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    Clinical Trial Results:
    A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Clinical Activity and Pharmacokinetics of Bosutinib (PF-05208763) Versus Placebo in Subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2010-023017-65
    Trial protocol
    		 SE   ES   CZ   HU   GB   PL   SK   LT   IT   BG  
    Global end of trial date
    29 Aug 2014

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B1871019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01233869
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer Inc., Pfizer ClinicalTrials.gov Call Center,, 001 8007181021,
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 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
    17 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate that bosutinib reduces the rate of kidney enlargement in subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD) entering the study with total kidney volume (TKV) >=750 cc and estimated glomerular filtration rate (eGFR) 60 >=mL/min/1.73m2.
    Protection of trial subjects
    An independent external Data Monitoring Committee (eDMC) reviewed accumulating safety data on an ongoing basis. The eDMC may have, at any time, requested additional information from the sponsor. Based on these reviews, the eDMC had capacity to make recommendations to the sponsor that might impact the future conduct of the study. These may have included continuing the study as planned, amending safety-monitoring procedures, modifying the protocol or consent, or terminating the study. In addition, the eDMC was responsible for reviewing the safety and efficacy data for the interim analysis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Moldova, Republic of: 8
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Slovakia: 7
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    169
    EEA total number of subjects
    117
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    169
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 172 subjects were enrolled in this study, of which 169 received at least 1 dose of study treatment.

    Period 1
    Period 1 title
    Initial Treatment Period (24 Months)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bosutinib 200 mg/day
    Arm description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg in the morning with food

    Arm title
    		 Bosutinib 400 mg/day
    Arm description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg in the morning with food

    Arm title
    		 Bosutinib 400/200 mg/day
    Arm description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg (dose-reduced to 200 mg) in the morning with food

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matched

    Number of subjects in period 1
    		Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Started
    58
    31
    24
    56
    Completed
    34
    3
    22
    34
    Not completed
    24
    28
    2
    22
         Adverse event, serious fatal
    1
    -
    -
    -
         Adverse event, non-fatal
    9
    17
    -
    3
         Not Related to Study Drug
    14
    11
    2
    19
    Period 2
    Period 2 title
    Washout Period 30 Days
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bosutinib 200 mg/day
    Arm description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg in the morning with food

    Arm title
    		 Bosutinib 400 mg/day
    Arm description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg in the morning with food

    Arm title
    		 Bosutinib 400/200 mg/day
    Arm description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg (dose-reduced to 200 mg) in the morning with food

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matched

    Number of subjects in period 2
    		Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Started
    34
    3
    22
    34
    Completed
    34
    3
    22
    34
    Period 3
    Period 3 title
    Extended Treatment Period (46 Months)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bosutinib 200 mg/day
    Arm description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg in the morning with food

    Arm title
    		 Bosutinib 400 mg/day
    Arm description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg in the morning with food

    Arm title
    		 Bosutinib 400/200 mg/day
    Arm description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg (dose-reduced to 200 mg) in the morning with food

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, Subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matched

    Number of subjects in period 3
    		Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Started
    34
    3
    22
    34
    Completed
    20
    0
    17
    18
    Not completed
    14
    3
    5
    16
         Consent withdrawn by subject
    10
    3
    5
    11
         Adverse event, non-fatal
    1
    -
    -
    1
         Unspecified
    3
    -
    -
    3
         Lost to follow-up
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bosutinib 200 mg/day
    Reporting group description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Bosutinib 400 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.

    Reporting group title
    Bosutinib 400/200 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.

    Reporting group values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo Total
    Number of subjects
    		 58 31 24 56 169
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 58 31 24 56 169
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 37.9 ( 8 ) 41.3 ( 4.9 ) 36.4 ( 7.8 ) 38.5 ( 7.4 ) -
    Gender, Male/Female
    Units: participants
        Male
    		 30 17 9 21 77
        Female
    		 28 14 15 35 92

    End points

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    End points reporting groups
    Reporting group title
    Bosutinib 200 mg/day
    Reporting group description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Bosutinib 400 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.

    Reporting group title
    Bosutinib 400/200 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
    Reporting group title
    Bosutinib 200 mg/day
    Reporting group description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Bosutinib 400 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.

    Reporting group title
    Bosutinib 400/200 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
    Reporting group title
    Bosutinib 200 mg/day
    Reporting group description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Bosutinib 400 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.

    Reporting group title
    Bosutinib 400/200 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, Subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.

