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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination with Rituximab for Previously Treated Chronic Lymphocytic Leukemia

    Summary
    EudraCT number
    		 2011-005180-24
    Trial protocol
    		 GB   DE  
    Global end of trial date
    20 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-312-0116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01539512
    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
    20 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of idelalisib in combination with rituximab on the onset, magnitude, and duration of tumor control in participants previously treated for chronic lymphocytic leukemia (CLL). Eligible patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either idelalisib plus rituximab or placebo plus rituximab. Participants who are tolerating primary study therapy but experience definitive CLL progression are eligible to receive active idelalisib therapy in the extension study, GS-US-312-0117.
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Apr 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    United States: 163
    Country: Number of subjects enrolled
    United Kingdom: 32
    Worldwide total number of subjects
    220
    EEA total number of subjects
    57
    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)
    48
    From 65 to 84 years
    165
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at a total of 53 study sites in the United States and Europe. The first participant was screened on 03 April 2012. The last study visit occurred on 20 April 2014.

    Pre-assignment
    Screening details
    		 Participants were evaluated at a screening visit, and eligible participants were randomized at a 1:1 ratio into 1 of 2 treatment groups.

    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
    		 Investigator, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Idelalisib + rituximab
    Arm description
    		 Participants were randomized to receive idelalisib plus rituximab for the duration of the study.
    Arm type
    		 Active comparator

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

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan®, MabThera®
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab administered as 8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter

    Arm title
    		 Placebo + rituximab
    Arm description
    		 Participants were randomized to receive placebo to match idelalisib plus rituximab for the duration of the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match idelalisib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match idelalisib administered orally twice daily

    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
    Rituximab administered as 8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter

    Number of subjects in period 1
    		Idelalisib + rituximab Placebo + rituximab
    Started
    110
    110
    Completed
    87
    97
    Not completed
    23
    13
         Adverse event, serious fatal
    -
    4
         Physician decision
    1
    1
         Consent withdrawn by subject
    12
    5
         Adverse event, non-fatal
    9
    3
         Richter's Transformation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Idelalisib + rituximab
    Reporting group description
    		 Participants were randomized to receive idelalisib plus rituximab for the duration of the study.

    Reporting group title
    Placebo + rituximab
    Reporting group description
    		 Participants were randomized to receive placebo to match idelalisib plus rituximab for the duration of the study.

    Reporting group values
    		 Idelalisib + rituximab Placebo + rituximab Total
    Number of subjects
    		 110 110 220
    Age, Customized
    Units: participants
        < 65 years
    		 21 27 48
        ≥ 65 years
    		 89 83 172
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71 ( 7.7 ) 70 ( 8.1 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 34 42 76
        Male
    		 76 68 144
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 2 5
        Not Hispanic or Latino
    		 101 102 203
        Not Permitted
    		 6 6 12
    Race
    Units: Subjects
        White
    		 100 98 198
        Black or African American
    		 3 3 6
        Other
    		 2 2 4
        Not Permitted
    		 5 7 12
    Karnofsky Performance Status
    Classifies patients according to their functional impairment. Scores range from 0-100; the lower the score, the worse the survival for most serious illnesses.
    Units: Subjects
        40
    		 1 1 2
        50
    		 3 4 7
        60
    		 6 5 11
        70
    		 20 13 33
        80
    		 42 46 88
        90
    		 23 28 51
        100
    		 15 13 28
    Rai Stage at Screening
    Rai staging categorizes the disease progression of chronic lymphocytic leukemia (CLL), with classifications of low- (Stage 0), intermediate- (Stage 1 and 2), and high-risk (Stages 3 and 4) categories. Rai Stage 0: high number of lymphocytes in the blood (lymphocytosis) only. Rai Stage 1: lymphocytosis with enlarged lymphoid tissues (lymphadenopathy). Rai Stage 2: lymphocytosis with enlarged liver (hepatomegaly) or spleen (splenomegaly). Rai Stage 3: lymphocytosis with low red blood cell count (anemia). Rai Stage 4: lymphocytosis with low number of blood platelets (thrombocytopenia).
    Units: Subjects
        Rai Stage 0
    		 0 1 1
        Rai Stage 1
    		 18 19 37
        Rai Stage 2
    		 16 10 26
        Rai Stage 3
    		 22 18 40
        Rai Stage 4
    		 48 54 102
        Missing
    		 6 8 14
    Binet Stage at Screening
    Binet staging classifies CLL according to the number of lymphoid tissues involved, as well as the presence of anemia or thrombocytopenia. Stage A: fewer than three areas of enlarged lymphoid tissue; enlarged lymph nodes of the neck, underarms, and groin, as well as the spleen, are each considered "one group" whether unilateral (one-sided) or bilateral (on both sides). Binet Stage B: more than three areas of enlarged lymphoid tissue. Binet Stage C: anemia plus thrombocytopenia.
    Units: Subjects
        Binet Stage A
    		 7 4 11
        Binet Stage B
    		 29 32 61
        Binet Stage C
    		 63 60 123
        Missing
    		 11 14 25
    Time Since Diagnosis
    Units: months
        arithmetic mean (standard deviation)
    		 108.3 ( 62.28 ) 106.4 ( 52.73 ) -

    End points

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    End points reporting groups
    Reporting group title
    Idelalisib + rituximab
    Reporting group description
    		 Participants were randomized to receive idelalisib plus rituximab for the duration of the study.

