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

    Summary
    EudraCT number
    2012-001236-65
    Trial protocol
    BE   IE   GB   SE   ES   DK   FR  
    Global end of trial date
    15 Aug 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Aug 2019
    First version publication date
    21 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-312-0119
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01659021
    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
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@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
    15 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2018
    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 ofatumumab on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL).
    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
    04 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    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
    Poland: 36
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    United States: 93
    Country: Number of subjects enrolled
    Australia: 29
    Country: Number of subjects enrolled
    Canada: 22
    Worldwide total number of subjects
    261
    EEA total number of subjects
    117
    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)
    94
    From 65 to 84 years
    166
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at study sites in North America, Europe, and Australia. The first participant was screened on 04 December 2012. The last study visit occurred on 15 August 2018.

    Pre-assignment
    Screening details
    310 participants were screened.

    Period 1
    Period 1 title
    Main Study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Idelalisib+Ofatumumab
    Arm description
    Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.
    Arm type
    Experimental

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

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Arzerra®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses)

    Arm title
    Ofatumumab
    Arm description
    Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.
    Arm type
    Active comparator

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Arzerra®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses)

    Number of subjects in period 1
    Idelalisib+Ofatumumab Ofatumumab
    Started
    174
    87
    Randomized and Treated
    173
    86
    Completed: Disease Progression or Death
    100
    50
    Completed
    100
    50
    Not completed
    74
    37
         Study Terminated by Sponsor
    16
    1
         Physician decision
    34
    16
         Withdrawal by Subject
    19
    16
         Unknown Reasons
    2
    1
         Adverse Event
    2
    3
         Lost to follow-up
    1
    -
    Period 2
    Period 2 title
    Long-Term Follow Up
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    The arms in the LTFU period are mutually exclusive, but due to system restrictions, "No" was entered for this field to allow entry of appropriate data.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Idelalisib+Ofatumumab (LTFU)
    Arm description
    Long-Term Follow-up (LTFU): Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Ofatumumab (LTFU)
    Arm description
    LTFU: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Idelalisib+Ofatumumab (LTFU) Ofatumumab (LTFU)
    Started
    138
    69
    Completed
    133
    65
    Not completed
    5
    4
         Withdrawal by Subject
    2
    1
         Lost to follow-up
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Idelalisib+Ofatumumab
    Reporting group description
    Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

    Reporting group title
    Ofatumumab
    Reporting group description
    Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

    Reporting group values
    Idelalisib+Ofatumumab Ofatumumab Total
    Number of subjects
    174 87 261
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    67 ± 9.0 67 ± 9.7 -
    Gender categorical
    Units: Subjects
        Female
    50 25 75
        Male
    124 62 186
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    7 3 10
        Not Hispanic or Latino
    141 74 215
        Unknown or Not Reported
    26 10 36
    Race
    Units: Subjects
        White
    149 71 220
        Black or African American
    0 4 4
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Asian
    2 0 2
        Other
    2 3 5
        Not Permitted
    20 9 29
    17p deletion and/ or TP53 mutation
    Units: Subjects
        Either
    70 33 103
        Neither
    104 54 158
    Immunoglobulin heavy chain variable region (IGHV) mutation status
    Units: Subjects
        Mutated
    37 19 56
        Unmutated
    137 68 205
    Disease Status
    Refractory: CLL progression < 6 months from completion of prior therapy; Relapsed: CLL progression ≥ 6 months from completion of prior therapy.
    Units: Subjects
        Refractory
    82 47 129
        Relapsed
    92 40 132
    Time Since Diagnosis
    Only participants who were randomized and treated are included. Idelalisib+Ofatumumab = 173 participants; Ofatumumab = 86 participants
    Units: months
        arithmetic mean (standard deviation)
    101.0 ± 60.21 94.3 ± 52.51 -

    End points

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    End points reporting groups
    Reporting group title
    Idelalisib+Ofatumumab
    Reporting group description
    Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.

