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    Clinical Trial Results:
    A Phase 2 Study of SAR245409 in Patients With Relapsed or Refractory Mantle Cell Lymphoma, Follicular Lymphoma, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or Diffuse Large B-cell Lymphoma

    Summary
    EudraCT number
    2011-001616-57
    Trial protocol
    BE   DE  
    Global end of trial date
    12 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Mar 2016
    First version publication date
    24 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ARD12130
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01403636
    WHO universal trial number (UTN)
    U1111-1118-6417
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of SAR245409 as determined by the objective response rate (ORR) in subjects with one of the following relapsed or refractory (R/R) lymphoma or leukemia subtypes: mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), or diffuse large B cell lymphoma (DLBCL).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Oct 2011
    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: 10
    Country: Number of subjects enrolled
    United States: 81
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 14
    Worldwide total number of subjects
    167
    EEA total number of subjects
    76
    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)
    62
    From 65 to 84 years
    102
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 30 centers in 6 countries. A total of 167 subjects were enrolled between 19 October 2011 and 24 July 2013.

    Pre-assignment
    Screening details
    All enrolled subjects were treated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SAR245409: R/R MCL Subjects
    Arm description
    Subjects with R/R MCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, serious adverse event [SAE] requiring treatment discontinuation, consent withdrawal or lost to follow-up).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR245409
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    SAR245409 50 mg twice daily (BID)

    Arm title
    SAR245409: R/R FL Subjects
    Arm description
    Subjects with R/R Grade 1, 2 or 3a FL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR245409
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    SAR245409 50 mg BID

    Arm title
    SAR245409: R/R CLL/SLL Subjects
    Arm description
    Subjects with R/R CLL/SLL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR245409
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    SAR245409 50 mg BID

    Arm title
    SAR245409: R/R DLBCL Subjects
    Arm description
    Subjects with R/R DLBCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR245409
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    SAR245409 50 mg BID

    Number of subjects in period 1
    SAR245409: R/R MCL Subjects SAR245409: R/R FL Subjects SAR245409: R/R CLL/SLL Subjects SAR245409: R/R DLBCL Subjects
    Started
    42
    47
    36
    42
    Completed
    0
    0
    0
    0
    Not completed
    42
    47
    36
    42
         Poor compliance to protocol
             1
             -
             -
             -
         Other than specified above
             -
             4
             2
             2
         Disease progression
             31
             20
             24
             32
         Adverse Event
             8
             11
             9
             5
         Roll over to the treatment extension study
             2
             12
             1
             3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SAR245409: R/R MCL Subjects
    Reporting group description
    Subjects with R/R MCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, serious adverse event [SAE] requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R FL Subjects
    Reporting group description
    Subjects with R/R Grade 1, 2 or 3a FL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R CLL/SLL Subjects
    Reporting group description
    Subjects with R/R CLL/SLL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R DLBCL Subjects
    Reporting group description
    Subjects with R/R DLBCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group values
    SAR245409: R/R MCL Subjects SAR245409: R/R FL Subjects SAR245409: R/R CLL/SLL Subjects SAR245409: R/R DLBCL Subjects Total
    Number of subjects
    42 47 36 42 167
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.9 ± 9.4 63.3 ± 12.2 68.6 ± 7.8 64.2 ± 13.5 -
    Gender categorical
    Units: Subjects
        Female
    9 20 10 14 53
        Male
    33 27 26 28 114

    End points

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    End points reporting groups
    Reporting group title
    SAR245409: R/R MCL Subjects
    Reporting group description
    Subjects with R/R MCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, serious adverse event [SAE] requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R FL Subjects
    Reporting group description
    Subjects with R/R Grade 1, 2 or 3a FL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R CLL/SLL Subjects
    Reporting group description
    Subjects with R/R CLL/SLL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R DLBCL Subjects
    Reporting group description
    Subjects with R/R DLBCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Primary: Percentage of Subjects with Objective Response (OR)