    Reporting group title
    Placebo + rituximab
    Reporting group description
    		 Participants were randomized to receive placebo to match idelalisib plus rituximab for the duration of the study.

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    Progression-free survival was defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression was CLL progression based on standard criteria (other than lymphocytosis alone) as defined by the 2008 update of the International Workshop on CLL guidelines, ie, appearance of any new lesion; increase by ≥ 50% in the sum of the products of the perpendicular diameters of measured lymph nodes (SPD); new or ≥ 50% enlargement of liver or spleen; transformation to a more aggressive histology (eg, Richter's or prolymphocytic transformation); reduction in the number of blood cells (cytopenia) attributable to CLL. 99999 = Upper limit of the 95% CI not reached due to insufficient number of events.
    End point type
    Primary
    End point timeframe
    Up to 21 months
    End point values
    		 Idelalisib + rituximab Placebo + rituximab
    Number of subjects analysed
    110
    110
    Units: months
        median (confidence interval 95%)
    19.4 (12.3 to 99999)
    6.5 (4 to 7.3)
    Statistical analysis title
    		 Difference in median months
    Comparison groups
    Idelalisib + rituximab v Placebo + rituximab
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.24
    Notes
    [1] - P-value is from stratified log-rank test, adjusted for randomization stratification factors.

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Overall response rate was defined as the percentage of participants who achieved a best overall response of complete response or partial response. Complete response was defined as no lymphadenopathy, hepatomegaly, splenomegaly; normal complete blood count; confirmed by bone marrow aspirate & biopsy. Partial response was defined as >1 of the following criteria: a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver size, spleen size; plus ≥ 1 of the following: ≥ 1500/μL absolute neutrophil count, > 100000/μL platelets, > 11.0 g/dL hemoglobin or 50% improvement for either of these parameters without transfusions or growth factors.
    End point type
    Secondary
    End point timeframe
    Up to 21 months
    End point values
    		 Idelalisib + rituximab Placebo + rituximab
    Number of subjects analysed
    110
    110
    Units: percentage of participants
        number (confidence interval 95%)
    83.6 (75.4 to 90)
    15.5 (9.3 to 23.6)
    No statistical analyses for this end point

    Secondary: Lymph Node Response Rate

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    End point title
    		 Lymph Node Response Rate
    End point description
    Lymph node response rate was defined as the percentage of participants who achieved a ≥ 50% decrease from baseline in the SPD of index lymph nodes.
    End point type
    Secondary
    End point timeframe
    Up to 21 months
    End point values
    		 Idelalisib + rituximab Placebo + rituximab
    Number of subjects analysed
    110
    110
    Units: percentage of participants
        number (confidence interval 95%)
    96.2 (90.6 to 99)
    6.7 (2.7 to 13.4)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival was defined as the interval from randomization to death from any cause. 999 = Lower limit of the 95% CI not reached due to insufficient number of events. 9999 = Median not reached due to insufficient number of events. 99999 = Upper limit of the 95% CI not reached due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 21 months
    End point values
    		 Idelalisib + rituximab Placebo + rituximab
    Number of subjects analysed
    110
    110
    Units: months
        median (confidence interval 95%)
    9999 (999 to 99999)
    20.8 (14.8 to 99999)
    Statistical analysis title
    		 Difference in median months
    Comparison groups
    Idelalisib + rituximab v Placebo + rituximab
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.6

    Secondary: Complete Response Rate

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    End point title
    		 Complete Response Rate
    End point description
    Complete response rate was defined as the percentage of participants who achieved a complete response.
    End point type
    Secondary
    End point timeframe
    Up to 21 months
    End point values
    		 Idelalisib + rituximab Placebo + rituximab
    Number of subjects analysed
    110
    110
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 21 months plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set: randomized participants who received at least 1 dose of study drug, with treatment assignments designated according to the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Idelalisib + rituximab
    Reporting group description
    		 Idelalisib 150 mg tablet administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)

    Reporting group title
    Placebo + rituximab
    Reporting group description
    		 Placebo to match idelalisib administered orally twice daily plus rituximab (8 intravenous doses through Week 20: Day 1: 375 mg/m^2, and 500 mg/m^2 thereafter)

