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    Clinical Trial Results:
    A randomized phase 2 non-comparative study of the efficacy of PF-04691502 and PF-05212384 in patients with recurrent endometrial cancer

    Summary
    EudraCT number
    		 2011-003062-32
    Trial protocol
    		 SK   ES   PL   DE   GB  
    Global end of trial date
    25 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Dec 2016
    First version publication date
    14 Dec 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B1271004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    27 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Dec 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Arm A: To assess the clinical benefit response (CBR) of the oral PI3K/mTOR inhibitor PF-04691502 in patients with recurrent endometrial cancer that is classified as PI3K basal. Arm B: To assess the CBR of the IV PI3K/mTOR inhibitor PF-05212384 in patients with recurrent endometrial cancer that is classified as PI3K basal. Arm C: To assess the CBR of the oral PI3K/mTOR inhibitor PF-04691502 in patients with recurrent endometrial cancer that is classified as PI3K activated. Arm D: To assess the CBR of the IV PI3K/mTOR inhibitor PF-05212384 in patients with recurrent endometrial cancer that is classified as PI3K activated.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the declaration of Helsinki and in compliance with all International Council on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those affording greater protection to the safety of study participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Japan: 12
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    67
    EEA total number of subjects
    24
    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)
    29
    From 65 to 84 years
    37
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 6 centers in Australia, Canada, Japan, Poland, Spain and the United States. All enrolled participants from 6 centers were included in the trial.

    Pre-assignment
    Screening details
    		 This study was conducted in parallel-arms in adult participants with recurrent endometrial cancer. Randomized arms included PF-05212384 (154mg dosage) and PF-04691502 (8mg which was lowered to 6mg) for both PI3K Basal or Activated. Lead-in Cohorts included PF-05212384 (89mg or 154mg) and PF-04691502 (4mg).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-04691502 8 mg (PI3K Basal)
    Arm description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 8 mg orally, once daily (QD) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-04691502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants self-administered PF-04691502 8 mg orally, once daily (QD) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Investigational medicinal product name
    PF-04691502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received PF-04691502 8 mg by 30 minute infusion at the study site, once weekly (Quaque, QW) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Arm title
    		 PF-04691502 6 mg (PI3K Basal)
    Arm description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-04691502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Arm title
    		 PF-04691502 8 mg (PI3K Activated)
    Arm description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 8 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-04691502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants self-administered PF-04691502 8 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.

    Arm title
    		 PF-04691502 6 mg (PI3K Activated)
    Arm description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-04691502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Arm title
    		 PF-05212384 154 mg (PI3K Basal)
    Arm description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, once weekly (Quaque, QW) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-05212384
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received PF-05212384 154 mg by 30 minute infusion at the study site, once weekly (Quaque, QW) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Arm title
    		 PF-05212384 154 mg (PI3K Activated)
    Arm description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, QW until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-05212384
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received PF-05212384 154 mg by 30 minute infusion at the study site, QW until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Arm title
    		 Lead-in-cohort (LIC) PF-04691502 (4 mg)
    Arm description
    		 Participants who were enrolled in the PF-04691502 LIC began dosing with PF-04691502 4 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05691502 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-04691502
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who were enrolled in the PF-04691502 LIC began dosing with PF-04691502 4 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05691502 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Arm title
    		 LIC PF-05212384 (89 mg)
    Arm description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 89 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-05212384
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 89 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Arm title
    		 LIC PF-05212384 (154 mg)
    Arm description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 154 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    05212384
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 154 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until hey experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Number of subjects in period 1
    		PF-04691502 8 mg (PI3K Basal) PF-04691502 6 mg (PI3K Basal) PF-04691502 8 mg (PI3K Activated) PF-04691502 6 mg (PI3K Activated) PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) Lead-in-cohort (LIC) PF-04691502 (4 mg) LIC PF-05212384 (89 mg) LIC PF-05212384 (154 mg)
    Started
    3
    1
    11
    3
    20
    20
    3
    3
    3
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    3
    1
    11
    3
    20
    20
    3
    3
    3
         Other Reasons
    -
    -
    1
    -
    -
    -
    -
    -
    -
         Death
    1
    -
    8
    -
    7
    12
    -
    1
    1
         Study Terminated by Sponsor
    2
    1
    1
    3
    11
    7
    3
    2
    2
         Lost to follow-up
    -
    -
    -
    -
    1
    1
    -
    -
    -
         Subject Refused Futher Follow-up
    -
    -
    1
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-04691502 8 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 8 mg orally, once daily (QD) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.

    Reporting group title
    PF-04691502 6 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-04691502 8 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 8 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.

    Reporting group title
    PF-04691502 6 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-05212384 154 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, once weekly (Quaque, QW) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-05212384 154 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, QW until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    Lead-in-cohort (LIC) PF-04691502 (4 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-04691502 LIC began dosing with PF-04691502 4 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05691502 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    LIC PF-05212384 (89 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 89 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    LIC PF-05212384 (154 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 154 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group values
    		 PF-04691502 8 mg (PI3K Basal) PF-04691502 6 mg (PI3K Basal) PF-04691502 8 mg (PI3K Activated) PF-04691502 6 mg (PI3K Activated) PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) Lead-in-cohort (LIC) PF-04691502 (4 mg) LIC PF-05212384 (89 mg) LIC PF-05212384 (154 mg) Total
    Number of subjects
    		 3 1 11 3 20 20 3 3 3 67
    Age Categorical
    Units: Subjects
        < 18 years
    		 0 0 0 0 0 0 0 0 0 0
        18 - 44 years
    		 0 0 0 0 0 0 0 1 0 1
        45 - 64 years
    		 2 1 4 3 9 4 2 1 2 28
        >= 65 years
    		 1 0 7 0 11 16 1 1 1 38
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3 ( 61.7 ) 1 ( 54 ) 11 ( 66.5 ) 3 ( 60 ) 20 ( 65.7 ) 20 ( 69.6 ) 3 ( 64.3 ) 3 ( 56.7 ) 3 ( 62.7 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 3 1 11 3 20 20 3 3 3 67
        Male
    		 0 0 0 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    PF-04691502 8 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 8 mg orally, once daily (QD) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.

    Reporting group title
    PF-04691502 6 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-04691502 8 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 8 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.

