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    Clinical Trial Results:
    A Phase 3 Study of Duvelisib (IPI-145) vs Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

    Summary
    EudraCT number
    		 2013-002405-61
    Trial protocol
    		 ES   HU   IT   GB   BE   AT   DE   LV   GR  
    Global end of trial date
    23 Dec 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Oct 2023
    First version publication date
    15 Dec 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update of contact information.

    Trial information

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    Trial identification
    Sponsor protocol code
    IPI-145-07
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02004522
    WHO universal trial number (UTN)
    		 U1111-1138-8603
    Sponsors
    Sponsor organisation name
    Secura Bio, Inc.
    Sponsor organisation address
    1995 Village Center Circle, Suite 128, Las Vegas, NV, United States, 89134
    Public contact
    Beth Gregory, PharmD, MBA, Secura Bio, Inc., +1 702 -254- 0011, bgregory@securabio.com
    Scientific contact
    Beth Gregory, PharmD, MBA, Secura Bio, Inc., +1 702 -254- 0011, bgregory@securabio.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
    25 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A phase 3 clinical trial to examine the efficacy of duvelisib monotherapy versus ofatumumab monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
    Protection of trial subjects
    This study was conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 65
    Country: Number of subjects enrolled
    Italy: 41
    Country: Number of subjects enrolled
    New Zealand: 12
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 51
    Worldwide total number of subjects
    319
    EEA total number of subjects
    218
    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)
    102
    From 65 to 84 years
    211
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening was performed at least 30 days prior to dosing (Cycle 1 Day 1).

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Duvelisib
    Arm description
    		 Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Duvelisib
    Investigational medicinal product code
    Other name
    Copiktra, IPI-145, PI3K Inhibitor
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received starting dose of 25 mg duvelisib twice a day initially over the course of 21-day treatment cycle followed by 28-day treatment cycles for up to 18 cycles or until disease progression or unacceptable toxicity (whichever comes first).

    Arm title
    		 Ofatumumab
    Arm description
    		 Ofatumumab is administered as an intravenous (IV) infusion and is supplied in single-use vials at two strengths, 100 mg/5 mL and 1000 mg/50 mL.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    Other name
    Arzerra
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received ofatumumab at the dose and schedule outlined in the approved product labelling for monotherapy in relapsed CLL at the time the study was initiated.

    Number of subjects in period 1
    		Duvelisib Ofatumumab
    Started
    160
    159
    Completed
    34
    0
    Not completed
    126
    159
         Consent withdrawn by subject
    13
    7
         Physician decision
    3
    4
         Disease progression
    35
    31
         Adverse event, non-fatal
    55
    6
         Death
    12
    3
         Other reason listed by PI
    4
    1
         Completed treatment cycles per protocol
    1
    103
         Never dosed
    2
    4
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Duvelisib
    Reporting group description
    		 Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules.

    Reporting group title
    Ofatumumab
    Reporting group description
    		 Ofatumumab is administered as an intravenous (IV) infusion and is supplied in single-use vials at two strengths, 100 mg/5 mL and 1000 mg/50 mL.

    Reporting group values
    		 Duvelisib Ofatumumab Total
    Number of subjects
    		 160 159 319
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 48 54 102
        From 65-84 years
    		 109 102 211
        85 years and over
    		 3 3 6
    Gender categorical
    Units: Subjects
        Female
    		 64 64 128
        Male
    		 96 95 191

    End points

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    End points reporting groups
    Reporting group title
    Duvelisib
    Reporting group description
    		 Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules.

    Reporting group title
    Ofatumumab
    Reporting group description
    		 Ofatumumab is administered as an intravenous (IV) infusion and is supplied in single-use vials at two strengths, 100 mg/5 mL and 1000 mg/50 mL.

    Subject analysis set title
    Intent to Treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects with treatment group designated according to randomization.

    Subject analysis set title
    Subjects With Abnormal Hematologic Values at Baseline
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with abnormally high values for neutrophil count, haemoglobin, or platelet count at Baseline.