    Reporting group title
    Ofatumumab
    Reporting group description
    Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation.
    Reporting group title
    Idelalisib+Ofatumumab (LTFU)
    Reporting group description
    Long-Term Follow-up (LTFU): Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

    Reporting group title
    Ofatumumab (LTFU)
    Reporting group description
    LTFU: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

    Primary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS 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. PFS was analyzed using Kaplan-Meier (KM) estimates. Intent-to-Treat (ITT) Analysis Set included participants who were randomized regardless of whether they received any study drug(s), or received a different regimen from that to which they were randomized. Treatment was according to randomization.
    End point type
    Primary
    End point timeframe
    Randomization to End of Study (up to 60 months)
    End point values
    Idelalisib+Ofatumumab Ofatumumab
    Number of subjects analysed
    174
    87
    Units: months
        median (confidence interval 95%)
    16.6 (13.7 to 19.6)
    8.0 (5.7 to 8.4)
    Statistical analysis title
    Statistical Analysis for Progression-Free Survival
    Comparison groups
    Idelalisib+Ofatumumab v Ofatumumab
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    0.37
    Notes
    [1] - P-value: stratified log-rank test, adjusted for randomization stratification factors (17p deletion/TP53 mutation, IGHV mutation, and disease status). Hazard Ratio & 95% CIs: proportional hazard model, 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. Overall response rate was analyzed using KM estimates. Participants in the ITT Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to End of Study (up to 60 months)
    End point values
    Idelalisib+Ofatumumab Ofatumumab
    Number of subjects analysed
    174
    87
    Units: percentage of participants
        number (confidence interval 95%)
    75.3 (68.2 to 81.5)
    17.2 (10.0 to 26.8)
    Statistical analysis title
    Statistical Analysis for Overall Response Rate
    Comparison groups
    Ofatumumab v Idelalisib+Ofatumumab
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    16.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.17
         upper limit
    34.76
    Notes
    [2] - P-value, odds ratio, and 95% CIs were calculated from the Cochran-Mantel-Haenszel (CMH) Chi-square test stratified by stratification factors.

    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 proportion of participants who achieved a ≥ 50% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes. Participants in the ITT Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to End of Study (up to 60 months)
    End point values
    Idelalisib+Ofatumumab Ofatumumab
    Number of subjects analysed
    164
    81
    Units: percentage of participants
        number (confidence interval 95%)
    92.7 (87.6 to 96.2)
    4.9 (1.4 to 12.2)
    Statistical analysis title
    Statistical Analysis for Lymph Node Response Rate
    Comparison groups
    Idelalisib+Ofatumumab v Ofatumumab
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    483.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    94.63
         upper limit
    2467.02
    Notes
    [3] - P-value, odds ratio, and 95% CI were calculated from the CMH Chi-square test stratified by stratification factors.

    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. Overall survival was analyzed using KM estimates. Participants in the ITT Analysis Set were analyzed. 999 = Not applicable, too few events to estimate the upper limit of the confidence interval.
    End point type
    Secondary
    End point timeframe
    Randomization to Last Long-Term Follow-Up Visit (up to maximum of 5 years)
    End point values
    Idelalisib+Ofatumumab Ofatumumab
    Number of subjects analysed
    174
    87
    Units: months
        median (confidence interval 95%)
    45.2 (34.1 to 999)
    39 (23.0 to 999)
    Statistical analysis title
    Statistical Analysis for Overall Survival
    Comparison groups
    Idelalisib+Ofatumumab v Ofatumumab
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.247 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.15
    Notes
    [4] - P-value is from stratified log-rank test, adjusted for randomization stratification factors (17p deletion/TP53 mutation, IGHV mutation, and disease status).

    Secondary: Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation

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    End point title
    Progression-Free Survival in Subgroup of Participants With Chromosome 17p Deletion and/or TP53 Mutation
    End point description
    Progression-free survival in subgroup of participants with chromosome 17p deletion and/or TP53 mutation was analyzed using KM estimates. Participants in the ITT Analysis Set with chromosome 17p deletion and/or TP53 mutation were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to End of Study (up to 60 months)
    End point values
    Idelalisib+Ofatumumab Ofatumumab
    Number of subjects analysed
    70
    33
    Units: months
        median (confidence interval 95%)
    16.2 (11.1 to 19.1)
    5.8 (4.5 to 8.4)
    Statistical analysis title
    Statistical Analysis for PFS in Subgroup
    Comparison groups
    Idelalisib+Ofatumumab v Ofatumumab
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.51
    Notes
    [5] - Hazard ratio and 95% CIs were calculated using the Cox proportional hazards model without any adjustments.