    Serious adverse events
    		 Idelalisib + rituximab Placebo + rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    65 / 110 (59.09%)
    43 / 108 (39.81%)
         number of deaths (all causes)
    10
    15
         number of deaths resulting from adverse events
    2
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 110 (1.82%)
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    10 / 110 (9.09%)
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 110 (1.82%)
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haemoptysis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 110 (1.82%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 110 (3.64%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (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 / 110 (0.91%)
    0 / 108 (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
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         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 / 110 (0.00%)
    1 / 108 (0.93%)
         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
    1 / 110 (0.91%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         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 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iiird nerve disorder
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    5 / 110 (4.55%)
    6 / 108 (5.56%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 110 (2.73%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic infarction
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric mucosa erythema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (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
    8 / 110 (7.27%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    6 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    4 / 110 (3.64%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral pain
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin disorder
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alpha haemolytic streptococcal infection
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 110 (0.91%)
    4 / 108 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         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 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (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
    3 / 110 (2.73%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeriosis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 110 (2.73%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal infection
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    4 / 110 (3.64%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 110 (11.82%)
    10 / 108 (9.26%)
         occurrences causally related to treatment / all
    4 / 15
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pneumonia fungal
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (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
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 110 (6.36%)
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Sepsis syndrome
         subjects affected / exposed
    2 / 110 (1.82%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 110 (0.00%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Soft tissue infection
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stenotrophomonas infection
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 110 (0.91%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 110 (2.73%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 110 (1.82%)
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 110 (0.91%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Idelalisib + rituximab Placebo + rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 110 (93.64%)
    102 / 108 (94.44%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    4 / 110 (3.64%)
    7 / 108 (6.48%)
         occurrences all number
    4
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 110 (7.27%)
    8 / 108 (7.41%)
         occurrences all number
    8
    9
    Chills
         subjects affected / exposed
    27 / 110 (24.55%)
    16 / 108 (14.81%)
         occurrences all number
    33
    20
    Fatigue
         subjects affected / exposed
    34 / 110 (30.91%)
    35 / 108 (32.41%)
         occurrences all number
    38
    39
    Oedema peripheral
         subjects affected / exposed
    12 / 110 (10.91%)
    10 / 108 (9.26%)
         occurrences all number
    14
    11
    Pyrexia
         subjects affected / exposed
    40 / 110 (36.36%)
    18 / 108 (16.67%)
         occurrences all number
    59
    22
    Pain
         subjects affected / exposed
    8 / 110 (7.27%)
    1 / 108 (0.93%)
         occurrences all number
    8
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    27 / 110 (24.55%)
    34 / 108 (31.48%)
         occurrences all number
    28
    35
    Dyspnoea
         subjects affected / exposed
    17 / 110 (15.45%)
    22 / 108 (20.37%)
         occurrences all number
    21
    26
    Nasal congestion
         subjects affected / exposed
    6 / 110 (5.45%)
    4 / 108 (3.70%)
         occurrences all number
    6
    4
    Oropharyngeal pain
         subjects affected / exposed
    6 / 110 (5.45%)
    6 / 108 (5.56%)
         occurrences all number
    7
    6
    Productive cough
         subjects affected / exposed
    6 / 110 (5.45%)
    4 / 108 (3.70%)
         occurrences all number
    7
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 110 (2.73%)
    7 / 108 (6.48%)
         occurrences all number
    3
    7
    Insomnia
         subjects affected / exposed
    10 / 110 (9.09%)
    7 / 108 (6.48%)
         occurrences all number
    10
    7
    Investigations
    Weight decreased
         subjects affected / exposed
    11 / 110 (10.00%)
    9 / 108 (8.33%)
         occurrences all number
    12
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 110 (7.27%)
    0 / 108 (0.00%)
         occurrences all number
    13
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 110 (7.27%)
    0 / 108 (0.00%)