    Reporting group title
    PF-04691502 6 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-05212384 154 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, once weekly (Quaque, QW) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-05212384 154 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, QW until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    Lead-in-cohort (LIC) PF-04691502 (4 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-04691502 LIC began dosing with PF-04691502 4 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05691502 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    LIC PF-05212384 (89 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 89 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    LIC PF-05212384 (154 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 154 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants were analyzed on safety analysis set which was defined as all enrolled patients who started treatment.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC eporting arm were not a part of the per protocol analysis set for summarizing response.

    Subject analysis set title
    Pharmacokinetics Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.

    Subject analysis set title
    Pharmacodynamic Analysis Biomarkers Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.

    Subject analysis set title
    Molecular Profiling Tumor Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects were analyzed as the molecular profiling tumor analysis set was defined as all enrolled patients who started treatment and had baseline tumor tissues (archived paraffin block or unstained slides or fresh tumor tissue sample) successfully analyzed for at least one of the biomarkers.

    Subject analysis set title
    PF-05212384 (PI3K Basal + Activated)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal + activated). Participants were given PF-05212384 QW (Days 1, 8, 15 and 22 of each cycle), with a ±3 day window.

    Subject analysis set title
    PF-04691502 (PI3K Basal)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 orally, once daily (QD) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Subject analysis set title
    PF-04691502 (PI3K Activated)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 8 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Primary: Clinical Benefit Response for PF-04691502

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    End point title
    		 Clinical Benefit Response for PF-04691502 [1]
    End point description
    Clinical benefit response was defined as best overall response of complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks from Cycle 1 Day 1 (C1D1) to the first time of disease progression. The outcome data table below presents the number of participants with clinical benefit response as "yes" or "no". On 09 Oct 2012, Pfizer decided to stop enrollment into PF-04691502. While tumor assessment for PF-04691502 was included as a listing in the final report, formal efficacy analysis for PF-04691502 was not performed. Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.
    End point type
    Primary
    End point timeframe
    16 weeks from Cycle 1 Day 1
    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 has no statistical analysis.
    End point values
    		 PF-04691502 (PI3K Basal) PF-04691502 (PI3K Activated)
    Number of subjects analysed
    4
    11
    Units: Participants
        Participants with "Yes" response
    1
    0
        Participants with "No" response
    3
    11
    No statistical analyses for this end point

    Primary: Percentage of participants with clinical benefit response for PF-05212384

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    End point title
    		 Percentage of participants with clinical benefit response for PF-05212384 [2] [3]
    End point description
    Clinical benefit response was defined as best overall response of complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks from Cycle 1 Day 1 (C1D1) to the first time of disease progression. The primary analysis is based on the clinical benefit rate which is calculated as proportion of participants with a clinical benefit response relative to total number of response evaluable participants. Per RECIST v1.1 for target lesions: CR defined as disappearance of all target lesions; PR defined as >=30% decrease in the sum of the longest diameter of target lesions; SD does not qualify for CR, PR or Progression. All target lesions must be assessed. SD can follow PR only in the rare case that the sum increases by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds. A Clopper-Pearson exact 95% CI for the clinical benefit rate is presented in the below table.
    End point type
    Primary
    End point timeframe
    16 weeks from Cycle 1 Day 1
    Notes
    [2] - 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 has no statistical analysis.
    [3] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    10
    5
    15
    Units: Percentage of participants
        number (confidence interval 95%)
    52.6 (28.9 to 75.6)
    26.3 (9.1 to 51.2)
    39.5 (24 to 56.6)
    No statistical analyses for this end point

    Secondary: Objective Response for PF-04691502

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    End point title
    		 Objective Response for PF-04691502
    End point description
    Objective response is defined as CR or PR. CR: Complete response: 2 or more objective statuses of CR a minimum of 4 weeks apart documented before PD. Partial response: 2 or more objective statuses of PR or better a minimum of 4 weeks apart documented before PD, but not qualifying as CR. Per RECIST v1.1 for target lesions: CR defined as disappearance of all target lesions; PR defined as >=30% decrease in the sum of the longest diameter of target lesions. The outcome data table below presents the number of participants with objective response as "yes" or "no". On 09 Oct 2012, Pfizer decided to stop enrollment into PF-04691502. While tumor assessment for PF-04691502 was included as a listing in the final report, formal efficacy analysis for PF-04691502 was not performed. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.
    End point type
    Secondary
    End point timeframe
    Randomization to objective progression, death or last tumor assessment without progression (up to 12 months)
    End point values
    		 PF-04691502 (PI3K Basal) PF-04691502 (PI3K Activated)
    Number of subjects analysed
    4
    11
    Units: Participants response
        Participants with "Yes" response
    0
    0
        Participants with "No" response
    4
    11
    No statistical analyses for this end point

    Secondary: Percentage of participants with objective response for PF-05212384

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    End point title
    		 Percentage of participants with objective response for PF-05212384 [4]
    End point description
    Objective response is defined as CR or PR. CR: Complete response: 2 or more objective statuses of CR a minimum of 4 weeks apart documented before PD. Partial response: 2 or more objective statuses of PR or better a minimum of 4 weeks apart documented before PD, but not qualifying as CR. Per RECIST v1.1 for target lesions: CR defined as disappearance of all target lesions; PR defined as >=30% decrease in the sum of the longest diameter of target lesions. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.
    End point type
    Secondary
    End point timeframe
    Randomization to objective progression, death or last tumor assessment without progression (up to 12 months)
    Notes
    [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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    19
    19
    38
    Units: Percentage of participants
        number (confidence interval 95%)
    21.1 (6.1 to 45.6)
    15.8 (3.4 to 39.6)
    18.4 (7.7 to 34.3)
    No statistical analyses for this end point

    Secondary: Progression free survival for PF-04691502

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    End point title
    		 Progression free survival for PF-04691502
    End point description
    PFS is defined as the time from the date of cycle 1 day 1 to the date that objective progressive disease is documented or death due to any cause, whichever occurs first. PFS was characterized in terms of the median. Approximate 95% confidence interval corresponding to this estimate was computed. Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions with a minimum absolute increase of 5 mm, or an unequivocal progression of non-target lesion, or the appearance of new lesions. On 09 Oct 2012, Pfizer decided to stop enrollment into PF-04691502. While tumor assessment for PF-04691502 was included as a listing in the final report, formal efficacy analysis for PF-04691502 was not performed. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months)
    End point values
    		 PF-04691502 (PI3K Basal) PF-04691502 (PI3K Activated)
    Number of subjects analysed
    4
    11
    Units: Time to Event (Days)
        Participant 1
    1
    0
        Participant 2
    108
    0
        Participant 3
    50
    0
        Participant 4
    199
    0
        Participant 5
    0
    54
        Participant 6
    0
    55
        Participant 7
    0
    51
        Participant 8
    0
    1
        Participant 9
    0
    54
        Participant 10
    0
    62
        Participant 11
    0
    53
        Participant 12
    0
    105
        Participant 13
    0
    1
        Participant 14
    0
    54
        Participant 15
    0
    54
    No statistical analyses for this end point