    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 achieve a complete response and maintain their response for at least 8 weeks (with a 1-week window). Participants in the ITT Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to End of Study (up to 60 months)
    End point values
    Idelalisib+Ofatumumab Ofatumumab
    Number of subjects analysed
    174
    87
    Units: percentage of participants
        number (not applicable)
    1.1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events: Start of Treatment to End of Treatment (up to 60 months) plus 30 days; All-Cause Mortality: Baseline to Last Long-Term Follow-Up Visit (up to maximum of 5 years)
    Adverse event reporting additional description
    All-Cause Mortality was assessed in all randomized participants. All other adverse events were assessed in the Safety Analysis Set (participants who received ≥ 1 dose of study treatment, with treatment assignments designated according to the actual treatment received).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Idelalisib+Ofatumumab
    Reporting group description
    Randomized Initial Therapy (24 weeks): Idelalisib 150 mg tablets twice daily + ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 1000 mg weekly for 7 weeks, and then 1000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Idelalisib 150 mg tablets twice daily until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation Long-Term Follow-up: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

    Reporting group title
    Ofatumumab
    Reporting group description
    Randomized Initial Therapy (24 weeks): Ofatumumab for a total of 12 infusions (300 mg on Day 1, followed by 2000 mg weekly for 7 weeks, and then 2000 mg every 4 weeks for 4 doses); Continuing Therapy/Observation: Observation until the earliest of subject withdrawal from study, definitive progression of CLL, intolerable idelalisib-related toxicity, pregnancy or initiation of breast feeding, substantial noncompliance with study procedures, or study discontinuation Long-Term Follow-up: Participants were followed for up to 5 years. Information on medical status, anti-tumor treatments, secondary malignancies, and survival status were collected annually during a routine clinic visit or other contact, such as telephone.