    Primary: Change From Baseline in Total Kidney Volume (TKV) at Month 25

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    End point title
    		 Change From Baseline in Total Kidney Volume (TKV) at Month 25
    End point description
    TKV was measured by centrally evaluated Magnetic Resonance Imaging (MRI).
    End point type
    Primary
    End point timeframe
    Baseline and Month 25 (end of Initial Treatment Period Visit [ITPV])
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    27
    6
    21
    33
    Units: centimeter cube (cm^3)
    arithmetic mean (standard deviation)
        Baseline (n=27,6,21,33)
    1686.38 ( 944.3 )
    1418.96 ( 629.34 )
    1487.48 ( 531.96 )
    1670.33 ( 640.69 )
        Change at Month 25 (n=23,3,20,30)
    85.05 ( 231.09 )
    102.45 ( 257.3 )
    -6.18 ( 119.79 )
    175.36 ( 191.43 )
    Statistical analysis title
    		 Annualized Rate of Kidney Enlargement
    Statistical analysis description
    Placebo versus Pooled Bosutinib
    Comparison groups
    Bosutinib 200 mg/day v Bosutinib 400 mg/day v Bosutinib 400/200 mg/day v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.02
         upper limit
    		 5.74
    Statistical analysis title
    		 Annualized Rate of Kidney Enlargement
    Statistical analysis description
    Bosutinib 200 mg/day versus Bosutinib 400/200 mg/day
    Comparison groups
    Bosutinib 200 mg/day v Bosutinib 400/200 mg/day
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1234
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 4.22
    Statistical analysis title
    		 Annualized Rate of Kidney Enlargement
    Statistical analysis description
    Placebo versus Bosutinib 200 mg/day
    Comparison groups
    Bosutinib 200 mg/day v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 5.23
    Statistical analysis title
    		 Annualized Rate of Kidney Enlargement
    Statistical analysis description
    Placebo versus Bosutinib 400 mg/day
    Comparison groups
    Bosutinib 400 mg/day v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1336
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 8.05
    Statistical analysis title
    		 Annualized Rate of Kidney Enlargement
    Statistical analysis description
    Placebo versus Bosutinib 400/200 mg/day
    Comparison groups
    Bosutinib 400/200 mg/day v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.65
         upper limit
    		 7.3

    Secondary: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination

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    End point title
    		 Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination
    End point description
    eGFR was centrally evaluated. Glomerular filtration rate (GFR) is an index of kidney function that describes the flow of filtered fluid through the kidney. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate eGFR. Month 25 is the end of the ITPV. '99999' means data is 'not applicable'.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24, Month 25 (ITPV), and early termination
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    27
    6
    21
    33
    Units: mL/min/1.73m^2
    arithmetic mean (standard deviation)
        Change at Month 12 (n=26,4,21,31)
    -6.38 ( 11.6 )
    -7.56 ( 11.27 )
    -11.52 ( 10.86 )
    1.3 ( 9.71 )
        Change at Month 24 (n=23,3,20,30)
    -8.47 ( 15.02 )
    -21.59 ( 13.74 )
    -13.16 ( 13.41 )
    -7.95 ( 12.91 )
        Change at ITPV (n=23,3,20,30)
    -5 ( 10.78 )
    -13.24 ( 12.45 )
    -9.92 ( 14.55 )
    -2.74 ( 18.01 )
        Change at Early Termination (n=6,3,1,4)
    -11.91 ( 8.79 )
    0.78 ( 4.83 )
    -10.24 ( 99999 )
    -2.75 ( 21.35 )
    No statistical analyses for this end point

    Secondary: Time to First Occurrence or Worsening of Hypertension

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    End point title
    		 Time to First Occurrence or Worsening of Hypertension
    End point description
    The time to first occurrence or worsening of hypertension was observed (defined as the need for increased dose of or need for additional anti-hypertensive medication). The numbers presented correspond to the very first occurrence or worsening of hypertension in that treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 25 (end of ITPV)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    42
    9
    24
    43
    Units: days
    15
    180
    90
    30
    No statistical analyses for this end point