    Secondary: Progression free survival for PF-05212384

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    End point title
    		 Progression free survival for PF-05212384 [5]
    End point description
    PFS is defined as the time from the date of cycle 1 day 1 to the date that objective progressive disease is documented or death due to any cause, whichever occurs first. PFS was characterized in terms of the median. Approximate 95% confidence interval corresponding to this estimate was computed. Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions with a minimum absolute increase of 5 mm, or an unequivocal progression of non-target lesion, or the appearance of new lesions. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 to objective progressive disease or death due to any cause whichever occurs first (up to 12 months)
    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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    19
    19
    38
    Units: Days
        median (confidence interval 95%)
    112 (59 to 167)
    89 (56 to 172)
    108 (62 to 149)
    No statistical analyses for this end point

    Secondary: Percentage of participants with progression free survival (PFS) at 6 months for PF-05212384

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    End point title
    		 Percentage of participants with progression free survival (PFS) at 6 months for PF-05212384 [6]
    End point description
    Progression free survival is defined as the time from the date of cycle 1 day 1 to the date that objective progressive disease is documented or death due to any cause, whichever occurs first. PFS was characterized in terms of the probability of remaining progression-free at 6 months (based on Kaplan-Meier estimates). Progression is defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions with a minimum absolute increase of 5 mm, or an unequivocal progression of non-target lesion, or the appearance of new lesions. Per protocol dataset included participants enrolled for treatment, with baseline tumor, measurable disease and with disease under study. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.
    End point type
    Secondary
    End point timeframe
    6 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    19
    19
    38
    Units: Percentage of participants
        number (confidence interval 95%)
    23.2 (7.3 to 44.1)
    25 (7.8 to 47.2)
    24.3 (11.6 to 39.5)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) for PF-05212384

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    End point title
    		 Overall Survival (OS) for PF-05212384 [7]
    End point description
    OS is defined as the time from the date of Cycle 1 Day 1 to the date of death. Survival analysis was not performed as the study was terminated early. No data are available because data were not collected. The LIC reporting arm were not a part of the per protocol analysis set for summarizing response.
    End point type
    Secondary
    End point timeframe
    12 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Percentage of participants
    Notes
    [8] - Survival analysis was not performed as the study was terminated early. No data are available.
    [9] - Survival analysis was not performed as the study was terminated early. No data are available.
    [10] - Survival analysis was not performed as the study was terminated early. No data are available.
    No statistical analyses for this end point

    Secondary: Level of each pharmacodynamic parameter at specified timepoints- Glucose (mg/dL)

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    End point title
    		 Level of each pharmacodynamic parameter at specified timepoints- Glucose (mg/dL) [11]
    End point description
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. Subjects were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days
    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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    18
    18
    36
    Units: Glucose (mg/dL)
    arithmetic mean (standard deviation)
        Baseline
    98.5 ( 12.76 )
    101.7 ( 26.56 )
    100.1 ( 20.6 )
        Cycle 1 Day 15 (n=18,17,35)
    105.3 ( 18.44 )
    117.2 ( 61.04 )
    111.1 ( 44.26 )
        Cycle 1 Day 22 (n=2,1,3)
    103 ( 19.31 )
    114 ( 39.42 )
    108.7 ( 15.19 )
        Cycle 2 Day 1 (n=17,14,31)
    103.7 ( 19.31 )
    114 ( 39.42 )
    108.3 ( 29.99 )
        Cycle 2 Day 15 (n=17,8,25)
    104.8 ( 13.94 )
    106.4 ( 19.36 )
    105.3 ( 15.47 )
        Cycle 3 Day 1 (n=14,10,24)
    100.6 ( 16.29 )
    125.9 ( 74.5 )
    111.1 ( 49.85 )
        Cycle 4 Day 1 (n=12,7,19)
    96.3 ( 10.4 )
    98.9 ( 10.2 )
    97.3 ( 10.12 )
        Cycle 5 Day 1 (n=9,4,13)
    103.2 ( 15.17 )
    112.2 ( 24.37 )
    106 ( 17.9 )
    No statistical analyses for this end point

    Secondary: Level of each pharmacodynamic parameter at specified timepoints- Insulin (UIU/mL)

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    End point title
    		 Level of each pharmacodynamic parameter at specified timepoints- Insulin (UIU/mL) [12]
    End point description
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. Subjects were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one ost-baseline measurement for at least one PD biomarker. The PD biomarkers include serum glucose, insulin, HbA1c, cholesterol, and triglycerides.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days
    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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    17
    14
    31
    Units: Insulin (UIU/mL)
    arithmetic mean (standard deviation)
        Baseline
    15.2 ( 12.68 )
    14.4 ( 7.03 )
    14.8 ( 10.36 )
        Cycle 1 Day 15 (n=16,12,28)
    23.6 ( 14.69 )
    35.9 ( 37.05 )
    28.9 ( 26.79 )
        Cycle 1 Day 22 (n=2,1,3)
    57.6 ( 51.18 )
    29.1 ( 0 )
    48.1 ( 39.75 )
        Cycle 2 Day 1 (n=17,10,27)
    30.3 ( 28.92 )
    28.9 ( 27.85 )
    29.8 ( 27.99 )
        Cycle 2 Day 15 (n=14,6,20)
    28.2 ( 29.56 )
    21.9 ( 10.49 )
    26.3 ( 25.21 )
        Cycle 3 Day 1 (n=13,9,22)
    20.7 ( 13.65 )
    35.1 ( 38.66 )
    26.6 ( 26.99 )
        Cycle 4 Day 1 (n=11,6,17)
    17.1 ( 10.04 )
    24.8 ( 32.32 )
    19.8 ( 20.1 )
        Cycle 5 Day 1 (n=7,4,11)
    17 ( 15.56 )
    15.7 ( 6.2 )
    16.5 ( 12.54 )
    No statistical analyses for this end point

