
    24 / 156 (15.38%)
    12 / 154 (7.79%)
         occurrences all number
    33
    12
    Oropharyngeal pain
         subjects affected / exposed
    8 / 156 (5.13%)
    9 / 154 (5.84%)
         occurrences all number
    10
    10
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    11 / 156 (7.05%)
    9 / 154 (5.84%)
         occurrences all number
    12
    9
    Depression
         subjects affected / exposed
    8 / 156 (5.13%)
    2 / 154 (1.30%)
         occurrences all number
    8
    3
    Insomnia
         subjects affected / exposed
    17 / 156 (10.90%)
    12 / 154 (7.79%)
         occurrences all number
    21
    18
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    22 / 156 (14.10%)
    3 / 154 (1.95%)
         occurrences all number
    33
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 156 (11.54%)
    2 / 154 (1.30%)
         occurrences all number
    27
    2
    Neutrophil count decreased
         subjects affected / exposed
    8 / 156 (5.13%)
    2 / 154 (1.30%)
         occurrences all number
    17
    3
    Weight decreased
         subjects affected / exposed
    19 / 156 (12.18%)
    4 / 154 (2.60%)
         occurrences all number
    22
    4
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    21 / 156 (13.46%)
    33 / 154 (21.43%)
         occurrences all number
    24
    41
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    8 / 156 (5.13%)
    3 / 154 (1.95%)
         occurrences all number
    9
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 156 (8.33%)
    13 / 154 (8.44%)
         occurrences all number
    13
    15
    Dysgeusia
         subjects affected / exposed
    10 / 156 (6.41%)
    11 / 154 (7.14%)
         occurrences all number
    11
    12
    Headache
         subjects affected / exposed
    16 / 156 (10.26%)
    25 / 154 (16.23%)
         occurrences all number
    22
    28
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    40 / 156 (25.64%)
    29 / 154 (18.83%)
         occurrences all number
    52
    42
    Neutropenia
         subjects affected / exposed
    84 / 156 (53.85%)
    90 / 154 (58.44%)
         occurrences all number
    179
    180
    Thrombocytopenia
         subjects affected / exposed
    19 / 156 (12.18%)
    16 / 154 (10.39%)
         occurrences all number
    26
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 156 (8.97%)
    14 / 154 (9.09%)
         occurrences all number
    17
    17
    Constipation
         subjects affected / exposed
    26 / 156 (16.67%)
    34 / 154 (22.08%)
         occurrences all number
    33
    45
    Diarrhoea
         subjects affected / exposed
    63 / 156 (40.38%)
    46 / 154 (29.87%)
         occurrences all number
    111
    72
    Dry mouth
         subjects affected / exposed
    11 / 156 (7.05%)
    4 / 154 (2.60%)
         occurrences all number
    11
    4
    Dyspepsia
         subjects affected / exposed
    15 / 156 (9.62%)
    12 / 154 (7.79%)
         occurrences all number
    16
    17
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 156 (5.77%)
    4 / 154 (2.60%)
         occurrences all number
    9
    4
    Nausea
         subjects affected / exposed
    61 / 156 (39.10%)
    63 / 154 (40.91%)
         occurrences all number
    102
    95
    Stomatitis
         subjects affected / exposed
    10 / 156 (6.41%)
    4 / 154 (2.60%)
         occurrences all number
    12
    4
    Vomiting
         subjects affected / exposed
    37 / 156 (23.72%)
    23 / 154 (14.94%)
         occurrences all number
    61
    31
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    14 / 156 (8.97%)
    4 / 154 (2.60%)
         occurrences all number
    16
    5
    Erythema
         subjects affected / exposed
    12 / 156 (7.69%)
    8 / 154 (5.19%)
         occurrences all number
    17
    10
    Pruritus
         subjects affected / exposed
    24 / 156 (15.38%)
    32 / 154 (20.78%)
         occurrences all number
    27
    36
    Rash
         subjects affected / exposed
    63 / 156 (40.38%)
    34 / 154 (22.08%)
         occurrences all number
    87
    53
    Rash macular
         subjects affected / exposed
    8 / 156 (5.13%)
    2 / 154 (1.30%)
         occurrences all number
    8
    2
    Rash maculo-papular
         subjects affected / exposed
    29 / 156 (18.59%)
    12 / 154 (7.79%)
         occurrences all number
    40
    14