    Primary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS) [1]
    End point description
    The primary efficacy endpoint for the study was PFS, defined as time from randomization to the first documentation of PD as determined by blinded independent review or death due to any cause.
    End point type
    Primary
    End point timeframe
    From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics (median plus confidence interval) are reported for PFS.
    End point values
    		 Duvelisib Ofatumumab
    Number of subjects analysed
    160 [2]
    159 [3]
    Units: Months
        median (confidence interval 95%)
    13.3 (12.1 to 16.8)
    9.9 (9.2 to 11.3)
    Notes
    [2] - Intent to Treat
    [3] - Intent to Treat
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR is a key secondary efficacy endpoint with overall response defined as best response of CR, CRi, PR, or PRwL, according to the modified IWCLL/IWG Response Criteria, with modification for treatment-related lymphocytosis as defined in the protocol.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity assessed up to 6 years
    End point values
    		 Duvelisib Ofatumumab
    Number of subjects analysed
    160 [4]
    159 [5]
    Units: Count of participants
    118
    72
    Notes
    [4] - Intent to Treat
    [5] - Intent to Treat
    No statistical analyses for this end point

    Secondary: Number of Subjects With Hematologic Improvements

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    End point title
    		 Number of Subjects With Hematologic Improvements
    End point description
    Subjects with hematologic improvement included those subjects with abnormally high values for neutrophil count, haemoglobin, or platelet count at Baseline determined to have consistently met the criteria of an improvement for those parameters for a period of at least 60 days during which the subject did not have a transfusion or exogenous cytokines.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Duvelisib Ofatumumab
    Number of subjects analysed
    94 [6]
    95 [7]
    Units: Count of participants
    56
    51
    Notes
    [6] - Subjects With Abnormal Hematologic Values at Baseline
    [7] - Subjects With Abnormal Hematologic Values at Baseline
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    A stratified Cox regression analysis was used to test for any treatment effect. 9999 = Upper limit not estimable due to an insufficient number of events at the time of analysis.
    End point type
    Secondary
    End point timeframe
    Every 6 months for up to 3 years after first dose
    End point values
    		 Duvelisib Ofatumumab
    Number of subjects analysed
    160 [8]
    159 [9]
    Units: Months
        median (confidence interval 95%)
    54.94 (43.00 to 67.99)
    63.25 (44.15 to 9999)
    Notes
    [8] - Intent to Treat
    [9] - Intent to Treat
    No statistical analyses for this end point

    Secondary: Lymph Node Response Rate

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    End point title
    		 Lymph Node Response Rate
    End point description
    Lymph node response defined as greater than or equal to 50% decrease in the SPD of target lymph nodes.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Duvelisib Ofatumumab
    Number of subjects analysed
    160 [10]
    159 [11]
    Units: Count of participants
    136
    25
    Notes
    [10] - Intent to Treat
    [11] - Intent to Treat
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of response is defined only for subjects demonstrating a response (eg, CR, CRi, PR, PRwL), with the response and progression statuses both determined by the blinded, central independent review. The analysis will be descriptive for each treatment group only.
    End point type
    Secondary
    End point timeframe
    Time from the first documentation of response to first documentation of progressive disease or death due to any cause
    End point values
    		 Duvelisib Ofatumumab
    Number of subjects analysed
    160 [12]
    159 [13]
    Units: Months
        median (confidence interval 95%)
    11.1 (9.2 to 18.3)
    9.3 (7.7 to 11.0)
    Notes
    [12] - Intent to Treat
    [13] - Intent to Treat
    No statistical analyses for this end point

    Secondary: Treatment-Emergent Adverse Events (TEAEs) and Changes in Safety Laboratory Values

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    End point title
    		 Treatment-Emergent Adverse Events (TEAEs) and Changes in Safety Laboratory Values
    End point description
    An analysis of TEAEs with an onset within the first 24 weeks of treatment was performed to examine and compare the incidence of events across an equal period for each treatment arm. Twenty-four weeks was anticipated to be the median exposure to ofatumumab.
    End point type
    Secondary
    End point timeframe
    From 04 Feb 2014 until 19 June 2018
    End point values
    		 Duvelisib Ofatumumab
    Number of subjects analysed
    160 [14]
    159 [15]
    Units: Count of participants
    150
    143
    Notes
    [14] - Intent to Treat
    [15] - Intent to Treat
    No statistical analyses for this end point

