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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 Indolent Non-Hodgkin Lymphomas

    Summary
    EudraCT number
    		 2012-004013-13
    Trial protocol
    		 DE   GB   SE   ES   HU   CZ   IT   PT  
    Global end of trial date
    18 May 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

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    Trial identification
    Sponsor protocol code
    GS-US-313-0124
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01732913
    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 Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials 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
    18 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 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 effect of the addition of idelalisib to rituximab on progression-free survival (PFS) in adults with previously treated indolent non-Hodgkin lymphoma (iNHL).
    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
    16 Jan 2013
    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: 12
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 30
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Singapore: 9
    Country: Number of subjects enrolled
    United States: 99
    Country: Number of subjects enrolled
    Japan: 32
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Worldwide total number of subjects
    295
    EEA total number of subjects
    122
    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)
    129
    From 65 to 84 years
    156
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the North America, Europe, and Asia Pacific. The first participant was screened on 16 January 2013. The last study visit occurred on 18 May 2016.

    Pre-assignment
    Screening details
    		 385 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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Idelalisib + Rituximab
    Arm description
    		 Idelalisib (Zydelig®) 150 mg tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions
    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
    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 at a dose of 375 mg/m^2 starting on Day 1 for a total of 8 infusions.

    Arm title
    		 Placebo + Rituximab
    Arm description
    		 Placebo tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions
    Arm type
    		 Experimental

    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
    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 at a dose of 375 mg/m^2 starting on Day 1 for a total of 8 infusions.

    Number of subjects in period 1
    		Idelalisib + Rituximab Placebo + Rituximab
    Started
    198
    97
    Completed
    42
    28
    Not completed
    156
    69
         Physician decision
    14
    7
         Initiation of Other Anti-Cancer Therapy
    3
    2
         Other Reason
    7
    1
         Withdrawal by Subject
    27
    4
         Study Terminated by Sponsor
    105
    55

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Idelalisib + Rituximab
    Reporting group description
    		 Idelalisib (Zydelig®) 150 mg tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions

    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions

    Reporting group values
    		 Idelalisib + Rituximab Placebo + Rituximab Total
    Number of subjects
    		 198 97 295
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64 ( 11.4 ) 67 ( 11.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 99 48 147
        Male
    		 99 49 148
    Race
    Units: Subjects
        Asian
    		 35 17 52
        Black or African American
    		 5 4 9
        White
    		 123 54 177
        Other
    		 3 3 6
        Not Permitted
    		 32 19 51
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 12 3 15
        Not Hispanic or Latino
    		 150 75 225
        Unknown or Not Reported
    		 36 19 55

    End points

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    End points reporting groups
    Reporting group title
    Idelalisib + Rituximab
    Reporting group description
    		 Idelalisib (Zydelig®) 150 mg tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions

    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival [1]
    End point description
    Progression-free survival (PFS) is defined as the interval from randomization to the earlier of the first documentation of definitive iNHL disease progression or death from any cause. 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 participants, 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 + Rituximab Placebo + 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

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    End point title
    		 Overall Response Rate
    End point description
    Overall Response Rate (ORR) is defined as the proportion of participants who achieve a complete response or partial response (or very good partial response or minor response for participants with Waldenstrom's). 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 + Rituximab Placebo + 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: Lymph Node Response Rate

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    End point title
    		 Lymph Node Response Rate
    End point description
    Lymph node response rate is defined as the proportion of participants who achieve ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters of index lesions. Lymph node 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 + Rituximab Placebo + 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

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    End point title
    		 Complete Response Rate
    End point description
    Complete response rate is defined as the proportion of participants who achieve a 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 + Rituximab Placebo + 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

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    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 + Rituximab Placebo + 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

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 27 months plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set included all participants who took at least 1 dose of study drug. 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 + rituximab
    Reporting group description
    		 Idelalisib 150 mg tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions

    Reporting group title
    Placebo + rituximab
    Reporting group description
    		 Placebo tablet orally twice daily + rituximab 375 mg/m^2 intravenously starting on Day 1 for a total of 8 infusions