    Secondary: Percentage of participants in each treatment arm with gene and/or protein expression biomarkers in biopsied tumor tissue- Summary of Biomarkers - Molecular Profiling Tumor Analysis Set: Stathmin H Score (N)

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    End point title
    		 Percentage of participants in each treatment arm with gene and/or protein expression biomarkers in biopsied tumor tissue- Summary of Biomarkers - Molecular Profiling Tumor Analysis Set: Stathmin H Score (N) [13]
    End point description
    Gene and/or protein expression biomarkers in biopsied tumor tissue relating to PI3K and/or mTOR pathway activation, such as PIK3CA and PIK3R1 mutations, PTEN protein levels, and PIK3CA gene amplification were to be assessed. Subjects were analyzed as the molecular profiling tumor analysis set was defined as all enrolled patients who started treatment and had baseline tumor tissues (archived paraffin block or unstained slides or fresh tumor tissue sample) successfully analyzed for at least one of the biomarkers.
    End point type
    Secondary
    End point timeframe
    Baseline and Cycle1 to Cycle 5 where each cycle consist of 28 days
    Notes
    [13] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    19
    19
    40
    Units: Score
        arithmetic mean (standard deviation)
    96.4 ( 33.76 )
    201.3 ( 34.87 )
    146.2 ( 62.9 )
    No statistical analyses for this end point

    Secondary: Percentage of participants in each treatment arm with gene and/or protein expression biomarkers- PIK3CA Amplification, KRAS Mutation P/N, KRAS Mutation OBSV, PTEN Stroma Manual Score, PTEN Tumor Manual Score, KRAS SCC and Stathmin H/L,Tissue.

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    End point title
    		 Percentage of participants in each treatment arm with gene and/or protein expression biomarkers- PIK3CA Amplification, KRAS Mutation P/N, KRAS Mutation OBSV, PTEN Stroma Manual Score, PTEN Tumor Manual Score, KRAS SCC and Stathmin H/L,Tissue. [14]
    End point description
    Gene and/or protein expression biomarkers in biopsied tumor tissue relating to PI3K and/or mTOR pathway activation, such as PIK3CA and PIK3R1 mutations, PTEN protein levels, and PIK3CA gene amplification were to be assessed. Subjects were analyzed as the molecular profiling tumor analysis set was defined as all enrolled patients who started treatment and had baseline tumor tissues (archived paraffin block or unstained slides or fresh tumor tissue sample) successfully analyzed for at least one of the biomarkers.
    End point type
    Secondary
    End point timeframe
    Baseline and Cycle 1 to Cycle 5 where each cycle consist of 28 days
    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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    20 [15]
    20 [16]
    40
    Units: Percentage
    number (not applicable)
        PIK3CA Amplification, Amplified (n=17,15,32)
    5.9
    6.7
    6.3
        PIK3CA Amplification, Nonamplified (n=17,15,32)
    94.1
    93.3
    93.8
        KRAS Mutation, Positive (n=21,18,39)
    19
    5.6
    12.8
        KRAS Mutation, Negative (n=21,18,39)
    81
    94.4
    87.2
        KRAS Mutation OBSV, Gly12Asp (n=4,1,5)
    25
    100
    40
        KRAS Mutation OBSV, Gly12Cys (n=4,1,5)
    25
    0
    20
        KRAS Mutation OBSV, Gly12Val (n=4,1,5)
    50
    0
    40
        PTEN Stroma Manual Score, 1+ (n=21,19,40)
    4.8
    0
    2.5
        PTEN Stroma Manual Score, 2+ (n=21,19,40)
    28.6
    26.3
    27.5
        PTEN Stroma Manual Score, 3+ (n=21,19,40)
    66.7
    73.7
    70
        PTEN Tumor Manual Score, 0 (n=21,19,40)
    23.8
    21.1
    22.5
        PTEN Tumor Manual Score, 1+ (n=21,19,40)
    38.1
    31.6
    35
        PTEN Tumor Manual Score, 2+ (n=21,19,40)
    38.1
    47.4
    42.5
        KRAS SCC, Acceptable (n=21,18,39)
    100
    100
    100
        Stathmin H/L,Tissue, High (n=21,19,40)
    0
    100
    47.5
        Stathmin H/L,Tissue, Low (n=21,19,40)
    100
    0
    52.5
    Notes
    [15] - N=21 One subject had the stathmin status changed and was categorized under Basal.
    [16] - N= 19 One subject had their stathmin status changed and was categorized under Basal.
    No statistical analyses for this end point

    Secondary: Area under the serum concentration time profile from time zero extrapolated to infinity (AUCinf) of PF-05212384 at each specified time points.

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    End point title
    		 Area under the serum concentration time profile from time zero extrapolated to infinity (AUCinf) of PF-05212384 at each specified time points. [17]
    End point description
    AUCinf of PF-05212384 at each specified time points. Subjects were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.
    End point type
    Secondary
    End point timeframe
    From Day 1 until 35 days post last dose
    Notes
    [17] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated)
    Number of subjects analysed
    19
    15
    Units: ng.hr/mL
        geometric mean (geometric coefficient of variation)
    15280 ( 24 )
    14870 ( 40 )
    No statistical analyses for this end point

    Secondary: Area under the serum concentration time profile from time zero to the time of the last quantifiable concentration (AUClast) of PF-05212384 at each specified time points.

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    End point title
    		 Area under the serum concentration time profile from time zero to the time of the last quantifiable concentration (AUClast) of PF-05212384 at each specified time points. [18]
    End point description
    AUClast of PF-05212384 at each specified time points. Subjects were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.
    End point type
    Secondary
    End point timeframe
    From Day 1 until 35 days post last dose
    Notes
    [18] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated)
    Number of subjects analysed
    19
    15
    Units: ng.hr/mL
        geometric mean (geometric coefficient of variation)
    15080 ( 24 )
    15890 ( 52 )
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of PF-05212384 at each specified time points.

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    End point title
    		 Maximum plasma concentration (Cmax) of PF-05212384 at each specified time points. [19]
    End point description
    Cmax of PF-05212384 at each specified time points. Subjects were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.
    End point type
    Secondary
    End point timeframe
    From Day 1 until 35 days post last dose
    Notes
    [19] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated)
    Number of subjects analysed
    19
    15
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    9078 ( 36 )
    7057 ( 84 )
    No statistical analyses for this end point

    Secondary: Terminal elimination half life (t½) of PF-05212384 at each specified time points.