    Secondary: Number of Subjects With Samples Available for Duvelisib Pharmacokinetics (PK)

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    End point title
    		 Number of Subjects With Samples Available for Duvelisib Pharmacokinetics (PK) [16]
    End point description
    Number of subjects with samples available for duvelisib Pharmacokinetics (PK).
    End point type
    Secondary
    End point timeframe
    Cycle 2, Cycle 3, and Cycle 7
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No PK samples were collected for ofatumumab subjects.
    End point values
    		 Duvelisib
    Number of subjects analysed
    160
    Units: Number of participants
    158
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    39 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ofatumumab
    Reporting group description
    		 Ofatumumab is administered as an IV infusion and is supplied in single-use vials at two strengths, 100 mg/5 mL and 1000 mg/50 mL.

    Reporting group title
    Duvelisib
    Reporting group description
    		 Duvelisib is administered orally and supplied as 5 mg and 25 mg formulated capsules.

    Serious adverse events
    		 Ofatumumab Duvelisib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    50 / 155 (32.26%)
    124 / 158 (78.48%)
         number of deaths (all causes)
    70
    78
         number of deaths resulting from adverse events
    7
    24
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Richter’s syndrome
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Disease progression
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 155 (0.00%)
    4 / 158 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infusion site extravasation
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 155 (0.65%)
    7 / 158 (4.43%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (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
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural haemorrhage
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 155 (0.00%)
    6 / 158 (3.80%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 155 (1.29%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    3 / 155 (1.94%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 155 (0.65%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem haemorrhage
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Headache
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 155 (1.29%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 155 (1.94%)
    10 / 158 (6.33%)
         occurrences causally related to treatment / all
    2 / 4
    6 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph node pain
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 155 (0.65%)
    20 / 158 (12.66%)
         occurrences causally related to treatment / all
    0 / 1
    20 / 21
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 155 (0.65%)
    18 / 158 (11.39%)
         occurrences causally related to treatment / all
    0 / 1
    17 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal ulcer
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal hypertensive gastropathy
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 155 (0.00%)
    4 / 158 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 155 (1.29%)
    4 / 158 (2.53%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Aspergillus infection
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchiolitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 155 (0.65%)
    5 / 158 (3.16%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis viral
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (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
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Escherichia sepsis
         subjects affected / exposed
    3 / 155 (1.94%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Escherichia urinary tract infection
         subjects affected / exposed
    2 / 155 (1.29%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 155 (0.65%)
    4 / 158 (2.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion site cellulitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 155 (0.65%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 155 (3.23%)
    25 / 158 (15.82%)
         occurrences causally related to treatment / all
    3 / 5
    13 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 155 (1.29%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia bordetella
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonas aeruginosa
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomonas bronchitis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 155 (0.65%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Septic shock
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 155 (0.00%)
    3 / 158 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 155 (0.65%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    2 / 155 (1.29%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 155 (0.65%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ofatumumab Duvelisib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    130 / 155 (83.87%)
    149 / 158 (94.30%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 155 (2.58%)
    13 / 158 (8.23%)
         occurrences all number
    4
    18
    Hypotension
         subjects affected / exposed
    8 / 155 (5.16%)
    4 / 158 (2.53%)
         occurrences all number
    8
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    17 / 155 (10.97%)
    20 / 158 (12.66%)
         occurrences all number
    19
    37
    Fatigue
         subjects affected / exposed
    18 / 155 (11.61%)
    25 / 158 (15.82%)
         occurrences all number
    21
    38
    Oedema peripheral
         subjects affected / exposed
    7 / 155 (4.52%)
    16 / 158 (10.13%)