    Serious adverse events
    Idelalisib+Ofatumumab Ofatumumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    136 / 173 (78.61%)
    36 / 86 (41.86%)
         number of deaths (all causes)
    87
    40
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    7 / 173 (4.05%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anogenital warts
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system leukaemia
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colon cancer metastatic
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycosis fungoides
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    23 / 173 (13.29%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    17 / 37
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 173 (1.16%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired self-care
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated hernia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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
    Infusion related reaction
         subjects affected / exposed
    3 / 173 (1.73%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    6 / 173 (3.47%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    6 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 173 (0.58%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 173 (1.73%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         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 / 173 (0.58%)
    0 / 86 (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
    Pneumonitis
         subjects affected / exposed
    7 / 173 (4.05%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 173 (3.47%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    4 / 173 (2.31%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower respiratory tract inflammation
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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
    19 / 173 (10.98%)
    3 / 86 (3.49%)
         occurrences causally related to treatment / all
    19 / 25
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    13 / 173 (7.51%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    10 / 18
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    8 / 173 (4.62%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 173 (2.89%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Granulocytopenia
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Locked-in syndrome
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    External ear inflammation
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    23 / 173 (13.29%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    25 / 32
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    13 / 173 (7.51%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    14 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    7 / 173 (4.05%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    4 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 173 (1.73%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 173 (1.73%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 173 (2.89%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 173 (1.73%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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
    Dermatitis allergic
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    6 / 173 (3.47%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    3 / 173 (1.73%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 173 (1.73%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 173 (2.31%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudohyperkalaemia
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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
    Pneumonia
         subjects affected / exposed
    27 / 173 (15.61%)
    9 / 86 (10.47%)
         occurrences causally related to treatment / all
    13 / 35
    2 / 9
         deaths causally related to treatment / all
    3 / 7
    1 / 2
    Sepsis
         subjects affected / exposed
    11 / 173 (6.36%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    6 / 13
    0 / 1
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 173 (4.05%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    4 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    8 / 173 (4.62%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    6 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 173 (4.05%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    4 / 173 (2.31%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    5 / 173 (2.89%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 4
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    3 / 173 (1.73%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 173 (2.31%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 173 (2.31%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 173 (0.58%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 173 (0.00%)
    2 / 86 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pseudomonal bacteraemia
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 173 (1.16%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida pneumonia
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (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 bacterial
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 173 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral sepsis
         subjects affected / exposed