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    End point title
    Percentage of Subjects with Objective Response (OR) [1]
    End point description
    Modified revised IWRC criteria- MCL, FL, DLBCL and SLL=complete response (CR), unconfirmed CR (CRu) or partial response (PR). CR: disappearance of all evidence of disease. CRu: CR with indeterminate bone marrow (BM) histology or >75% decrease from baseline (BL) in SPD of all measurable lesions but with residual mass. PR: Regression of measurable disease and no new sites. Modified IWCLL criteria-CLL=CR, incomplete marrow recovery [CRi], nodular PR [nPR] or PR. CR: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/ constitutional symptoms; neutrophils >1500/µL, platelets (PL) >100000/µL, Hb >11 g/dL, lymphocytes (LC) <4000/µL, BM sample is normocellular for age, <30% LC, no lymphoid nodule. PR: ≥50% decrease in LC, Ly, size of liver and spleen and one of following results: PL >100000/µL or 50% improvement over BL, Hb >11 g/dL or 50% improvement over BL, LC <4000/µL.Efficacy population: subjects who received at least 2 cycles with baseline and at least 1 post-baseline tumor assessment.
    End point type
    Primary
    End point timeframe
    Baseline; At the end of Cycle 2 following the first dose of investigational medicinal product (IMP), and then every 3 cycles for a period of 2 years or until disease progression or withdrawal from study
    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: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    SAR245409: R/R MCL Subjects SAR245409: R/R FL Subjects SAR245409: R/R CLL/SLL Subjects SAR245409: R/R DLBCL Subjects
    Number of subjects analysed
    42
    46
    35
    41
    Units: Percentage of Subjects
        number (confidence interval 95%)
    11.9 (4 to 25.6)
    41.3 (27 to 56.8)
    11.4 (3.2 to 26.7)
    4.9 (0.6 to 16.5)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS was defined as time (days) from start of treatment to the date of progression or death regardless of cause. Actual dates of tumor assessments were used for this calculation. If death or progression was not observed, data on PFS was censored at date of last tumor assessment without evidence of progression. Data after initiation of subsequent anticancer therapy was not used for endpoint. PFS was estimated using Kaplan-Meier method. Disease progression was defined as one of following: Lymphadenopathy; increase in liver or spleen size by 50% or more or de novo appearance of hepatomegaly or splenomegaly; increase in number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per µL; transformation to a more aggressive histology (eg, Richter syndrome); Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL. Analysis was performed on efficacy population. In this section, '99999' represents data not calculated for maximum range of median.
    End point type
    Secondary
    End point timeframe
    Baseline; at the end of Cycle 2 following the first dose of IMP, and then every 3 cycles for a period of 2 years or until disease progression or withdrawal from study
    End point values
    SAR245409: R/R MCL Subjects SAR245409: R/R FL Subjects SAR245409: R/R CLL/SLL Subjects SAR245409: R/R DLBCL Subjects
    Number of subjects analysed
    42
    46
    35
    41
    Units: Weeks
        median (full range (min-max))
    8.9 (7.86 to 12.86)
    58 (26 to 99999)
    24.1 (16.57 to 31.57)
    7.1 (5.14 to 8.14)
    No statistical analyses for this end point

    Secondary: Progression Free Survival at 6 Months

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    End point title
    Progression Free Survival at 6 Months
    End point description
    PFS was estimated using the Kaplan-Meier method as defined in the previous endpoint. Analysis was performed on efficacy population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    SAR245409: R/R MCL Subjects SAR245409: R/R FL Subjects SAR245409: R/R CLL/SLL Subjects SAR245409: R/R DLBCL Subjects
    Number of subjects analysed
    42
    46
    35
    41
    Units: Percentage of Subjects
        number (not applicable)
    21.4
    54.3
    45.7
    7.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Cycle 13 and beyond [maximum exposure:128 weeks for some subjects]) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events and death are treatment-emergent that is AEs that developed/worsened and death that occurred during the ‘on treatment period’ (within 30 days from the last dose of SAR245409).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    SAR245409: R/R MCL Subjects
    Reporting group description
    Subjects with R/R MCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R FL Subjects
    Reporting group description
    Subjects with R/R Grade 1, 2 or 3a FL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R CLL/SLL Subjects
    Reporting group description
    Subjects with R/R CLL/SLL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Reporting group title
    SAR245409: R/R DLBCL Subjects
    Reporting group description
    Subjects with R/R DLBCL received SAR245409 for 28-day continuous dosing cycle until withdrawal criteria met (until disease progression, unacceptable toxicity, SAE requiring treatment discontinuation, consent withdrawal or lost to follow-up).

    Serious adverse events
    SAR245409: R/R MCL Subjects SAR245409: R/R FL Subjects SAR245409: R/R CLL/SLL Subjects SAR245409: R/R DLBCL Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 42 (54.76%)
    25 / 47 (53.19%)
    27 / 36 (75.00%)
    22 / 42 (52.38%)
         number of deaths (all causes)
    8
    3
    7
    6
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic Stenosis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior Vena Cava Syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical Device Removal
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemic Infiltration Pulmonary
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Neoplasm Of Orbit
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Richter's Syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter Site Oedema
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Discomfort
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 3
    Fatigue
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 47 (2.13%)
    3 / 36 (8.33%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
    Malaise
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 47 (6.38%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional Overdose
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative Thoracic Procedure Complication
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 47 (4.26%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    C-Reactive Protein Increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen Saturation Decreased
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 47 (6.38%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune Haemolytic Anaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed Level Of Consciousness
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Age-Related Macular Degeneration
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum Intestinal
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal Failure Acute
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash Macular
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic Skin Eruption
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metatarsalgia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia Of Malignancy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure To Thrive
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Histoplasmosis Disseminated
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic Herpes Zoster
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 42 (9.52%)
    5 / 47 (10.64%)
    3 / 36 (8.33%)
    4 / 42 (9.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumonia Haemophilus
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Staphylococcal
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Septic Shock
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection Pseudomonal
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SAR245409: R/R MCL Subjects SAR245409: R/R FL Subjects SAR245409: R/R CLL/SLL Subjects SAR245409: R/R DLBCL Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 42 (92.86%)
    43 / 47 (91.49%)
    35 / 36 (97.22%)
    38 / 42 (90.48%)
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hypertension
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 47 (8.51%)
    4 / 36 (11.11%)
    1 / 42 (2.38%)
         occurrences all number
    4
    4
    4
    1
    Hypotension
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 47 (4.26%)
    3 / 36 (8.33%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    3
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 42 (9.52%)
    8 / 47 (17.02%)
    3 / 36 (8.33%)
    4 / 42 (9.52%)
         occurrences all number
    5
    8
    3
    4
    Chills
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 47 (10.64%)
    5 / 36 (13.89%)
    3 / 42 (7.14%)
         occurrences all number
    2
    6
    6
    4
    Fatigue
         subjects affected / exposed
    14 / 42 (33.33%)
    14 / 47 (29.79%)
    9 / 36 (25.00%)
    15 / 42 (35.71%)
         occurrences all number
    17
    17
    9
    21
    General Physical Health Deterioration
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 47 (0.00%)
    3 / 36 (8.33%)
    3 / 42 (7.14%)
         occurrences all number
    4
    0
    3
    3
    Influenza Like Illness
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Malaise
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Oedema Peripheral
         subjects affected / exposed
    8 / 42 (19.05%)
    2 / 47 (4.26%)
    6 / 36 (16.67%)
    8 / 42 (19.05%)
         occurrences all number
    10
    3
    6
    9
    Pyrexia
         subjects affected / exposed
    10 / 42 (23.81%)
    9 / 47 (19.15%)
    13 / 36 (36.11%)
    7 / 42 (16.67%)
         occurrences all number
    14
    19
    19
    8
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Depression
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    1
    2
    2
    1
    Insomnia
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 47 (6.38%)
    5 / 36 (13.89%)
    0 / 42 (0.00%)
         occurrences all number
    0
    3
    5
    0
    Injury, poisoning and procedural complications
    Tendon Rupture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 47 (8.51%)
    8 / 36 (22.22%)
    7 / 42 (16.67%)
         occurrences all number
    3
    6
    9
    8
    Amylase Increased
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    5
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 47 (4.26%)
    4 / 36 (11.11%)
    7 / 42 (16.67%)
         occurrences all number
    4
    3
    4
    7
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    5 / 36 (13.89%)
    1 / 42 (2.38%)
         occurrences all number
    2
    2
    6
    1
    Blood Creatinine Increased
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    3 / 42 (7.14%)
         occurrences all number
    6
    0
    3
    4
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    2
    0
    C-Reactive Protein Increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    5 / 36 (13.89%)
    3 / 42 (7.14%)
         occurrences all number
    1
    0
    5
    3
    Platelet Count Decreased
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 47 (2.13%)
    4 / 36 (11.11%)
    3 / 42 (7.14%)
         occurrences all number
    3
    1
    4
    3
    Weight Decreased
         subjects affected / exposed
    6 / 42 (14.29%)
    7 / 47 (14.89%)
    6 / 36 (16.67%)
    0 / 42 (0.00%)
         occurrences all number
    6
    8
    6
    0
    White Blood Cell Count Decreased
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 47 (8.51%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    5
    5
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 42 (11.90%)
    3 / 47 (6.38%)
    12 / 36 (33.33%)
    9 / 42 (21.43%)
         occurrences all number
    8
    4
    23
    12
    Leukocytosis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Leukopenia
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    1
    2
    2
    1
    Lymphopenia
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 47 (8.51%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences all number
    0
    6
    1
    0
    Neutropenia
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 47 (10.64%)
    5 / 36 (13.89%)
    4 / 42 (9.52%)
         occurrences all number
    3
    6
    9
    4
    Thrombocytopenia
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 47 (8.51%)
    8 / 36 (22.22%)
    6 / 42 (14.29%)
         occurrences all number
    4
    7
    16
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 42 (23.81%)
    10 / 47 (21.28%)
    10 / 36 (27.78%)
    10 / 42 (23.81%)
         occurrences all number
    10
    10
    14
    14
    Dysphonia
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    7 / 42 (16.67%)
    5 / 47 (10.64%)
    10 / 36 (27.78%)
    6 / 42 (14.29%)
         occurrences all number
    7
    5
    17
    6
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 47 (6.38%)
    1 / 36 (2.78%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3
    1
    3
    Epistaxis
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    4 / 36 (11.11%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    4
    1
    Lung Infiltration
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    4 / 36 (11.11%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    4
    1
    Pleural Effusion
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Productive Cough
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 47 (4.26%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences all number
    3
    2
    3
    0
    Wheezing
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    0
    2
    3
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    3
    2
    2
    1
    Dysgeusia
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 47 (8.51%)
    1 / 36 (2.78%)
    3 / 42 (7.14%)
         occurrences all number
    2
    4
    1
    3
    Headache
         subjects affected / exposed
    10 / 42 (23.81%)
    7 / 47 (14.89%)
    5 / 36 (13.89%)
    5 / 42 (11.90%)
         occurrences all number
    13
    10
    5
    7
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    6 / 42 (14.29%)
    3 / 47 (6.38%)
    4 / 36 (11.11%)
    2 / 42 (4.76%)
         occurrences all number
    7
    3
    5
    2
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 42 (4.76%)
    9 / 47 (19.15%)
    3 / 36 (8.33%)
    2 / 42 (4.76%)
         occurrences all number
    5
    11
    3
    2
    Aphthous Stomatitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Constipation
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 47 (10.64%)
    4 / 36 (11.11%)
    5 / 42 (11.90%)
         occurrences all number
    2
    6
    4
    5
    Diarrhoea
         subjects affected / exposed
    15 / 42 (35.71%)
    18 / 47 (38.30%)
    12 / 36 (33.33%)
    13 / 42 (30.95%)
         occurrences all number
    18
    33
    18
    18
    Dry Mouth
         subjects affected / exposed
    4 / 42 (9.52%)
    3 / 47 (6.38%)
    0 / 36 (0.00%)
    2 / 42 (4.76%)
         occurrences all number
    4
    3
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 42 (0.00%)
    6 / 47 (12.77%)
    0 / 36 (0.00%)
    5 / 42 (11.90%)
         occurrences all number
    0
    8
    0
    5
    Dysphagia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    2 / 42 (4.76%)
    5 / 47 (10.64%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences all number
    2
    5
    1
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 47 (6.38%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Nausea
         subjects affected / exposed
    13 / 42 (30.95%)
    13 / 47 (27.66%)
    7 / 36 (19.44%)
    11 / 42 (26.19%)
         occurrences all number
    16
    17
    11
    12
    Stomatitis
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    4 / 42 (9.52%)
         occurrences all number
    2
    1
    2
    4
    Vomiting
         subjects affected / exposed
    6 / 42 (14.29%)
    9 / 47 (19.15%)
    6 / 36 (16.67%)
    8 / 42 (19.05%)
         occurrences all number
    6
    15
    9
    10
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    1 / 36 (2.78%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    1
    4
    Urinary Retention
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 47 (8.51%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    4
    0
    1
    Ecchymosis
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    2 / 42 (4.76%)
         occurrences all number
    2
    2
    2
    2
    Intertrigo
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Night Sweats
         subjects affected / exposed
    5 / 42 (11.90%)
    2 / 47 (4.26%)
    0 / 36 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    5
    2
    0
    4
    Photosensitivity Reaction
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pruritus
         subjects affected / exposed
    2 / 42 (4.76%)
    6 / 47 (12.77%)
    0 / 36 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    3
    7
    0
    0
    Rash
         subjects affected / exposed
    2 / 42 (4.76%)
    8 / 47 (17.02%)
    2 / 36 (5.56%)
    2 / 42 (4.76%)
         occurrences all number
    2
    10
    2
    4
    Rash Maculo-Papular
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 47 (10.64%)