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    End point title
    		 Terminal elimination half life (t½) of PF-05212384 at each specified time points. [20]
    End point description
    t½ of PF-05212384 at each specified time points. Subjects were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.
    End point type
    Secondary
    End point timeframe
    From Day 1 until 35 days post last dose
    Notes
    [20] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated)
    Number of subjects analysed
    19
    15
    Units: hr
        arithmetic mean (standard deviation)
    35.02 ( 5.32 )
    34.09 ( 8.87 )
    No statistical analyses for this end point

    Secondary: Time for Cmax (Tmax) of PF-05212384 at each specified time points.

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    End point title
    		 Time for Cmax (Tmax) of PF-05212384 at each specified time points. [21]
    End point description
    Tmax of PF-05212384 at each specified time points. Subjects were analyzed on PK parameter analysis set which was defined as all treated patients who had at least one of the PK parameters of interest estimated.
    End point type
    Secondary
    End point timeframe
    From Day 1 until 35 days post last dose
    Notes
    [21] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated)
    Number of subjects analysed
    19
    15
    Units: hr
        median (full range (min-max))
    0.525 (0.5 to 1.07)
    0.65 (0.5 to 1.08)
    No statistical analyses for this end point

    Secondary: Clearance (CL) of PF-05212384 at each specified time points.

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    End point title
    		 Clearance (CL) of PF-05212384 at each specified time points. [22]
    End point description
    End point type
    Secondary
    End point timeframe
    From Day 1 until 35 days post last dose
    Notes
    [22] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated)
    Number of subjects analysed
    19
    15
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    10.09 ( 24 )
    10.36 ( 40 )
    No statistical analyses for this end point

    Secondary: Steady state volume of distribution (Vss) of PF-05212384 at each specified time points.

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    End point title
    		 Steady state volume of distribution (Vss) of PF-05212384 at each specified time points. [23]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 5
    Notes
    [23] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated)
    Number of subjects analysed
    19
    15
    Units: Litres
        geometric mean (geometric coefficient of variation)
    165.6 ( 32 )
    174.9 ( 57 )
    No statistical analyses for this end point

    Secondary: Summary of treatment-emergent adverse events (TEAEs) - all causalities

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    End point title
    		 Summary of treatment-emergent adverse events (TEAEs) - all causalities [24]
    End point description
    Safety of participants in terms of TEAEs.
    End point type
    Secondary
    End point timeframe
    From baseline (-3 days) until 35 days post last dose
    Notes
    [24] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    2
    1
    3
    Units: Participants
        Number of Adverse Events (AEs)
    10
    6
    16
        Participants with AEs
    2
    1
    3
        Participants with Serious Adverse Events (SAEs)
    0
    0
    0
        Participants with Grade 3 or Grade 4 AEs
    1
    1
    2
        Participants with Grade 5 AEs
    0
    0
    0
        Permanently Discontinued due to AEs
    1
    1
    2
        Dose Reduced due to AEs
    0
    0
    0
        Temporary Discontinuations due to AEs
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Summary of treatment-related TEAEs

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    End point title
    		 Summary of treatment-related TEAEs [25]
    End point description
    Safety of subject in terms of number of participants with treatment related AEs.
    End point type
    Secondary
    End point timeframe
    From baseline (-3 days) until 35 days post last dose
    Notes
    [25] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    2
    1
    3
    Units: Participants
        Number of AEs
    9
    5
    14
        Participants with AEs
    2
    1
    3
        Participants with SAEs
    0
    0
    0
        Participants with Grade 3 or Grade 4 AEs
    1
    1
    2
        Participants with Grade 5 AEs
    0
    0
    0
        Permanently Discontinued due to AEs
    1
    1
    2
        Dose Reduced due to AEs
    0
    0
    0
        Temporary Discontinuations due to AEs
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Level of each pharmacodynamic parameter at specified timepoints- Glycosylated Hemoglobin (HbA1c)

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    End point title
    		 Level of each pharmacodynamic parameter at specified timepoints- Glycosylated Hemoglobin (HbA1c) [26]
    End point description
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -3) and Cycle1 to Cycle 5 where each cycle consist of 28 days
    Notes
    [26] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    18
    18
    36
    Units: HbA1c
    arithmetic mean (standard deviation)
        Baseline (n=15,14,29)
    7.8 ( 8.58 )
    7.5 ( 6.15 )
    7.7 ( 7.37 )
        Cycle 1 Day 15 (n=4,2,6)
    14.7 ( 19 )
    7.1 ( 1.34 )
    12.2 ( 15.25 )
        Cycle 2 Day 1 (n=14,11,25)
    1.08 ( 0.056 )
    1.13 ( 0.088 )
    1.1 ( 0.075 )
        Cycle 2 Day 15 (n=3,0,3)
    6.7 ( 0.71 )
    0 ( 0 )
    6.7 ( 0.71 )
        Cycle 3 Day 1 (n=10,4,14)
    6 ( 0.78 )
    7.3 ( 1.7 )
    6.4 ( 1.19 )
        Cycle 4 Day 1 (n=12,7,19)
    8.9 ( 10.13 )
    6.9 ( 1.05 )
    8.2 ( 8.01 )
        Cycle 5 Day 1 (n=8,2,10)
    5.9 ( 0.89 )
    31.5 ( 36.06 )
    11 ( 16.17 )
    No statistical analyses for this end point

    Secondary: Level of each pharmacodynamic parameter at specified timepoints- Cholesterol (mg/dL)

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    End point title
    		 Level of each pharmacodynamic parameter at specified timepoints- Cholesterol (mg/dL) [27]
    End point description
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected. Subjects were analyzed on PD analysis set which consisted of all enrolled patients who started treatment and had a baseline as well as at least one post-baseline measurement for at least one PD biomarker.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -3) and Cycle 1 to Cycle 3 where each cycle consist of 28 days
    Notes
    [27] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    18
    18
    36
    Units: Cholesterol (mg/dL)
    arithmetic mean (standard deviation)
        Baseline (n=11,4,15)
    213 ( 54.48 )
    186.5 ( 52.43 )
    205.9 ( 53.45 )
        Cycle 1 Day 28 (n=15,7,22)
    214.9 ( 49.15 )
    161.6 ( 86.51 )
    198 ( 66.28 )
        Cycle 2 Day 22 (n=16,6,22)
    229.8 ( 44.31 )
    127.9 ( 108.69 )
    202 ( 79.83 )
        Cycle 3 Day 28 (n=11,4,15)
    230.5 ( 48.63 )
    137.6 ( 107.02 )
    205.7 ( 77.15 )
    No statistical analyses for this end point