    Serious adverse events
    		 Idelalisib + rituximab Placebo + rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    103 / 198 (52.02%)
    11 / 95 (11.58%)
         number of deaths (all causes)
    11
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer recurrent
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    9 / 198 (4.55%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    Bronchitis chronic
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    3 / 198 (1.52%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    8 / 198 (4.04%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    7 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 198 (1.52%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    11 / 198 (5.56%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 198 (5.05%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 198 (0.51%)
    2 / 95 (2.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    Cerebrovascular accident
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 198 (1.52%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 198 (1.52%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    7 / 198 (3.54%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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 / 198 (1.52%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    8 / 198 (4.04%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    8 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    18 / 198 (9.09%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    21 / 23
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland disorder
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 198 (1.52%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland enlargement
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    3 / 198 (1.52%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    4 / 198 (2.02%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 198 (2.53%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema herpeticum
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster meningomyelitis
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 198 (0.51%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 198 (0.00%)
    1 / 95 (1.05%)
         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
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (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
    19 / 198 (9.60%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    10 / 22
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 198 (2.53%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 198 (2.02%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 198 (2.02%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 198 (0.51%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 198 (1.01%)
    0 / 95 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Idelalisib + rituximab Placebo + rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    189 / 198 (95.45%)
    83 / 95 (87.37%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 198 (6.06%)
    2 / 95 (2.11%)
         occurrences all number
    14
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 198 (7.58%)
    9 / 95 (9.47%)
         occurrences all number
    17
    11
    Chills
         subjects affected / exposed
    11 / 198 (5.56%)
    4 / 95 (4.21%)
         occurrences all number
    16
    4
    Fatigue
         subjects affected / exposed
    41 / 198 (20.71%)
    20 / 95 (21.05%)
         occurrences all number
    47
    21
    Oedema peripheral
         subjects affected / exposed
    14 / 198 (7.07%)
    5 / 95 (5.26%)
         occurrences all number
    15
    5
    Pyrexia
         subjects affected / exposed
    50 / 198 (25.25%)
    11 / 95 (11.58%)
         occurrences all number
    67
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 198 (14.14%)
    14 / 95 (14.74%)
         occurrences all number
    29
    16
    Dyspnoea
         subjects affected / exposed
    12 / 198 (6.06%)
    2 / 95 (2.11%)
         occurrences all number
    13
    2
    Oropharyngeal pain
         subjects affected / exposed
    12 / 198 (6.06%)
    3 / 95 (3.16%)
         occurrences all number
    15
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    10 / 198 (5.05%)
    3 / 95 (3.16%)
         occurrences all number
    10
    3
    Insomnia
         subjects affected / exposed
    21 / 198 (10.61%)
    11 / 95 (11.58%)
         occurrences all number
    25
    12
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    65 / 198 (32.83%)
    0 / 95 (0.00%)
         occurrences all number
    90
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    56 / 198 (28.28%)
    0 / 95 (0.00%)
         occurrences all number
    72
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 198 (5.56%)
    1 / 95 (1.05%)
         occurrences all number
    11
    1
    Transaminases increased
         subjects affected / exposed
    12 / 198 (6.06%)
    1 / 95 (1.05%)
         occurrences all number
    17
    1
    Weight decreased
         subjects affected / exposed
    20 / 198 (10.10%)
    1 / 95 (1.05%)
         occurrences all number
    20
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    36 / 198 (18.18%)
    20 / 95 (21.05%)
         occurrences all number
    42
    27
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 198 (6.06%)
    6 / 95 (6.32%)
         occurrences all number
    15
    6
    Headache