    2 / 36 (5.56%)
    3 / 42 (7.14%)
         occurrences all number
    3
    5
    3
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 42 (2.38%)
    8 / 47 (17.02%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences all number
    1
    8
    1
    1
    Back Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 47 (10.64%)
    3 / 36 (8.33%)
    2 / 42 (4.76%)
         occurrences all number
    1
    6
    3
    2
    Groin Pain
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 47 (6.38%)
    1 / 36 (2.78%)
    2 / 42 (4.76%)
         occurrences all number
    2
    3
    1
    2
    Muscle Spasms
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    1
    1
    2
    2
    Muscular Weakness
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    1
    0
    2
    1
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 47 (6.38%)
    5 / 36 (13.89%)
    0 / 42 (0.00%)
         occurrences all number
    0
    3
    6
    0
    Myalgia
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 47 (10.64%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    1
    5
    2
    1
    Pain In Extremity
         subjects affected / exposed
    5 / 42 (11.90%)
    3 / 47 (6.38%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    5
    4
    2
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    8 / 42 (19.05%)
    10 / 47 (21.28%)
    8 / 36 (22.22%)
    8 / 42 (19.05%)
         occurrences all number
    8
    12
    9
    10
    Diabetes Mellitus
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    4 / 42 (9.52%)
    6 / 47 (12.77%)
    1 / 36 (2.78%)
    0 / 42 (0.00%)
         occurrences all number
    5
    10
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    3 / 36 (8.33%)
    1 / 42 (2.38%)
         occurrences all number
    1
    2
    6
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    1 / 42 (2.38%)
         occurrences all number
    1
    2
    2
    1
    Hypocalcaemia
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 47 (0.00%)
    3 / 36 (8.33%)
    1 / 42 (2.38%)
         occurrences all number
    2
    0
    6
    1
    Hypoglycaemia
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 47 (4.26%)
    3 / 36 (8.33%)
    3 / 42 (7.14%)
         occurrences all number
    6
    3
    12
    11
    Hypomagnesaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    3 / 36 (8.33%)
    1 / 42 (2.38%)
         occurrences all number
    0
    0
    4
    2
    Hypophosphataemia
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 47 (6.38%)
    5 / 36 (13.89%)
    2 / 42 (4.76%)
         occurrences all number
    2
    4
    14
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 42 (7.14%)
    7 / 47 (14.89%)
    4 / 36 (11.11%)
    2 / 42 (4.76%)
         occurrences all number
    3
    7
    5
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 47 (6.38%)
    0 / 36 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    0
    4
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 47 (4.26%)
    3 / 36 (8.33%)
    1 / 42 (2.38%)
         occurrences all number
    4
    4
    4
    1
    Oropharyngeal Candidiasis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Oral Herpes
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 47 (8.51%)
    1 / 36 (2.78%)
    2 / 42 (4.76%)
         occurrences all number
    0
    4
    1
    2
    Pharyngitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 47 (2.13%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Pneumonia
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 47 (2.13%)
    3 / 36 (8.33%)
    0 / 42 (0.00%)
         occurrences all number
    2
    1
    4
    0
    Pneumonia Fungal
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 47 (0.00%)
    2 / 36 (5.56%)
    2 / 42 (4.76%)
         occurrences all number
    0
    0
    2
    2
    Rhinitis
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 47 (4.26%)
    2 / 36 (5.56%)
    0 / 42 (0.00%)
         occurrences all number
    2
    3
    2
    0
    Sinusitis
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 47 (6.38%)
    1 / 36 (2.78%)
    1 / 42 (2.38%)
         occurrences all number
    2
    4
    1
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 42 (9.52%)
    9 / 47 (19.15%)
    0 / 36 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    4
    11
    0
    6
    Urinary Tract Infection
         subjects affected / exposed
    1 / 42 (2.38%)
    7 / 47 (14.89%)
    2 / 36 (5.56%)
    3 / 42 (7.14%)
         occurrences all number
    1
    14
    2
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2011
    It included following changes: -Clarification on disease assessment requirements and definitions. - Description of safety review process by the Sponsor and clarification on data collection conventions. - A consultation with a geriatrician during screening was recommended by French Agency for the Safety of Health Products (AFSSAPS) to ensure the eligibility of elderly subjects to participate. - Change in frequency of on-study ophthalmologic assessment, fasting glucose and urinalysis. - Exclusion criteria was modified to allow enrollment of subjects with chronic, well controlled Grade 2 atrial fibrillation. - Addition of collection of plasma samples to assess chemokines variation during study treatment and addition of whole blood sample to evaluate whether BH3 profiling could be used as a biomarker to predict clinical response to SAR245409. - Hair follicle collection was no longer required for pharmacodynamic assessments. - The requirement for buccal mucosal swabs for DNA testing (pharmacogenomics) in subjects with CLL/SLL was changed to collection of saliva samples to ensure adequate yield of normal cells.
    21 Jun 2012
    It included following changes: - Addition of a cohort of subjects with R/R diffuse large B-cell lymphoma. - Collection of an additional saliva sample during screening for matching normal DNA. - The definition and reporting of symptomatic / non symptomatic events of overdose had been harmonized across all studies with SAR245409.

    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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