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    9 / 156 (5.77%)
    3 / 154 (1.95%)
         occurrences all number
    9
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 156 (10.26%)
    12 / 154 (7.79%)
         occurrences all number
    18
    13
    Back pain
         subjects affected / exposed
    11 / 156 (7.05%)
    18 / 154 (11.69%)
         occurrences all number
    12
    18
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 156 (3.21%)
    8 / 154 (5.19%)
         occurrences all number
    5
    8
    Influenza
         subjects affected / exposed
    6 / 156 (3.85%)
    8 / 154 (5.19%)
         occurrences all number
    6
    9
    Nasopharyngitis
         subjects affected / exposed
    8 / 156 (5.13%)
    14 / 154 (9.09%)
         occurrences all number
    8
    21
    Oral candidiasis
         subjects affected / exposed
    8 / 156 (5.13%)
    4 / 154 (2.60%)
         occurrences all number
    8
    4
    Oral herpes
         subjects affected / exposed
    5 / 156 (3.21%)
    8 / 154 (5.19%)
         occurrences all number
    7
    9
    Pneumonia
         subjects affected / exposed
    10 / 156 (6.41%)
    3 / 154 (1.95%)
         occurrences all number
    11
    3
    Respiratory tract infection
         subjects affected / exposed
    9 / 156 (5.77%)
    4 / 154 (2.60%)
         occurrences all number
    14
    4
    Sinusitis
         subjects affected / exposed
    9 / 156 (5.77%)
    4 / 154 (2.60%)
         occurrences all number
    9
    4
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 156 (16.03%)
    21 / 154 (13.64%)
         occurrences all number
    32
    29
    Urinary tract infection
         subjects affected / exposed
    15 / 156 (9.62%)
    6 / 154 (3.90%)
         occurrences all number
    15
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 156 (16.67%)
    21 / 154 (13.64%)
         occurrences all number
    32
    26
    Dehydration
         subjects affected / exposed
    12 / 156 (7.69%)
    2 / 154 (1.30%)
         occurrences all number
    17
    3
    Hypokalaemia
         subjects affected / exposed
    25 / 156 (16.03%)
    4 / 154 (2.60%)
         occurrences all number
    33
    5
    Hypophosphataemia
         subjects affected / exposed
    9 / 156 (5.77%)
    0 / 154 (0.00%)
         occurrences all number
    10
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2014
    The following changes were to align with the bendamustine and rituximab Summary of Product Characteristics (SmPC): ● To align the protocol with the male contraceptive requirements in the SmPC for bendamustine ● To exclude subjects with known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for idelalisib, bendamustine, or rituximab ● To exclude subjects who received yellow fever vaccine within 30 days prior to randomization ● To exclude subjects who have undergone major surgery within 30 days prior to randomization ● To include information regarding the use of live vaccines ● To refer investigators to local prescribing guidelines for each specific concomitant medicine with potential for safety considerations and discuss any questions with the Gilead Medical Monitor before initiation of such treatments
    06 Nov 2014
    To change MRD from a primary to a secondary endpoint, update to the guidance to investigators for evaluation, intervention, and drug interruption/discontinuation for specific adverse events, and revisions to the information regarding the interaction of idelalisib and CYP3A inhibitors, inducers, and substrates.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Mar 2016
    An increased rate of deaths and serious adverse events (SAEs) among participants with front-line CLL and early-line indolent non-Hodgkin lymphoma (iNHL) treated with idelalisib in combination with standard therapies was observed by the independent data monitoring committee (DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data and terminated this study in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA). Due to the early termination of the study, efficacy data were not available for all participants, and therefore the prespecified analyses were not conducted.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.
    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.

    European Medicines Agency © 1995-Thu Apr 25 02:11:48 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA