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    Clinical Trial Results:
    A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With ER+/HER2- Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With Everolimus in Combination With Exemestane or Fulvestrant

    Summary
    EudraCT number
    2014-001921-34
    Trial protocol
    BE   FR  
    Global end of trial date
    03 Jul 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    08 May 2020
    First version publication date
    14 Jul 2019
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    C31001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02049957
    WHO universal trial number (UTN)
    U1111-1195-3894
    Sponsors
    Sponsor organisation name
    Takeda Oncology
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, United States, 02139
    Public contact
    Medical Director, Takeda Oncology, +1 8778253327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Takeda Oncology, +1 8778253327, clinicaltrialregistry@tpna.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
    03 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1b - To evaluate the safety and tolerability of MLN0128 in combination with either exemestane or fulvestrant. Phase 2 - To evaluate the antitumor activity by clinical benefit rate (CBR) at 16 weeks (CBR-16 is defined as the proportion of patients who achieve complete response [CR] or partial response of any duration, or have stable disease [SD] at 16 weeks) of treatment with MLN0128 in combination with either exemestane or fulvestrant.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 95
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    France: 16
    Worldwide total number of subjects
    118
    EEA total number of subjects
    23
    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)
    83
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 40 investigative sites in Belgium, France and the United States from 13 February 2014 to 03 July 2019.

    Pre-assignment
    Screening details
    Postmenopausal women with estrogen receptor positive/human epidermal growth factor receptor-2 negative advanced/metastatic breast cancer who progressed with everolimus (everolimus sensitive-achieved CR/PR of any duration/stable disease for ≥6 months; resistant-without CR/PR/SD < 6 months) were enrolled to receive MLN0128+exemestane/fulvestrant.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane
    Arm description
    Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane coated tablets

    Arm title
    Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant
    Arm description
    Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant Intramuscular (IM) injection

    Arm title
    Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane
    Arm description
    Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane coated tablets

    Arm title
    Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant
    Arm description
    Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant Intramuscular (IM) injection

    Arm title
    Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Arm description
    Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles).
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane coated tablets

    Arm title
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)
    Arm description
    Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants.
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane coated tablets

    Arm title
    Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)
    Arm description
    Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants.
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant Intramuscular (IM) injection

    Arm title
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)
    Arm description
    Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles) in everolimus resistant participants.
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane coated tablets

    Arm title
    Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Arm description
    Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.
    Arm type
    Experimental

    Investigational medicinal product name
    Sapanisertib
    Investigational medicinal product code
    Other name
    MLN0128
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Sapanisertib capsules

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Fulvestrant Intramuscular (IM) injection

    Number of subjects in period 1
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Started
    6
    6
    3
    3
    6
    43
    8
    35
    8
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    6
    6
    3
    3
    6
    43
    8
    35
    8
         Study Terminated by Sponsor
    -
    1
    -
    -
    -
    -
    1
    -
    -
         Physician decision
    -
    -
    -
    -
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    1
    1
    1
    -
    -
    5
    -
    6
    1
         Progressive Disease
    5
    4
    2
    2
    6
    35
    7
    26
    6
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    2
    -
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    All enrolled participants

    Reporting group values
    Overall Study Total
    Number of subjects
    118 118
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    83 83
        From 65-84 years
    35 35
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    57.31 (32 to 83) -
    Sex: Female, Male
    9999 = Data for this arm group is available in subject analysis set 'Phase 1 (Part 2): Sapanisertib 3 mg QD+Exemestane/Fulvestrant'.
    Units: Subjects
        Female
    118 118
        Male
    0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    4 4
        Not Hispanic or Latino
    103 103
        Unknown or Not Reported
    11 11
    Race/Ethnicity, Customized
    Units: Subjects
        White
    98 98
        Not Reported
    6 6
        Black or African American
    7 7
        Asian
    4 4
        Other
    3 3
    Region of Enrollment
    Units: Subjects
        United States
    95 95
        Belgium
    16 16
        France
    7 7
    Height
    Number analyzed is the number of participants with data available for height.
    Units: cm
        arithmetic mean (full range (min-max))
    165.02 (150 to 183) -
    Weight
    Number analyzed is the number of participants with data available for weight.
    Units: kg
        arithmetic mean (full range (min-max))
    70.37 (46.5 to 139) -

    End points

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    End points reporting groups
    Reporting group title
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane
    Reporting group description
    Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles).