    1 / 173 (0.58%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Idelalisib+Ofatumumab Ofatumumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 173 (96.53%)
    79 / 86 (91.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 173 (12.14%)
    6 / 86 (6.98%)
         occurrences all number
    23
    7
    Hypotension
         subjects affected / exposed
    14 / 173 (8.09%)
    5 / 86 (5.81%)
         occurrences all number
    18
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    11 / 173 (6.36%)
    3 / 86 (3.49%)
         occurrences all number
    20
    3
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    11 / 173 (6.36%)
    3 / 86 (3.49%)
         occurrences all number
    12
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    60 / 173 (34.68%)
    24 / 86 (27.91%)
         occurrences all number
    82
    25
    Pyrexia
         subjects affected / exposed
    55 / 173 (31.79%)
    19 / 86 (22.09%)
         occurrences all number
    106
    28
    Oedema peripheral
         subjects affected / exposed
    35 / 173 (20.23%)
    9 / 86 (10.47%)
         occurrences all number
    41
    11
    Chills
         subjects affected / exposed
    27 / 173 (15.61%)
    13 / 86 (15.12%)
         occurrences all number
    31
    17
    Asthenia
         subjects affected / exposed
    27 / 173 (15.61%)
    9 / 86 (10.47%)
         occurrences all number
    30
    9
    Influenza like illness
         subjects affected / exposed
    14 / 173 (8.09%)
    1 / 86 (1.16%)
         occurrences all number
    18
    1
    Pain
         subjects affected / exposed
    13 / 173 (7.51%)
    2 / 86 (2.33%)
         occurrences all number
    16
    2
    Peripheral swelling
         subjects affected / exposed
    12 / 173 (6.94%)
    1 / 86 (1.16%)
         occurrences all number
    13
    1
    Chest pain
         subjects affected / exposed
    9 / 173 (5.20%)
    2 / 86 (2.33%)
         occurrences all number
    10
    2
    Malaise
         subjects affected / exposed
    10 / 173 (5.78%)
    1 / 86 (1.16%)
         occurrences all number
    11
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    30 / 173 (17.34%)
    12 / 86 (13.95%)
         occurrences all number
    36
    12
    Anxiety
         subjects affected / exposed
    15 / 173 (8.67%)
    2 / 86 (2.33%)
         occurrences all number
    15
    2
    Confusional state
         subjects affected / exposed
    10 / 173 (5.78%)
    0 / 86 (0.00%)
         occurrences all number
    16
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    30 / 173 (17.34%)
    23 / 86 (26.74%)
         occurrences all number
    40
    35
    Contusion
         subjects affected / exposed
    18 / 173 (10.40%)
    3 / 86 (3.49%)
         occurrences all number
    21
    3
    Investigations
    Weight decreased
         subjects affected / exposed
    28 / 173 (16.18%)
    5 / 86 (5.81%)
         occurrences all number
    31
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 173 (10.98%)
    2 / 86 (2.33%)
         occurrences all number
    32
    2
    Neutrophil count decreased
         subjects affected / exposed
    16 / 173 (9.25%)
    2 / 86 (2.33%)
         occurrences all number
    29
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 173 (8.09%)
    2 / 86 (2.33%)
         occurrences all number
    22
    2
    Platelet count decreased
         subjects affected / exposed
    9 / 173 (5.20%)
    1 / 86 (1.16%)
         occurrences all number
    10
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    10 / 173 (5.78%)
    2 / 86 (2.33%)
         occurrences all number
    12
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    60 / 173 (34.68%)
    18 / 86 (20.93%)
         occurrences all number
    89
    21
    Dyspnoea
         subjects affected / exposed
    34 / 173 (19.65%)
    11 / 86 (12.79%)
         occurrences all number
    45
    15
    Oropharyngeal pain
         subjects affected / exposed
    17 / 173 (9.83%)
    3 / 86 (3.49%)
         occurrences all number
    20
    3
    Nasal congestion
         subjects affected / exposed
    11 / 173 (6.36%)
    6 / 86 (6.98%)
         occurrences all number
    13
    6
    Productive cough
         subjects affected / exposed
    17 / 173 (9.83%)
    0 / 86 (0.00%)
         occurrences all number
    23
    0
    Epistaxis
         subjects affected / exposed
    9 / 173 (5.20%)
    6 / 86 (6.98%)
         occurrences all number
    11
    6
    Rhinorrhoea
         subjects affected / exposed
    12 / 173 (6.94%)
    1 / 86 (1.16%)
         occurrences all number
    12
    1
    Dysphonia
         subjects affected / exposed
    9 / 173 (5.20%)
    1 / 86 (1.16%)
         occurrences all number
    11
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    57 / 173 (32.95%)
    14 / 86 (16.28%)
         occurrences all number
    136
    21
    Anaemia
         subjects affected / exposed
    38 / 173 (21.97%)
    7 / 86 (8.14%)
         occurrences all number
    50
    7
    Thrombocytopenia
         subjects affected / exposed
    25 / 173 (14.45%)
    5 / 86 (5.81%)
         occurrences all number
    26
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    37 / 173 (21.39%)
    9 / 86 (10.47%)
         occurrences all number
    67
    10
    Dizziness
         subjects affected / exposed
    17 / 173 (9.83%)
    5 / 86 (5.81%)
         occurrences all number
    20
    6
    Neuropathy peripheral
         subjects affected / exposed
    11 / 173 (6.36%)
    6 / 86 (6.98%)
         occurrences all number
    11
    6
    Paraesthesia
         subjects affected / exposed