         occurrences all number
    11
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    21 / 110 (19.09%)
    33 / 108 (30.56%)
         occurrences all number
    32
    63
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 110 (10.00%)
    9 / 108 (8.33%)
         occurrences all number
    12
    11
    Dizziness
         subjects affected / exposed
    7 / 110 (6.36%)
    9 / 108 (8.33%)
         occurrences all number
    9
    10
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    8 / 110 (7.27%)
    4 / 108 (3.70%)
         occurrences all number
    11
    4
    Neutropenia
         subjects affected / exposed
    28 / 110 (25.45%)
    21 / 108 (19.44%)
         occurrences all number
    53
    25
    Anaemia
         subjects affected / exposed
    13 / 110 (11.82%)
    11 / 108 (10.19%)
         occurrences all number
    14
    13
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 110 (1.82%)
    6 / 108 (5.56%)
         occurrences all number
    2
    6
    Abdominal pain
         subjects affected / exposed
    9 / 110 (8.18%)
    11 / 108 (10.19%)
         occurrences all number
    10
    11
    Abdominal pain upper
         subjects affected / exposed
    8 / 110 (7.27%)
    3 / 108 (2.78%)
         occurrences all number
    9
    3
    Colitis
         subjects affected / exposed
    6 / 110 (5.45%)
    1 / 108 (0.93%)
         occurrences all number
    6
    1
    Constipation
         subjects affected / exposed
    16 / 110 (14.55%)
    15 / 108 (13.89%)
         occurrences all number
    17
    15
    Diarrhoea
         subjects affected / exposed
    31 / 110 (28.18%)
    19 / 108 (17.59%)
         occurrences all number
    59
    24
    Gastrooesophageal reflux disease
         subjects affected / exposed
    11 / 110 (10.00%)
    0 / 108 (0.00%)
         occurrences all number
    11
    0
    Stomatitis
         subjects affected / exposed
    7 / 110 (6.36%)
    1 / 108 (0.93%)
         occurrences all number
    7
    1
    Nausea
         subjects affected / exposed
    30 / 110 (27.27%)
    25 / 108 (23.15%)
         occurrences all number
    35
    32
    Vomiting
         subjects affected / exposed
    16 / 110 (14.55%)
    9 / 108 (8.33%)
         occurrences all number
    17
    9
    Skin and subcutaneous tissue disorders
    Night sweats
         subjects affected / exposed
    12 / 110 (10.91%)
    13 / 108 (12.04%)
         occurrences all number
    13
    13
    Pruritus
         subjects affected / exposed
    6 / 110 (5.45%)
    5 / 108 (4.63%)
         occurrences all number
    6
    6
    Skin lesion
         subjects affected / exposed
    3 / 110 (2.73%)
    7 / 108 (6.48%)
         occurrences all number
    3
    8
    Rash
         subjects affected / exposed
    16 / 110 (14.55%)
    4 / 108 (3.70%)
         occurrences all number
    19
    9
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    8 / 110 (7.27%)
    7 / 108 (6.48%)
         occurrences all number
    9
    8
    Back pain
         subjects affected / exposed
    6 / 110 (5.45%)
    4 / 108 (3.70%)
         occurrences all number
    6
    4
    Arthralgia
         subjects affected / exposed
    9 / 110 (8.18%)
    4 / 108 (3.70%)
         occurrences all number
    18
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 110 (6.36%)
    4 / 108 (3.70%)
         occurrences all number
    9
    4
    Sinusitis
         subjects affected / exposed
    9 / 110 (8.18%)
    6 / 108 (5.56%)
         occurrences all number
    11
    7
    Pneumonia
         subjects affected / exposed
    4 / 110 (3.64%)
    6 / 108 (5.56%)
         occurrences all number
    4
    7
    Cellulitis
         subjects affected / exposed
    7 / 110 (6.36%)
    2 / 108 (1.85%)
         occurrences all number
    7
    2
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 110 (8.18%)
    13 / 108 (12.04%)
         occurrences all number
    12
    13
    Urinary tract infection
         subjects affected / exposed
    8 / 110 (7.27%)
    4 / 108 (3.70%)
         occurrences all number
    9
    4
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    8 / 110 (7.27%)
    6 / 108 (5.56%)
         occurrences all number
    10
    6
    Decreased appetite
         subjects affected / exposed
    18 / 110 (16.36%)
    12 / 108 (11.11%)
         occurrences all number
    18
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2012
    Increased number of study centers from 50 to 70; clarified the definition of CLL that warranted treatment; extended the screening period to 6 weeks in subjects for whom there was a delay in the analysis of stratification variables.
    19 Dec 2012
    Updated information regarding secondary and tertiary endpoints; clarified that the independent review committee (IRC) findings would be considered primary for analyses of PFS and other disease control endpoints.
    21 Jun 2013
    Increased planned sample size from 160 to 200 subjects in order to maintain the planned study duration.
    10 Sep 2013
    Updated figure of study scheme to add open-label extension to Study GS-US-312-0117 should the primary study be stopped early due to overwhelming efficacy.
    16 Dec 2013
    Added monitoring guidelines for subjects who are Hepatitis B core antibody positive at screening based on new recommendations and rituximab FDA black box warning ie, subjects who were HBc antibody positive at screening were monitored for hepatitis B virus (HBV) reactivation (manifested as detectable HBV DNA by quantitative PCR). Participants were tested monthly for the duration of rituximab therapy and every 3 months thereafter for 1 year from the end of therapy.

    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.
    Following a recommendation by an independent Data Monitoring Committee (DMC), the study was stopped early due to highly statistically significant results in the experimental arm for the primary efficacy endpoint of progression-free survival.
    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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