    Reporting group title
    Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant
    Reporting group description
    Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles).

    Reporting group title
    Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane
    Reporting group description
    Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles).

    Reporting group title
    Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant
    Reporting group description
    Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles).

    Reporting group title
    Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Reporting group description
    Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles).

    Reporting group title
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants.

    Reporting group title
    Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants.

    Reporting group title
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles) in everolimus resistant participants.

    Reporting group title
    Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.

    Primary: Phase 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Phase 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [1] [2]
    End point description
    An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug will be determined by the Investigator. Safety Population included participants who received at least 1 dose of any study drug.
    End point type
    Primary
    End point timeframe
    First dose of study drug through 30 days after the last dose (Up to 52 months)
    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: This endpoint was performed in Phase 1 of the study.
    [2] - 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: This endpoint was performed in Phase 1 of the study.
    End point values
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Number of subjects analysed
    6
    6
    3
    3
    6
    Units: participants
        Any AE
    6
    6
    3
    3
    6
        SAEs
    1
    2
    0
    0
    2
    No statistical analyses for this end point

    Primary: Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16)

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    End point title
    Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) [3] [4]
    End point description
    CBR-16 was defined as the percentage of participants who achieved confirmed complete response (CR) or partial response (PR) of any duration or had confirmed stable disease (SD) as best response and the first 2 or more post baseline scans had PR/SD and the duration of SD was >112 days. Disease response was assessed for target lesions by computed tomography (CT) or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression (PD). Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.
    End point type
    Primary
    End point timeframe
    Week 16
    Notes
    [3] - 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: This endpoint was performed in Phase 2 of the study.
    [4] - 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: This endpoint was performed in Phase 2 of the study.
    End point values
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Number of subjects analysed
    43
    8
    35
    8
    Units: percentage of participants
        number (confidence interval 95%)
    44 (29.1 to 60.1)
    50 (15.7 to 84.3)
    23 (10.4 to 40.1)
    25 (3.2 to 65.1)
    No statistical analyses for this end point

    Secondary: Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24)

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    End point title
    Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) [5]
    End point description
    CBR-24 was defined as the percentage of participants who achieved confirmed CR or PR at any time or had confirmed SD as best response and the first 2 or more post baseline scans had PR/SD and the duration of stable disease was >168 days. Disease response was assessed for target lesions by CT or MRI according to RECIST version 1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Week 24
    Notes
    [5] - 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: This endpoint was performed in Phase 2 of the study.
    End point values
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Number of subjects analysed
    43
    8
    35
    8
    Units: percentage of participants
        number (confidence interval 95%)
    28 (15.3 to 43.7)
    38 (8.5 to 75.5)
    23 (10.4 to 40.1)
    25 (3.2 to 65.1)
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Response Rate (ORR)

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    End point title
    Phase 2: Overall Response Rate (ORR) [6]
    End point description
    ORR is defined as the percentage of participants with confirmed CR or PR as per RECIST version1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline then every 2 cycles from Cycles 2 through 6, and every 3 cycles thereafter in a 28-day cycle up to End of Treatment (EOT) (Up to 24 months)
    Notes
    [6] - 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: This endpoint was performed in Phase 2 of the study.
    End point values
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Number of subjects analysed
    43
    8
    35
    8
    Units: percentage of participants
        number (confidence interval 95%)
    7 (1.5 to 19.1)
    13 (1 to 52.7)
    0 (0 to 0)
    13 (1 to 52.7)
    No statistical analyses for this end point

    Secondary: Phase 2: Progression-Free Survival (PFS)