    11 / 173 (6.36%)
    4 / 86 (4.65%)
         occurrences all number
    11
    4
    Dysgeusia
         subjects affected / exposed
    11 / 173 (6.36%)
    3 / 86 (3.49%)
         occurrences all number
    13
    3
    Hypoaesthesia
         subjects affected / exposed
    10 / 173 (5.78%)
    1 / 86 (1.16%)
         occurrences all number
    13
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 173 (3.47%)
    5 / 86 (5.81%)
         occurrences all number
    7
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    96 / 173 (55.49%)
    21 / 86 (24.42%)
         occurrences all number
    196
    33
    Nausea
         subjects affected / exposed
    62 / 173 (35.84%)
    23 / 86 (26.74%)
         occurrences all number
    93
    25
    Constipation
         subjects affected / exposed
    39 / 173 (22.54%)
    13 / 86 (15.12%)
         occurrences all number
    54
    13
    Vomiting
         subjects affected / exposed
    29 / 173 (16.76%)
    12 / 86 (13.95%)
         occurrences all number
    43
    13
    Abdominal pain
         subjects affected / exposed
    28 / 173 (16.18%)
    5 / 86 (5.81%)
         occurrences all number
    37
    6
    Abdominal pain upper
         subjects affected / exposed
    15 / 173 (8.67%)
    4 / 86 (4.65%)
         occurrences all number
    19
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    15 / 173 (8.67%)
    3 / 86 (3.49%)
         occurrences all number
    16
    3
    Colitis
         subjects affected / exposed
    17 / 173 (9.83%)
    0 / 86 (0.00%)
         occurrences all number
    19
    0
    Dyspepsia
         subjects affected / exposed
    13 / 173 (7.51%)
    3 / 86 (3.49%)
         occurrences all number
    15
    3
    Stomatitis
         subjects affected / exposed
    9 / 173 (5.20%)
    0 / 86 (0.00%)
         occurrences all number
    9
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    36 / 173 (20.81%)
    7 / 86 (8.14%)
         occurrences all number
    50
    10
    Night sweats
         subjects affected / exposed
    17 / 173 (9.83%)
    10 / 86 (11.63%)
         occurrences all number
    19
    10
    Pruritus
         subjects affected / exposed
    21 / 173 (12.14%)
    6 / 86 (6.98%)
         occurrences all number
    23
    6
    Dry skin
         subjects affected / exposed
    11 / 173 (6.36%)
    1 / 86 (1.16%)
         occurrences all number
    12
    1
    Rash maculo-papular
         subjects affected / exposed
    12 / 173 (6.94%)
    0 / 86 (0.00%)
         occurrences all number
    14
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    28 / 173 (16.18%)
    11 / 86 (12.79%)
         occurrences all number
    33
    12
    Arthralgia
         subjects affected / exposed
    19 / 173 (10.98%)
    5 / 86 (5.81%)
         occurrences all number
    26
    5
    Pain in extremity
         subjects affected / exposed
    19 / 173 (10.98%)
    5 / 86 (5.81%)
         occurrences all number
    21
    5
    Muscle spasms
         subjects affected / exposed
    18 / 173 (10.40%)
    2 / 86 (2.33%)
         occurrences all number
    22
    2
    Myalgia
         subjects affected / exposed
    15 / 173 (8.67%)
    1 / 86 (1.16%)
         occurrences all number
    16
    1
    Musculoskeletal pain
         subjects affected / exposed
    13 / 173 (7.51%)
    1 / 86 (1.16%)
         occurrences all number
    13
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    37 / 173 (21.39%)
    7 / 86 (8.14%)
         occurrences all number
    42
    8
    Hypokalaemia
         subjects affected / exposed
    32 / 173 (18.50%)
    4 / 86 (4.65%)
         occurrences all number
    55
    5
    Hyperglycaemia
         subjects affected / exposed
    15 / 173 (8.67%)
    1 / 86 (1.16%)
         occurrences all number
    18
    1
    Dehydration
         subjects affected / exposed
    14 / 173 (8.09%)
    0 / 86 (0.00%)
         occurrences all number
    22
    0
    Hypomagnesaemia
         subjects affected / exposed
    11 / 173 (6.36%)
    3 / 86 (3.49%)
         occurrences all number
    15
    3
    Hyponatraemia
         subjects affected / exposed
    12 / 173 (6.94%)
    1 / 86 (1.16%)
         occurrences all number
    15
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    47 / 173 (27.17%)
    9 / 86 (10.47%)
         occurrences all number
    61
    9
    Sinusitis
         subjects affected / exposed
    23 / 173 (13.29%)
    3 / 86 (3.49%)
         occurrences all number
    33
    3
    Bronchitis
         subjects affected / exposed
    25 / 173 (14.45%)
    0 / 86 (0.00%)
         occurrences all number
    31
    0
    Urinary tract infection
         subjects affected / exposed
    18 / 173 (10.40%)
    6 / 86 (6.98%)
         occurrences all number
    26
    6
    Pneumonia
         subjects affected / exposed
    21 / 173 (12.14%)
    2 / 86 (2.33%)
         occurrences all number
    23
    2
    Oral candidiasis
         subjects affected / exposed
    15 / 173 (8.67%)
    0 / 86 (0.00%)
         occurrences all number
    18
    0
    Lower respiratory tract infection
         subjects affected / exposed
    11 / 173 (6.36%)
    2 / 86 (2.33%)
         occurrences all number
    19
    2
    Oral herpes
         subjects affected / exposed
    10 / 173 (5.78%)
    2 / 86 (2.33%)
         occurrences all number
    14
    2
    Respiratory tract infection
         subjects affected / exposed
    9 / 173 (5.20%)
    1 / 86 (1.16%)
         occurrences all number
    13
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2012