         occurrences all number
    7
    22
    Pyrexia
         subjects affected / exposed
    15 / 155 (9.68%)
    46 / 158 (29.11%)
         occurrences all number
    18
    76
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 155 (14.19%)
    36 / 158 (22.78%)
         occurrences all number
    28
    69
    Dyspnoea
         subjects affected / exposed
    9 / 155 (5.81%)
    14 / 158 (8.86%)
         occurrences all number
    11
    15
    Productive cough
         subjects affected / exposed
    2 / 155 (1.29%)
    8 / 158 (5.06%)
         occurrences all number
    2
    8
    Rhinorrhoea
         subjects affected / exposed
    3 / 155 (1.94%)
    9 / 158 (5.70%)
         occurrences all number
    3
    10
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 155 (5.81%)
    8 / 158 (5.06%)
         occurrences all number
    10
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 155 (1.94%)
    13 / 158 (8.23%)
         occurrences all number
    3
    25
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 155 (1.94%)
    15 / 158 (9.49%)
         occurrences all number
    3
    26
    Weight decreased
         subjects affected / exposed
    3 / 155 (1.94%)
    21 / 158 (13.29%)
         occurrences all number
    3
    22
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    28 / 155 (18.06%)
    2 / 158 (1.27%)
         occurrences all number
    35
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 155 (3.23%)
    13 / 158 (8.23%)
         occurrences all number
    6
    14
    Headache
         subjects affected / exposed
    13 / 155 (8.39%)
    13 / 158 (8.23%)
         occurrences all number
    14
    17
    Paraesthesia
         subjects affected / exposed
    15 / 155 (9.68%)
    7 / 158 (4.43%)
         occurrences all number
    20
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 155 (10.32%)
    39 / 158 (24.68%)
         occurrences all number
    30
    89
    Neutropenia
         subjects affected / exposed
    32 / 155 (20.65%)
    53 / 158 (33.54%)
         occurrences all number
    68
    177
    Thrombocytopenia
         subjects affected / exposed
    9 / 155 (5.81%)
    27 / 158 (17.09%)
         occurrences all number
    12
    45
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 155 (1.94%)
    17 / 158 (10.76%)
         occurrences all number
    3
    19
    Abdominal pain upper
         subjects affected / exposed
    5 / 155 (3.23%)
    9 / 158 (5.70%)
         occurrences all number
    6
    9
    Colitis
         subjects affected / exposed
    1 / 155 (0.65%)
    8 / 158 (5.06%)
         occurrences all number
    1
    8
    Constipation
         subjects affected / exposed
    12 / 155 (7.74%)
    27 / 158 (17.09%)
         occurrences all number
    12
    36
    Diarrhoea
         subjects affected / exposed
    19 / 155 (12.26%)
    79 / 158 (50.00%)
         occurrences all number
    24
    196
    Dry mouth
         subjects affected / exposed
    1 / 155 (0.65%)
    8 / 158 (5.06%)
         occurrences all number
    1
    8
    Dyspepsia
         subjects affected / exposed
    4 / 155 (2.58%)
    9 / 158 (5.70%)
         occurrences all number
    5
    10
    Nausea
         subjects affected / exposed
    17 / 155 (10.97%)
    38 / 158 (24.05%)
         occurrences all number
    20
    49
    Paraesthesia oral
         subjects affected / exposed
    10 / 155 (6.45%)
    0 / 158 (0.00%)
         occurrences all number
    11
    0
    Vomiting
         subjects affected / exposed
    10 / 155 (6.45%)
    23 / 158 (14.56%)
         occurrences all number
    12
    29
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 155 (5.81%)
    11 / 158 (6.96%)
         occurrences all number
    11
    14
    Rash
         subjects affected / exposed
    18 / 155 (11.61%)
    17 / 158 (10.76%)
         occurrences all number
    23
    22
    Rash maculo-papular
         subjects affected / exposed
    2 / 155 (1.29%)
    9 / 158 (5.70%)
         occurrences all number
    2
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 155 (3.23%)
    11 / 158 (6.96%)
         occurrences all number
    5
    14
    Back pain
         subjects affected / exposed
    8 / 155 (5.16%)
    12 / 158 (7.59%)
         occurrences all number
    10
    16
    Muscle spasms
         subjects affected / exposed
    8 / 155 (5.16%)
    7 / 158 (4.43%)
         occurrences all number
    10
    7
    Pain in extremity
         subjects affected / exposed
    3 / 155 (1.94%)
    9 / 158 (5.70%)
         occurrences all number
    3
    11
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    12 / 155 (7.74%)
    20 / 158 (12.66%)
         occurrences all number
    16
    29
    Nasopharyngitis
         subjects affected / exposed
    4 / 155 (2.58%)
    13 / 158 (8.23%)
         occurrences all number
    4
    17
    Pneumonia
         subjects affected / exposed
    4 / 155 (2.58%)
    8 / 158 (5.06%)
         occurrences all number
    5
    8
    Respiratory tract infection
         subjects affected / exposed
    3 / 155 (1.94%)
    11 / 158 (6.96%)
         occurrences all number
    4
    18
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 155 (7.74%)
    22 / 158 (13.92%)
         occurrences all number
    13
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 155 (3.23%)
    24 / 158 (15.19%)
         occurrences all number
    5
    37
    Dehydration
         subjects affected / exposed
    1 / 155 (0.65%)
    8 / 158 (5.06%)
         occurrences all number
    1
    10
    Hyperkalaemia
         subjects affected / exposed
    5 / 155 (3.23%)
    11 / 158 (6.96%)
         occurrences all number
    5
    12
    Hypokalaemia
         subjects affected / exposed
    3 / 155 (1.94%)
    16 / 158 (10.13%)
         occurrences all number
    3
    32