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    End point title
    Phase 2: Progression-Free Survival (PFS) [7]
    End point description
    PFS is defined as the time in months from the date of first dose of study treatment to the date of the first documented disease progression or death. Disease progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; or the appearance of one or more new lesions. Safety Population included participants who received at least 1 dose of study drug. For a participant whose disease had not progressed and was last known to be alive, PFS was censored at the last response assessment that was stable disease or better. 99999: Upper limit of Confidence Interval (CI) was not reached due to low number of participants with events.
    End point type
    Secondary
    End point timeframe
    Baseline then every 2 cycles from Cycles 2 through 6, and every 3 cycles thereafter in a 28-day cycle, then every 3 months after EOT until disease progression or death (Up to 24 months)
    Notes
    [7] - 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: This endpoint was performed in Phase 2 of the study.
    End point values
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Number of subjects analysed
    43
    8
    35
    8
    Units: months
        median (confidence interval 95%)
    4.1 (1.9 to 5.5)
    5.5 (1.8 to 99999)
    3.3 (1.9 to 3.7)
    5.4 (1.7 to 8.3)
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    Phase 2: Overall Survival (OS) [8]
    End point description
    OS is the time in months from start of study treatment to date of death due to any cause. Data for the analysis of OS included the censored data at the timepoint that the participant was last known to be alive. Safety Population included participants who received at least 1 dose of study drug. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.
    End point type
    Secondary
    End point timeframe
    Up to 24 months
    Notes
    [8] - 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: This endpoint was performed in Phase 2 of the study.
    End point values
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Number of subjects analysed
    43
    8
    35
    8
    Units: months
        median (confidence interval 95%)
    15.9 (14.1 to 19.5)
    20.7 (8.6 to 20.7)
    14.0 (10.6 to 16.0)
    13.0 (4.1 to 21.3)
    No statistical analyses for this end point

    Secondary: Phase 2: Best Percent Change from Baseline in Tumor Size

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    End point title
    Phase 2: Best Percent Change from Baseline in Tumor Size [9]
    End point description
    Participants from Safety Population included participants who received at least 1 dose of study drug and provided both baseline and at least one post-baseline disease response.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 24
    Notes
    [9] - 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: This endpoint was performed in Phase 2 of the study.
    End point values
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Number of subjects analysed
    36
    7
    27
    7
    Units: percentage change in tumor size
        arithmetic mean (standard deviation)
    -0.46 ± 34.89
    0.96 ± 38.98
    1.76 ± 31.14
    -18.91 ± 19.71
    No statistical analyses for this end point

    Secondary: Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib

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    End point title
    Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib [10]
    End point description
    Pharmacokinetic (PK) Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. n= number analyzed is the number of participants with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose
    Notes
    [10] - 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: This endpoint was performed in Phase 1 of the study.
    End point values
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Number of subjects analysed
    6
    5
    3
    3
    6
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 15 (n=6,0,3,2,6)
    57.72 ± 9.927
    9999 ± 9999
    47.40 ± 6.583
    50.90 ± 23.476
    45.37 ± 9.644
        Cycle 2 Day 1 (n=5,5,3,3,5)
    38.68 ± 20.551
    44.96 ± 34.459
    43.47 ± 0.874
    45.30 ± 16.235
    44.68 ± 8.636
    No statistical analyses for this end point

    Secondary: Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib

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    End point title
    Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib [11]
    End point description
    PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. n=number analyzed is the number of participants with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose
    Notes
    [11] - 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: This endpoint was performed in Phase 1 of the study.
    End point values
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Number of subjects analysed
    6
    5
    3
    3
    6
    Units: hour
    median (full range (min-max))
        Cycle 1 Day 15 (n=6,0,3,2,6)
    3.005 (0.58 to 7.30)
    9999 (9999 to 9999)
    0.600 (0.45 to 1.00)
    1.035 (1.00 to 1.07)
    2.000 (0.50 to 3.55)
        Cycle 2 Day 1 (n=5,5,3,3,5)
    2.280 (0.85 to 3.58)
    3.500 (0.92 to 4.03)
    0.980 (0.68 to 1.00)
    1.000 (0.48 to 1.12)
    2.000 (0.50 to 3.77)
    No statistical analyses for this end point

    Secondary: Phase 1: AUC(0-24): Area under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours, Calculated using the Observed Value of the Last Quantifiable Concentration Over the Dosing Interval for Sapanisertib

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    End point title
    Phase 1: AUC(0-24): Area under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours, Calculated using the Observed Value of the Last Quantifiable Concentration Over the Dosing Interval for Sapanisertib [12]
    End point description
    AUC(0-24) is the area under the plasma concentration-time curve of the samples collected up to 8 hours and extrapolated up to 24 hours. Participants from PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. Number analyzed is the number of participants with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to 24 hours post-dose
    Notes
    [12] - 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: This endpoint was performed in Phase 1 of the study.
    End point values
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Number of subjects analysed
    6
    0 [13]
    3
    2
    5
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    577.081 ± 331.9813
    ±
    178.063 ± 46.1416
    332.618 ± 228.5641
    277.626 ± 64.0661
    Notes
    [13] - PK data was not available at Cycle 1 Day 15.
    No statistical analyses for this end point