    ● Added the exclusion criterion “Prior participation in a GS-1101 clinical trial” ● Updated information regarding secondary and tertiary/exploratory endpoints ● Clarified that the IRC findings would be primary for analyses of PFS and other tumor control endpoints ● Updated plan to control Type I error rate for secondary endpoints ● Increased washout period to 6 weeks ● Provided clarification on phototoxicity risk ● Added details regarding diagnosis/management of progressive multifocal leukoencephalopathy (PML) consistent with Arzerra product label ● Added guidelines for monitoring participants for ofatumumab infusion toxicity ● Added urine pregnancy testing at intervals ≤ 6 weeks after Week 48 ● Clarified timing of scans in participants who had a temporary cessation of therapy ● Clarified duration of therapy for each study treatment in Group A of the study ● Clarified that participants in Group B who prematurely discontinued 1 drug could continue the other ● Increased number of participating centers and study locations ● Updated safety and clinical information to align with IB Ed. 7 ● Added new references regarding modifications in the assessment of absolute lymphocyte counts (ALC) in determining disease response and progression in participants with CLL ● Modified protocol to achieve 129 events with planned sample size ● Added new section to differentiate discontinuation from study versus discontinuation of drug ● Clarified that modifications were to be made for AEs or laboratory abnormalities that the investigator considered related to study drug ● Provided description of the standard accountability procedures because Gilead was supplying ofatumumab ● Modified protocol to allow enrollment of individuals with a positive HBV antibody if HBV DNA was undetectable by quantitative polymerase chain reaction (PCR) ● Updated inclusion criteria relating to contraception ● Added the Per Protocol Analysis Set ● Modified the spleen ULN from 10 cm to 12 cm
    17 Oct 2013
    ● Increased planned sample size to 255 participants to ensure PFS events would be met in a timely manner; up to 270 participants could be enrolled to permit eligible participants who were in screening at the time of enrollment closure to join the study ● Updated “Hepatic Events” section to add monitoring guidelines for participants who were HBc antibody positive at screening ● Updated order of key secondary endpoints ● Updated the nonclinical toxicology and clinical pharmacology sections to align with current understanding and to simplify and remove redundancy with the investigator’s brochure (IB), Edition 8 ● Updated data for the recently completed Phase 1 monotherapy study (101-02) in participants with hematologic malignancies ● Removed AEs as a reason for discontinuation from study ● Updated the clinical response section to align with the criteria for the independent review committee (IRC) ● Updated the pregnancy risk language based on current nonclinical toxicology ● Updated AE reporting to align with Gilead guidelines
    13 Jan 2014
    ● Updated response sections for consistency with central reader rules and to align across Gilead oncology studies ● Added “Sample Storage” section to request tissue samples collected as part of standard of care ● Updated the “Long-Term Follow-Up” section to change the interval to annual and to describe the data to be collected
    04 Mar 2014
    ● Added a formal interim efficacy analysis to be conducted when approximately 50% of the planned 129 events occurred and a second interim to be performed when approximately 75% of expected events occurred ● Gave participants in Group B (ofatumumab monotherapy) the option to receive idelalisib (IDL) in the event that the data monitoring committee (DMC) observed substantial evidence of benefit in Group A (IDL + ofatumumab) based on the interim data
    26 Sep 2014
    ● Added secondary objective "To evaluate the effect of the addition of IDL to ofatumumab on the onset, magnitude, and duration of tumor control for participants with 17p deletion and/or TP53 mutation" ● Added information regarding the possible crossover of Group B participants to IDL in the event that the data monitoring committee (DMC) and Gilead decided to stop the study after the first interim or second interim analysis
    17 Dec 2014
    Removed crossover study allowance
    28 Mar 2016
    Updated the safety information and guidelines for toxicity management to be consistent across IDL study protocols; the specific changes included mandating prophylaxis for Pneumocystis jirovecii pneumonia, cytomegalovirus surveillance, and increased monitoring
    04 Aug 2016
    ● Clarified the definition of recommended versus required actions related to dose modifications for AEs ● Modified the safety measures to require monitoring of subjects for Pneumocystis jirovecii pneumonia prophylaxis for 2 to 6 months after the last dose of IDL
    24 Oct 2016
    In order to provide clear guidance for IDL administration in the event of pneumonitis, the language around actions to be taken was revised.
    30 Aug 2017
    Organizing pneumonia emerged as a potential safety signal during routine signal detection monitoring. This protocol was amended to add organizing pneumonia as a potential risk.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    15 Aug 2018
    This study was terminated by the sponsor. The last subject last observation occurred on 15 August 2018.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28257752
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