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2014
    • Modified Inclusion criterion #3 to more clearly define eligibility around previous purine-analogue therapy. This change included the addition of a timeframe regarding relapse following previous therapy. • Revised exclusions for use of medications or procedures within a specified timeframe to add the use of live or live attenuated vaccines within 30 days prior to randomization. Other investigational therapy was also modified to remove the following: − “subjects who have received investigational agents with a half-life > 3 days or of unknown length may be allowed on a case by case basis after discussion with the medical monitor”. • Changed Baseline QTcF exclusion criterion from > 480 ms to > 500 ms. • Updated treatment modifications (ie, dose interruptions/holds) with treatment interruption for duvelisib-treated subjects now based on new Grade 3 QTc > 20 ms from Baseline. • Added an additional secondary endpoint of lymph node response rate. • Reordered secondary endpoints based on re-examination of statistical assumptions. • Changed the statistical sections to improve the overall design of the trial: - Changed the efficacy boundaries for testing the primary endpoint of PFS from Pocock type to O’Brien-Fleming type for the following reasons: • The superiority of duvelisib compared to ofatumumab in PFS will not be declared by an independent data monitoring committee at an interim analysis unless very convincing evidence for efficacy is presented. • After this change, the criterion of stopping for efficacy was a one-sided p-value of 0.0015 (corresponding approximately to a HR of 0.540). Assuming the median PFS for ofatumumab arm is 9 months, the stopping rule will not be met unless the median PFS for duvelisib arm is approximately 16.7 months. • For the same number of events as the previous design (185 events), the overall power is greater than the previous design (93% vs 87%).
    02 Mar 2015
    • Changed the QTcF exclusion criteria from QTcF > 500 ms to > 480 ms; revised the “Dose Interruption/Hold/Modification Guidelines” to interrupt treatment for all QTcF prolongation ≥Grade 3 (≥ 500 ms). • Extended the length of survival follow-up from 3 to 6 years from randomization.
    09 Feb 2017
    • The Sponsor of Study IPI-145-07 was changed from Infinity to Verastem. • The maximum number of duvelisib treatment cycles (39 cycles) was removed to permit subjects experiencing clinical benefit after 39 cycles to continue duvelisib treatment until disease progression or unacceptable toxicity. • The criteria for receiving additional duvelisib beyond Cycle 19 was modified to reflect potential clinical benefit of a stable disease (SD) response.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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