    Secondary: Level of each pharmacodynamic parameter at specified timepoints- Triglycerides (mg/dL)

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    End point title
    		 Level of each pharmacodynamic parameter at specified timepoints- Triglycerides (mg/dL) [28]
    End point description
    PD biomarkers are measured at screening (baseline) and multiple time points post baseline. Baseline is defined as the last measurement prior to dosing, which is the measurement at screening or the cycle 1 day 1 pre-dose measurement if collected.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -3) and Cycle1 to Cycle 3 where each cycle consist of 28 days
    Notes
    [28] - 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 has no statistical analysis.
    End point values
    		 PF-05212384 154 mg (PI3K Basal) PF-05212384 154 mg (PI3K Activated) PF-05212384 (PI3K Basal + Activated)
    Number of subjects analysed
    18
    18
    36
    Units: Triglycerides (mg/dL)
    arithmetic mean (standard deviation)
        Baseline (n=11,4,15)
    104.2 ( 40.95 )
    133.4 ( 25.75 )
    112 ( 38.96 )
        Cycle 1 Day 28 (n=15,7,22)
    136.9 ( 70.03 )
    134.5 ( 57.21 )
    136.1 ( 64.85 )
        Cycle 2 Day 28 (n=16,6,22)
    133.2 ( 71.4 )
    117.1 ( 62.77 )
    128.8 ( 68.07 )
        Cycle 3 Day 28 (n=10,4,14)
    119.9 ( 64.22 )
    130.4 ( 58.01 )
    122.9 ( 60.47 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Maximum of treatment duration (i.e., 21 to 169 days for the PF 04691502 [PI3K basal and activated], 29 to 345 days for PF 05212384 PI3K basal and 1 to 400 days for PF 05212384 PI3K activated) + 28 days across all participants.
    Adverse event reporting additional description
    All causality AEs and SAEs are included in this section. The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    PF-04691502 8 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 8 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.

    Reporting group title
    PF-04691502 6 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-04691502 8 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 8 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death. Dose of the participants were reduced to 6 mg if they were on 8 mg dose.

    Reporting group title
    PF-04691502 6 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants self-administered PF-04691502 6 mg orally, QD until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-05212384 154 mg (PI3K Basal)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K basal). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, QW (Quaque [Once Weekly]) until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    Lead-in-cohort (LIC) PF-04691502 (4 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-04691502 LIC began dosing with PF-04691502 4 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05691502 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    PF-05212384 154 mg (PI3K Activated)
    Reporting group description
    		 Eligible participants were categorized by PI3K pathway activation status (i.e. PI3K activated). Participants received PF-05212384 154 mg by 30 minute infusion at the study site, QW until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    LIC PF-05212384 (89 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 89 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Reporting group title
    LIC PF-05212384 (154 mg)
    Reporting group description
    		 Participants who were enrolled in the PF-05212384 LIC began dosing with PF-05212384 154 mg at least 4 days (but no more than 10 days) prior to Cycle 1 Day 1 and continued taking PF-05212384 until they experienced unacceptable toxicity, disease progression, significant deviation, withdrawal of consent or death.