    Secondary: Phase 1: AUC(0-last): Area under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN0128

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    End point title
    Phase 1: AUC(0-last): Area under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN0128 [14]
    End point description
    AUC(0-last) is the area under the plasma concentration-time curve of the samples collected up to 8 hours and extrapolated up to last time point. PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. n=number analyzed is the number of participants with data available for analyses at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to last timepoint
    Notes
    [14] - 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: This endpoint was performed in Phase 1 of the study.
    End point values
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Number of subjects analysed
    6
    5
    3
    3
    6
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 15 (n=6,0,3,2,6)
    577.081 ± 331.9813
    9999 ± 9999
    164.123 ± 52.6287
    332.618 ± 228.5641
    251.165 ± 83.7121
        Cycle 1 Day 2 (n=5,5,3,3,5)
    101.599 ± 51.0248
    109.496 ± 82.3968
    89.576 ± 15.0117
    109.548 ± 52.8500
    116.557 ± 8.6059
    No statistical analyses for this end point

    Secondary: Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib

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    End point title
    Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib [15]
    End point description
    Participants from PK Population, participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose
    Notes
    [15] - 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: This endpoint was performed in Phase 1 of the study.
    End point values
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Number of subjects analysed
    2
    0 [16]
    3
    2
    4
    Units: hour
        arithmetic mean (standard deviation)
    6.639 ± 1.2176
    ±
    3.161 ± 1.6585
    7.777 ± 2.9177
    5.370 ± 1.4638
    Notes
    [16] - PK data was not available at Cycle 1 Day 15.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose up to 30 days post last dose of study drug (Up to 52 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane
    Reporting group description
    Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles).

    Reporting group title
    Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant
    Reporting group description
    Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles).

    Reporting group title
    Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane
    Reporting group description
    Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles).

    Reporting group title
    Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant
    Reporting group description
    Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles).

    Reporting group title
    Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
    Reporting group description
    Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles).

    Reporting group title
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants.

    Reporting group title
    Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 12 cycles) in everolimus resistant participants.

    Reporting group title
    Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants.

    Reporting group title
    Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Reporting group description
    Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.