         subjects affected / exposed
    30 / 198 (15.15%)
    12 / 95 (12.63%)
         occurrences all number
    42
    15
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 198 (6.06%)
    6 / 95 (6.32%)
         occurrences all number
    14
    12
    Neutropenia
         subjects affected / exposed
    25 / 198 (12.63%)
    5 / 95 (5.26%)
         occurrences all number
    49
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 198 (10.10%)
    4 / 95 (4.21%)
         occurrences all number
    24
    5
    Constipation
         subjects affected / exposed
    28 / 198 (14.14%)
    13 / 95 (13.68%)
         occurrences all number
    30
    14
    Diarrhoea
         subjects affected / exposed
    88 / 198 (44.44%)
    18 / 95 (18.95%)
         occurrences all number
    133
    26
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 198 (5.05%)
    3 / 95 (3.16%)
         occurrences all number
    10
    3
    Nausea
         subjects affected / exposed
    50 / 198 (25.25%)
    12 / 95 (12.63%)
         occurrences all number
    65
    14
    Vomiting
         subjects affected / exposed
    29 / 198 (14.65%)
    7 / 95 (7.37%)
         occurrences all number
    33
    10
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    25 / 198 (12.63%)
    4 / 95 (4.21%)
         occurrences all number
    29
    4
    Rash
         subjects affected / exposed
    38 / 198 (19.19%)
    12 / 95 (12.63%)
         occurrences all number
    42
    16
    Rash maculo-papular
         subjects affected / exposed
    16 / 198 (8.08%)
    2 / 95 (2.11%)
         occurrences all number
    19
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 198 (4.55%)
    6 / 95 (6.32%)
         occurrences all number
    12
    6
    Back pain
         subjects affected / exposed
    9 / 198 (4.55%)
    6 / 95 (6.32%)
         occurrences all number
    10
    7
    Pain in extremity
         subjects affected / exposed
    16 / 198 (8.08%)
    3 / 95 (3.16%)
         occurrences all number
    17
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 198 (4.55%)
    6 / 95 (6.32%)
         occurrences all number
    10
    8
    Nasopharyngitis
         subjects affected / exposed
    10 / 198 (5.05%)
    6 / 95 (6.32%)
         occurrences all number
    12
    9
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 198 (11.62%)
    8 / 95 (8.42%)
         occurrences all number
    30
    9
    Urinary tract infection
         subjects affected / exposed
    13 / 198 (6.57%)
    3 / 95 (3.16%)
         occurrences all number
    15
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 198 (13.13%)
    2 / 95 (2.11%)
         occurrences all number
    27
    2
    Dehydration
         subjects affected / exposed
    11 / 198 (5.56%)
    0 / 95 (0.00%)
         occurrences all number
    12
    0
    Hypokalaemia
         subjects affected / exposed
    21 / 198 (10.61%)
    4 / 95 (4.21%)
         occurrences all number
    22
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jan 2013
    • Updated information regarding secondary and tertiary endpoints • Updated inclusion criteria relating to contraception to comply with the European Union (EU) health authority • Clarified that the IRC findings were primary for analyses of PFS and other tumor control endpoints • Updated plan to control Type I error rate for secondary endpoints • Increased washout period for previous cancer therapies from 3 to 6 weeks • Provided clarification on phototoxicity risk • Clarified duration of therapy for each study treatment group • Clarified that subjects in Groups A and B who prematurely discontinued 1 study drug could continue other study drug • Updated safety and clinical information in alignment with Version 7 of the Investigator's Brochure (IB) • Added new section to differentiate discontinuation from study versus discontinuation of study drug • Clarified language around dose modifications that are made for adverse events (AEs) or laboratory abnormalities that the investigator considered related to study drug • Changed the criteria for splenomegaly with a splenic longest vertical dimension from 10 cm to 12 cm based on expert radiology recommendations
    17 Sep 2013
    Revised text to add 1 additional formal interim efficacy analysis after ~50% of the expected number of PFS events have occurred and changed the 2nd interim analysis from 66% of the planned events occurring to 75%
    22 Oct 2013
    Added monitoring guidelines for Hep B reactivation
    29 Jul 2014
    Added a double-blind extension to allow eligible subjects to receive idelalisib monotherapy at the time of iNHL disease progression
    31 Oct 2014
    • Updated the following information to align with investigator's brochure Edition 11. - Guidance to investigators for evaluation, intervention, and drug interruption/discontinuation for specific adverse events. - Information regarding the interaction of idelalisib with CYP3A inhibitors, inducers, and substrates.
    31 Jul 2015
    Added an open-label extension to permit subjects randomized to Group B (Placebo + Rituximab) the opportunity to receive open-label IDL150 mg twice daily

    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 chronic lymphocytic leukemia (CLL) and early-line 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.
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    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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