    Serious adverse events
    		 PF-04691502 8 mg (PI3K Basal) PF-04691502 6 mg (PI3K Basal) PF-04691502 8 mg (PI3K Activated) PF-04691502 6 mg (PI3K Activated) PF-05212384 154 mg (PI3K Basal) Lead-in-cohort (LIC) PF-04691502 (4 mg) PF-05212384 154 mg (PI3K Activated) LIC PF-05212384 (89 mg) LIC PF-05212384 (154 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    1 / 1 (100.00%)
    7 / 9 (77.78%)
    1 / 3 (33.33%)
    3 / 21 (14.29%)
    1 / 3 (33.33%)
    10 / 19 (52.63%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    3
    0
    6
    0
    8
    0
    11
    1
    1
         number of deaths resulting from adverse events
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric Cancer
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (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
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (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
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (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
    Disease Progression
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Distress Syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    2 / 2
    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
    Pneumothorax Spontaneous
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    Pulmonary Embolism
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 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
    Investigations
    Lymphocyte Count Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    7 / 7
    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
    Cardiac disorders
    Cardiac Failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (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
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    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
    Large Intestinal Obstruction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 5
    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
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Oral Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (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
    Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    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
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (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
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (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
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (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
    Fistula
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (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
    Infections and infestations
    Lung Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    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
    Pneumonia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    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
    Pyelonephritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (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
    Skin Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         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
    Urinary Tract Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    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
    Diabetic Ketoacidosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Hyperglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 PF-04691502 8 mg (PI3K Basal) PF-04691502 6 mg (PI3K Basal) PF-04691502 8 mg (PI3K Activated) PF-04691502 6 mg (PI3K Activated) PF-05212384 154 mg (PI3K Basal) Lead-in-cohort (LIC) PF-04691502 (4 mg) PF-05212384 154 mg (PI3K Activated) LIC PF-05212384 (89 mg) LIC PF-05212384 (154 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    1 / 1 (100.00%)
    9 / 9 (100.00%)
    3 / 3 (100.00%)
    21 / 21 (100.00%)
    3 / 3 (100.00%)
    18 / 19 (94.74%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oncologic Complication
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Tumour Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hot Flush
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    4 / 21 (19.05%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    10
    0
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Lymphoedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pallor
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    3 / 9 (33.33%)
    0 / 3 (0.00%)
    7 / 21 (33.33%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    5
    0
    10
    0
    3
    0
    0
    Catheter Site Bruise
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Catheter Site Oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Catheter Site Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    2
    0
    2
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    3 / 5 (60.00%)
    0 / 1 (0.00%)
    6 / 9 (66.67%)
    2 / 3 (66.67%)
    5 / 21 (23.81%)
    1 / 3 (33.33%)
    10 / 19 (52.63%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    4
    0
    13
    3
    5
    1
    19
    0
    3
    Gait Disturbance
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Influenza Like Illness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Infusion Site Extravasation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Infusion Site Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    2 / 3 (66.67%)
    1 / 19 (5.26%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    0
    0
    0
    0
    11
    4
    11
    2
    2
    Medical Device Complication
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Mucosal Dryness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Mucosal Inflammation
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    12 / 21 (57.14%)
    0 / 3 (0.00%)
    8 / 19 (42.11%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    6
    0
    4
    3
    22
    0
    17
    0
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    2
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    5 / 19 (26.32%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    3
    0
    2
    0
    7
    1
    0
    Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    0
    2
    1
    2
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    3
    0
    0
    0
    0
    Vulvovaginal Discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    7 / 21 (33.33%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    2
    0
    9
    1
    3
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    3 / 9 (33.33%)
    1 / 3 (33.33%)
    3 / 21 (14.29%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    1
    7
    1
    4
    0
    0
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    18
    0
    4
    2
    0
    Haemoptysis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    3 / 3 (100.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    3
    0
    5
    Pleural Effusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Productive Cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Rhinalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Upper-Airway Cough Syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pleurisy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    2
    0
    0
    Bradyphrenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Confusional State
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    2
    0
    0
    Delirium
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    0
    0
    Dysthymic Disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hallucination, Visual
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    1
    0
    Irritability
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    3
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    2
    Blood Alkaline Phosphatase
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    0
    0
    Blood Cholesterol Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    1
    Blood Creatinine
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Blood Magnesium Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Blood Pressure Diastolic Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Blood Triglycerides Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Chest X-Ray Abnormal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    0
    Glycosylated Haemoglobin Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Haemoglobin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Lymphocyte Count Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    4
    0
    0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    1
    0
    0
    0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 1 (100.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    0
    Weight Decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    2 / 3 (66.67%)
    3 / 19 (15.79%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    4
    3
    9
    5
    0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    0
    4
    1
    2
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Infusion Related Reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    1
    Limb Injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pelvic Fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Vascular Access Complication
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Sinus Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Amnesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    0
    3
    0
    3
    0
    1
    Dysgeusia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    6 / 21 (28.57%)
    0 / 3 (0.00%)
    8 / 19 (42.11%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    1
    1
    7
    0
    27
    0
    2
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    2
    1
    0
    Hypersomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    4
    0
    0
    Syncope
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    2
    0
    2
    0
    2
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    External Ear Inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    1
    0
    Eye disorders
    Abnormal Sensation In Eye
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    Eyelid Bleeding
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Iritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Vision Blurred
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Visual Impairment
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Dry Eyes
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Abdominal Distension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    0
    0
    0
    Abdominal Pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    7
    1
    1
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    0
    0
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    2
    0
    0
    Aphthous Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Ascites
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    1
    Constipation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    3 / 9 (33.33%)
    0 / 3 (0.00%)
    7 / 21 (33.33%)
    1 / 3 (33.33%)
    6 / 19 (31.58%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    3
    0
    8
    2
    7
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 5 (80.00%)
    0 / 1 (0.00%)
    7 / 9 (77.78%)
    2 / 3 (66.67%)
    8 / 21 (38.10%)
    1 / 3 (33.33%)
    10 / 19 (52.63%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    5
    0
    18
    3
    10
    2
    24
    1
    0
    Dry Mouth
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 1 (100.00%)
    2 / 9 (22.22%)
    2 / 3 (66.67%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    2
    2
    3
    0
    4
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    5 / 19 (26.32%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    3
    0
    9
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Glossodynia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Hyperchlorhydria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Hypoaesthesia Oral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Lip Ulceration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Mouth Ulceration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 5 (60.00%)
    1 / 1 (100.00%)
    5 / 9 (55.56%)
    1 / 3 (33.33%)
    12 / 21 (57.14%)
    1 / 3 (33.33%)
    10 / 19 (52.63%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
         occurrences all number
    8
    1
    7
    1
    19
    1
    24
    8
    5
    Odynophagia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Oral Discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Oral Dysaesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    0
    0
    0
    Oral Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Proctalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    1