    Serious adverse events
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    11 / 43 (25.58%)
    5 / 35 (14.29%)
    3 / 8 (37.50%)
    2 / 8 (25.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Clostridium test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive) Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    6 / 6 (100.00%)
    43 / 43 (100.00%)
    35 / 35 (100.00%)
    8 / 8 (100.00%)
    8 / 8 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    3
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    1
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    4 / 35 (11.43%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    7
    5
    0
    0
    Flushing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tumour pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 6 (66.67%)
    6 / 6 (100.00%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    4 / 6 (66.67%)
    19 / 43 (44.19%)
    16 / 35 (45.71%)
    6 / 8 (75.00%)
    2 / 8 (25.00%)
         occurrences all number
    7
    6
    1
    3
    4
    30
    16
    6
    2
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    3 / 35 (8.57%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    3
    3
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Injection site rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    4 / 35 (11.43%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    4
    1
    2
    Chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    3 / 43 (6.98%)
    3 / 35 (8.57%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    3
    4
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    3
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    1
    Dysphoria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Stress
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    2
    0
    0
    Irritability
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Hallucination
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hallucinations, mixed
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Initial insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Vulvovaginal dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Genital rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Humerus fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rib fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    Animal bite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Procedural nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Spinal compression fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 6 (50.00%)
    6 / 43 (13.95%)
    4 / 35 (11.43%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    2
    0
    2
    3
    8
    5
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    6 / 43 (13.95%)
    5 / 35 (14.29%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    0
    0
    0
    8
    6
    0
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    4 / 35 (11.43%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    5
    0
    3
    Amylase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    1 / 43 (2.33%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    3
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    6 / 35 (17.14%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    3
    7
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    4 / 43 (9.30%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    1
    0
    1
    4
    2
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    4 / 43 (9.30%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    0
    0
    0
    5
    2
    0
    2
    Blood cholesterol increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    3 / 43 (6.98%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    2
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    2
    1
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    4 / 43 (9.30%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    9
    2
    0
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    4 / 43 (9.30%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    6
    1
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    4 / 43 (9.30%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    5
    0
    1
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Blood urea increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Amylase decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Blood calcium increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    International normalised ratio decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Protein total increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Protein urine
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    8 / 43 (18.60%)
    2 / 35 (5.71%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    4
    0
    0
    1
    11
    2
    2
    0
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    7 / 43 (16.28%)
    4 / 35 (11.43%)
    3 / 8 (37.50%)
    2 / 8 (25.00%)
         occurrences all number
    1
    1
    0
    0
    1
    9
    4
    4
    2
    Hypoxia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 43 (4.65%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    1
    0
    0
    Atelectasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    1
    0
    0
    Pleurisy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Respiration abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    6 / 43 (13.95%)
    6 / 35 (17.14%)
    0 / 8 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    8
    8
    0
    2
    Leukocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    2 / 35 (5.71%)
    2 / 8 (25.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    2
    1
    Eosinophilia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    8 / 43 (18.60%)
    4 / 35 (11.43%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    4
    1
    0
    0
    0
    9
    4
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    7 / 43 (16.28%)
    3 / 35 (8.57%)
    2 / 8 (25.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    11
    3
    3
    0
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    11 / 43 (25.58%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    13
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    5 / 43 (11.63%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    6
    2
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    0
    0
    Ataxia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Hyperaesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Serotonin syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    VIth nerve paralysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Ageusia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Dystonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hypoglossal nerve disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Diplopia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    0
    1
    0
    Eye pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Retinal scar
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    4 / 6 (66.67%)
    17 / 43 (39.53%)
    9 / 35 (25.71%)
    3 / 8 (37.50%)
    6 / 8 (75.00%)
         occurrences all number
    5
    11
    2
    4
    5
    27
    10
    3
    9
    Nausea
         subjects affected / exposed
    6 / 6 (100.00%)
    4 / 6 (66.67%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    3 / 6 (50.00%)
    23 / 43 (53.49%)
    15 / 35 (42.86%)
    7 / 8 (87.50%)
    4 / 8 (50.00%)
         occurrences all number
    7
    5
    1
    2
    5
    29
    21
    8
    5
    Stomatitis
         subjects affected / exposed
    5 / 6 (83.33%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 6 (33.33%)
    10 / 43 (23.26%)
    8 / 35 (22.86%)
    3 / 8 (37.50%)
    2 / 8 (25.00%)
         occurrences all number
    10
    5
    0
    0
    3
    11
    11
    3
    2
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 6 (50.00%)
    10 / 43 (23.26%)
    10 / 35 (28.57%)
    1 / 8 (12.50%)
    5 / 8 (62.50%)
         occurrences all number
    1
    2
    2
    0
    4
    13
    13
    2
    7
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 6 (16.67%)
    6 / 43 (13.95%)
    5 / 35 (14.29%)
    1 / 8 (12.50%)
    2 / 8 (25.00%)
         occurrences all number
    1
    2
    0
    1
    1
    7
    5
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    5 / 43 (11.63%)
    2 / 35 (5.71%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    5
    2
    1
    0
    Toothache
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    2
    0
    1
    Dyspepsia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    3 / 3 (100.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    4 / 43 (9.30%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    3
    0
    0
    4
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    0
    0
    0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    2
    0
    0
    Gingival pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    7 / 43 (16.28%)
    3 / 35 (8.57%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    7
    3
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    1
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Colitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Eructation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Lip dry
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    1
    0
    0
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    1
    0
    0
    Oliguria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    1
    Azotaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Chronic kidney disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Leukocyturia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    3 / 6 (50.00%)
    11 / 43 (25.58%)
    6 / 35 (17.14%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    4
    3
    1
    4
    3
    14
    8
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 6 (33.33%)
    5 / 43 (11.63%)
    3 / 35 (8.57%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    8
    1
    1
    1
    6
    6
    3
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    4 / 35 (11.43%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    5
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    0
    Acne
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    1
    0
    1
    Dermatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    4 / 43 (9.30%)
    1 / 35 (2.86%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    0
    5
    1
    1
    1
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    3 / 43 (6.98%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    3
    1
    0
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    2
    0
    0
    Psoriasis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    4
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 6 (16.67%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Skin irritation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    0
    0
    Erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    0
    0
    Nail ridging
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    2 / 35 (5.71%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Onychoclasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    2 / 43 (4.65%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Pain of skin
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    0 / 43 (0.00%)
    1 / 35 (2.86%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)
    1 / 43 (2.33%)
    0 / 35 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 6 (0.00%)