    0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    4 / 9 (44.44%)
    0 / 3 (0.00%)
    5 / 21 (23.81%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
         occurrences all number
    1
    0
    6
    0
    23
    1
    16
    12
    7
    Tooth Disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    1 / 3 (33.33%)
    7 / 21 (33.33%)
    1 / 3 (33.33%)
    7 / 19 (36.84%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    3
    1
    12
    1
    15
    1
    3
    Noninfective Gingivitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    1
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    0
    Dermatitis Contact
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dry Skin
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    3
    1
    0
    Eczema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Hangnail
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    3 / 9 (33.33%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    0
    0
    0
    Ingrowing Nail
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Nail Disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Night Sweats
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Onycholysis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Pain Of Skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Papule
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    9
    5
    2
    Purpura
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    1 / 3 (33.33%)
    6 / 21 (28.57%)
    3 / 3 (100.00%)
    3 / 19 (15.79%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    4
    0
    4
    1
    9
    6
    4
    17
    2
    Rash Generalised
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    0
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    5 / 19 (26.32%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    0
    3
    0
    9
    0
    3
    Rash Papular
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin Disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Skin Exfoliation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin Lesion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Swelling Face
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 1 (100.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    0
    0
    Renal Colic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Urinary Incontinence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Urinary Retention
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    0
    0
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    12
    0
    0
    Back Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    3
    0
    3
    0
    3
    1
    0
    Fistula
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Inguinal Mass
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Muscle Spasms
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Osteopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Pain In Extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Candida Infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    1
    1
    Cystitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Fungal Skin Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Genital Herpes Zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Oral Candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Oral Fungal Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Oral Herpes
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    4
    3
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    5
    3
    0
    0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    1
    0
    0
    Skin Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    6
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    3
    4
    0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    5 / 19 (26.32%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    2
    0
    4
    0
    8
    0
    0
    Vulvitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Herpes Zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    6 / 9 (66.67%)
    1 / 3 (33.33%)
    9 / 21 (42.86%)
    0 / 3 (0.00%)
    8 / 19 (42.11%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    2
    0
    6
    1
    21
    0
    8
    1
    3
    Dehydration
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    2 / 9 (22.22%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    2
    0
    0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    1 / 3 (33.33%)
    1 / 21 (4.76%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    1
    5
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    2 / 21 (9.52%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    5 / 5 (100.00%)
    0 / 1 (0.00%)
    7 / 9 (77.78%)
    0 / 3 (0.00%)
    4 / 21 (19.05%)
    2 / 3 (66.67%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    5
    0
    26
    0
    6
    2
    3
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    3 / 21 (14.29%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    4
    0
    4
    Hypocalcaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 1 (100.00%)
    4 / 9 (44.44%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    5
    0
    2
    0
    3
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 1 (0.00%)
    4 / 9 (44.44%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    5
    0
    2
    0
    4
    0
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    2
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    1 / 9 (11.11%)
    0 / 3 (0.00%)
    0 / 21 (0.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 1 (0.00%)
    0 / 9 (0.00%)
    0 / 3 (0.00%)
    1 / 21 (4.76%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2011
    Amendment 1 • Clarification of starting dose for PF-05212384. • LIC, additional examinations and PK for Japanese patients. • Clarification of eligibility criteria for Japanese patients. • Lead-in PK sub-study. • Addition of appendices relevant only to Japanese amendment. • Other administrative changes.
    17 Apr 2012
    Amendment 2 Clarification of starting dose for PF-05212384. • Addition of PK sub-study. • Addition of PD endpoint of cholesterol and triglyceride changes. • Updated safety text to match Company standards. • Improvement of hyperglycemia management guidelines, including editing of two eligibility criteria.
    03 Aug 2012
    Amendment 3 • Addition of additional PK blood draws in PK sub-study. • Addition of language which defines end of survival follow-up period. • Updated requirement for triglyceride and cholesterol testing (fasted state). • Addition of standard Pfizer CSP template language regarding pregnancy testing for eligibility purposes and lifestyle guidelines with regards to birth control, safety data ollection, temperature monitoring in drug storage area, and record retention. • Clarification of language regarding statistical analysis of ECG data. • Addition of language to clarify provision of study drug to patients in the event that the sponsor ended the study prematurely.
    10 Aug 2012
    Amendment 4 (Japan Specific) • Addition of patients in LIC. • Addition of PK blood draws in PK sub-study. • Addition of PD endpoint of cholesterol and triglyceride changes (fasted state). • Revision of hyperglycemia management guidelines, including editing of two eligibility criteria. • Updated dose modification schedule for PF-04691502 and PF-05212384 in LIC. • Updated safety text to match Company standards. • Addition of language defining end of survival follow-up period. • Addition of standard Pfizer CSP template language regarding pregnancy testing for eligibility purposes and lifestyle guidelines with regards to birth control, safety data collection, temperature monitoring in drug storage area, and record retention. • Clarification of language regarding statistical analysis of ECG data. • Updated guidelines for safety data reviewing. • Addition of language to clarify provision of study drug to patients in the event that the sponsor ended the study prematurely.
    31 Aug 2012
    Amendment 5 • Reduction of the starting dose for PF-04691502. • Reduction of the dose of PF-04691502 for ongoing patients. • Updated phase 1 clinical data for PF-04691502 and PF-05212384. • Addition of required CT scans of chest at baseline and every 8 weeks. • Allowed for 20 patients with starting dose of 6 mg of PF-04691502 in Stage 1 for each PF-04691502 arm. • Updated dose modification guidelines with respiratory toxicities. • Modified CSP-specific SAEs.
    10 Sep 2012
    Amendment 6 (Japan Specific) • Reduction of the dose of PF-04691502 for ongoing patients of the main study. • Addition of 2 mg cohort in LIC. • Updated guidelines for safety data reviewing. • Updated phase 1 clinical data for PF-04691502 and PF-05212384. • Addition of required CT scans of chest at baseline and every 8 weeks. • Allowed for 20 patients with starting dose of 6 mg of PF-04691502 in Stage 1 for each PF-04691502 arm. • Updated dose modification guidelines with respiratory toxicities. • Modified CSP-specific SAEs.
    02 Nov 2012
    • Amendment 7 • Enrollment to arms of the study which utilized PF-04691502 was discontinued. • Long term follow up portion of the study was removed for those patients on the PF-04691502 arms of the study. • Changed timing for pregnancy testing during screening. • Glucose testing changed to fasted or non-fasted for all study patients. • Post study SAE reporting requirements changed to specify that SAEs clearly related to subsequent anti-cancer treatments (including other clinical studies) or disease progression were not to be reported. • Patients on the PF-04691502 arms of the study no longer needed to perform blood draws for PK or optional tumor biopsies for PD. • There was no formal PK analysis for PF-04691502, only concentration-time listings. • Total number of patients enrolled to the study was changed as a result of stopping further enrollment to the PF-04691502 arms of the study. • Female patients of childbearing potential had to agree to use 2 methods of highly effective contraception. • Specific criteria for QTc analyses were removed, to be addressed in the SAP. • Removal of analysis of PF-04691502 concentration vs. QT.
    09 Nov 2012
    Amendment 8 (Japan Specific) (09 November 2012) • Enrollment to arms of the study which utilized PF-04691502 was discontinued. • Long term follow up portion of the study was removed for those patients on the PF-04691502 arms of the study. • Changed timing for pregnancy testing during screening. • Glucose testing changed to fasted OR non-fasted for all study patients. • Post study SAE reporting requirements changed to specify that SAEs clearly related to subsequent anti-cancer treatments (including other clinical studies) or disease progression were not to be reported. • Patients on the PF-04691502 arms of the study no longer needed to perform blood draws for PK or optional tumor biopsies for PD. • There was no formal PK analysis for PF-04691502, only concentration-time listings. • Total number of patients enrolled to the study had changed as a result of stopping further enrollment to the PF-04691502 arms of the study. • Female subjects of childbearing potential had to agree to use 2 methods of highly effective contraception. • Specific criteria for QTc analyses were removed, to be addressed in the statistical analysis plan. • Removal of analysis of PF-04691502 concentration vs QT.
    19 Feb 2015
    Amendment 9 (Japan specific) • Text was added to describe termination of the study and rationale for termination. • Reduction of tumor assessment schedule. • Addition of plasma sampling for circulating DNA analysis. • Procedure for blood draw for this DNA analysis was added. • Study endpoint and objectives were updated accordingly to support this DNA analysis.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Jan 2014
    Enrollment to B1271004 was discontinued on 23 January 2014 following a strategic decision based on initial results which were contrary to the hypothesis that a Stathmin high status (PI3K activated) would predict for better efficacy. The CSP indicated that the study would proceed into Stage 2 of the study if at least 8 clinical benefit responders were observed in 20 response evaluable patients at the end of Stage 1. As of 14 January 2014, 9 clinical benefit responders had been identified in the ‘Stathmin low’ arm of the study. Although this met the CSP defined criteria for advancement in to Stage 2 of the study, the sponsor determined not to proceed to Stage 2 based on the overall clinical findings. Patients who were already receiving treatment in Stage 1 of the study continued to take study drug. Patients were no longer followed up for OS and the planned OS analysis was not performed.
    -

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