    Secondary: Time to First Occurrence or Worsening of Back and/or Flank Pain

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    End point title
    		 Time to First Occurrence or Worsening of Back and/or Flank Pain
    End point description
    The time to first occurrence or worsening of back and/or flank pain was observed (defined as initial onset of polycystic kidney disease [PKD]-related chronic back and/or flank pain; initiation of pain medication treatment for PKD-related chronic back and/or flank pain; addition of a pain medicine for treatment of PKD-related chronic back and/or flank pain; increase in dose of pain medication for treatment of PKD-related chronic back and/or flank pain). The numbers presented correspond to the very first occurrence or worsening of back and/or flank pain in that treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 25 (end of ITPV)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    42
    9
    24
    43
    Units: days
    30
    30
    270
    15
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of Gross Hematuria

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    End point title
    		 Time to First Occurrence of Gross Hematuria
    End point description
    Gross hematuria is the presence of blood in the urine (defined as pink, red, or cola-colored urine due to the presence of red blood cells). The numbers presented correspond to the very first occurrence of gross hematuria in that treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 25 (end of ITPV)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    42
    9
    24
    43
    Units: days
    330
    180
    180
    45
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of Proteinuria

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    End point title
    		 Time to First Occurrence of Proteinuria
    End point description
    Proteinuria is the presence of an excess of serum proteins in the urine, which may be an early sign of kidney disease The numbers presented correspond to the very first occurrence of proteinuria in that treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 25 (end of ITPV)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    42
    0 [1]
    24
    43
    Units: days
    360
    270
    540
    Notes
    [1] - No proteinuria was observed.
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days

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    End point title
    		 Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days
    End point description
    ESRD is when the kidneys permanently fail to work at a level needed for daily life.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 25 (end of ITPV)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    Units: days
    Notes
    [2] - No subjects developed ESRD during the treatment period.
    [3] - No subjects developed ESRD during the treatment period.
    [4] - No subjects developed ESRD during the treatment period.
    [5] - No subjects developed ESRD during the treatment period.
    No statistical analyses for this end point

    Secondary: Number of Subjects With High Blood Urea Nitrogen (BUN) Levels

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    End point title
    		 Number of Subjects With High Blood Urea Nitrogen (BUN) Levels
    End point description
    A BUN test can reveal how well the kidneys are working by measuring the amount of urea nitrogen in the blood. A high BUN level (>1.3 times the upper limit of normal) may suggest that the kidneys are not working properly. Month 25 is the end of the ITPV.
    End point type
    Secondary
    End point timeframe
    Day 15, Months 6, 12, 18, 24, and 25 (end of ITPV)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    58
    31
    24
    56
    Units: subjects
        Day 15
    0
    0
    2
    0
        Month 6
    0
    0
    0
    0
        Month 12
    0
    0
    0
    0
        Month 18
    0
    0
    0
    0
        Month 24
    0
    0
    1
    0
        End of ITPV
    0
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With High Serum Creatinine (SCr) Levels

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    End point title
    		 Number of Subjects With High Serum Creatinine (SCr) Levels
    End point description
    A SCr test can reveal how well the kidneys are working by measuring the amount of urea nitrogen in the blood. A high SCr level (>1.3 times the upper limit of normal) may suggest that the kidneys are not working properly. Month 25 is the end of the ITPV.
    End point type
    Secondary
    End point timeframe
    Day 15, Months 6, 12, 18, 24, and 25 (end of ITPV)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    58
    31
    24
    56
    Units: subjects
        Day 15
    0
    1
    0
    0
        Month 6
    0
    0
    0
    0
        Month 12
    0
    0
    0
    1
        Month 18
    0
    0
    0
    0
        Month 24
    0
    1
    1
    1
        End of ITPV
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Bosutinib

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Bosutinib [6]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose and 1, 3, 5 and 24 hours post-dose), Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
    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: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest; n=the number of participants analyzed at that time point in the respective arms.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    58
    31
    24
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Day 1 (n=58,31,24)
    32.61 ( 53 )
    74.87 ( 47 )
    84.57 ( 56 )
        Day 15 (n=58,16,22)
    68.72 ( 43 )
    127.9 ( 28 )
    155 ( 31 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib

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    End point title
    		 Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose and 1, 3, 5 and 24 hours post-dose), Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
    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: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest; n=the number of participants analyzed at that time point in the respective arms.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    58
    31
    24
    Units: hour
    median (full range (min-max))
        Day 1 (n=58,31,24)
    3 (1 to 24)
    3 (2.8 to 23.8)
    4.86 (1 to 5.25)
        Day 15 (n=58,16,22)
    3.95 (0 to 25.6)
    3 (1 to 8)
    5 (1 to 8.12)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib

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    End point title
    		 Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib [8]
    End point description
    Area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau=24 hours.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose and 1, 3, 5 and 24 hours post-dose), Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest; n=the number of participants analyzed at that time point in the respective arms.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    58
    31
    24
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        Day 1 (n=58,30,24)
    437 ( 48 )
    1040 ( 49 )
    1149 ( 50 )
        Day 15 (n=58,16,22)
    1059 ( 45 )
    2052 ( 36 )
    2384 ( 34 )
    No statistical analyses for this end point

    Secondary: Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib

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    End point title
    		 Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib [9]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    58
    16
    22
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    25.15 ( 49 )
    19.6 ( 20880 )
    50.67 ( 50 )
    No statistical analyses for this end point

    Secondary: Apparent Oral Clearance (CL/F) of Bosutinib

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    End point title
    		 Apparent Oral Clearance (CL/F) of Bosutinib [10]
    End point description
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
    End point type
    Secondary
    End point timeframe
    Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    58
    16
    22
    Units: liters per hour (L/hr)
        geometric mean (geometric coefficient of variation)
    188.8 ( 45 )
    195 ( 36 )
    167.8 ( 34 )
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution (Vz/F) of Bosutinib

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    End point title
    		 Apparent Volume of Distribution (Vz/F) of Bosutinib [11]
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose and 1, 3, 5 and 24 hours post-dose), Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    0 [12]
    0 [13]
    0 [14]
    Units: liters
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    Notes
    [12] - There was no sufficient data to well-characterize the terminal phase.
    [13] - There was no sufficient data to well-characterize the terminal phase.
    [14] - There was no sufficient data to well-characterize the terminal phase.
    No statistical analyses for this end point

    Secondary: Terminal Elimination Half-Life (t1/2) of Bosutinib

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    End point title
    		 Terminal Elimination Half-Life (t1/2) of Bosutinib [15]
    End point description
    t1/2 is the time measured for the plasma concentration to decrease by one half.
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose and 1, 3, 5 and 24 hours post-dose), Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    Units: hours
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [16] - There was no sufficient data to well-characterize the terminal phase.
    [17] - There was no sufficient data to well-characterize the terminal phase.
    [18] - There was no sufficient data to well-characterize the terminal phase.
    No statistical analyses for this end point

    Secondary: Observed Accumulation Ratio (Rac) of Bosutinib

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    End point title
    		 Observed Accumulation Ratio (Rac) of Bosutinib [19]
    End point description
    Observed accumulation ratio (Rac) was calculated as AUC from time 0 to 24 hours (Day 15) divided by AUC from time 0 to 24 hours (Day 1).
    End point type
    Secondary
    End point timeframe
    Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-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: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day
    Number of subjects analysed
    58
    16
    22
    Units: ratio
        geometric mean (geometric coefficient of variation)
    2.452 ( 36 )
    2.28 ( 42 )
    2.075 ( 41 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25

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    End point title
    		 Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25
    End point description
    The KDQoL-36 is a 36-item questionnaire on kidney disease-specific measure of patient-reported quality of life with 5 subscales: physical and mental functioning (items 1-12); burden of kidney disease subscale (Burden, items 13-16); symptoms and problems (items 17-28); effects of kidney disease on daily life subscale (KDQoL, items 29-36). The raw scores are transformed linearly to a range of 0 to 100, with higher scores indicating better quality of life. M25=Month 25.
    End point type
    Secondary
    End point timeframe
    Baseline and end of ITPV (Month 25)
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    42
    9
    24
    43
    Units: units on a scale
    arithmetic mean (standard deviation)
        Burden: Baseline (n=42,9,24,43)
    84.23 ( 18.48 )
    84.72 ( 20.99 )
    79.43 ( 24.97 )
    74.86 ( 30.21 )
        Burden: Change at M25 (n=32,3,22,34)
    -2.54 ( 15.7 )
    -2.08 ( 9.55 )
    0.57 ( 15.9 )
    1.84 ( 19.13 )
        KDQoL: Baseline (n=42,9,24,43)
    93.3 ( 8.58 )
    92.01 ( 11.06 )
    91.54 ( 11.53 )
    90.41 ( 14.1 )
        KDQoL: Change at M25; n=32,3,22,34
    1.07 ( 5.48 )
    3.13 ( 5.41 )
    -0.57 ( 9.72 )
    3.22 ( 9.5 )
        Mental: Baseline (n=42,9,24,43)
    54.31 ( 6.39 )
    51.11 ( 12.87 )
    50.19 ( 9.28 )
    51.33 ( 8.58 )
        Mental: Change at M25 (n=32,3,22,34)
    -1.5 ( 5.87 )
    6.55 ( 6.3 )
    1.34 ( 7.35 )
    0.12 ( 10.25 )
        Physical: Baseline (n=42,9,24,43)
    50.52 ( 6.93 )
    51.78 ( 6.4 )
    49.64 ( 8.35 )
    47.17 ( 10.93 )
        Physical: Change at M25 (n=32,3,22,34)
    -0.28 ( 5.81 )
    -7.59 ( 7.63 )
    -2.33 ( 8.16 )
    2.32 ( 8.34 )
        Symptoms/Problems: Baseline (n=42,9,24,43)
    93.13 ( 6.96 )
    93.69 ( 7.35 )
    90.72 ( 9.31 )
    90.86 ( 9.29 )
        Symptoms/Problems: Change at M25 (n=32,3,22,34)
    -2.42 ( 7.21 )
    -8.33 ( 9.19 )
    -3.75 ( 8.04 )
    0.27 ( 9.31 )
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-SAEs.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after last study drug administration
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    58
    31
    24
    56
    Units: subjects
        AEs (serious and non-serious)
    56
    30
    23
    51
        SAEs
    12
    4
    6
    5
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern

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    End point title
    		 Number of Subjects With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern
    End point description
    The following laboratory parameters were analyzed: hematology (hemoglobin, hematocrit, red blood cell [RBC] count, RBC morphology, platelet count, white blood cell [WBC] count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (blood urea nitrogen [BUN], creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, uric acid, albumin, and total protein; urinalysis (pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, microscopy [if urine dipstick was positive for blood, protein, nitrites or leukocyte esterase]); others (coagulation panel, circulating immune complex, and complement activation).
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after last study drug administration
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    58
    31
    24
    56
    Units: subjects
    53
    20
    23
    43
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Potentially Clinically Significant Vital Signs Findings

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Vital Signs Findings
    End point description
    Vital signs assessment included pulse rate and blood pressure. Criteria for vital sign values meeting potential clinical concern included: supine/sitting pulse rate <40 or >120 beats per minute (bpm), standing pulse rate <40 or >140 bpm; systolic blood pressure (SBP) of >=30 millimeters of mercury (mm Hg) change from baseline in same posture or SBP <90 mm Hg, diastolic blood pressure (DBP) >=20 mmHg change from baseline in same posture or DBP <50 mm Hg. In the results table, SBP and DBP data are measured in 'mm Hg'; pulse rate is 'HR' and measured in 'bpm'.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after last study drug administration
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    58
    31
    24
    56
    Units: subjects
        Supine SBP <90 (n=2,2,1,4)
    0
    0
    0
    0
        Sitting SBP <90 (n=58,29,24,54)
    0
    0
    1
    0
        Supine DBP <50 (n=2,2,1,4)
    0
    0
    0
    0
        Sitting DBP <50 (n=58,29,24,54)
    0
    1
    1
    0
        Supine HR <40 or >120 (n=2,2,1,4)
    0
    0
    0
    0
        Sitting HR <40 or >120 (n=58,29,24,54)
    1
    0
    0
    0
        Supine SBP Decrease (n=2,2,1,4)
    0
    0
    1
    0
        Sitting SBP Decrease (n=58,29,24,54)
    2
    1
    2
    2
        Supine DBP Decrease (n=2,2,1,4)
    0
    0
    1
    0
        Sitting DBP Decrease (n=58,29,24,54)
    12
    3
    3
    5
        Supine SBP Increase (n=2,2,1,4)
    0
    0
    0
    0
        Sitting SBP Increase (n=58,29,24,54)
    3
    1
    3
    3
        Supine DBP Increase (n=2,2,1,4)
    0
    0
    0
    0
        Sitting DBP Increase (n=58,29,24,54)
    5
    3
    5
    5
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Potentially Clinically Significant Electrocardiogram (ECG) Findings

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    End point title
    		 Number of Subjects With Potentially Clinically Significant Electrocardiogram (ECG) Findings
    End point description
    ECGs were centrally evaluated. ECG parameters included PR interval, QRS interval, and corrected QT interval using Fridericia's formula (QTcF). Criteria for ECG changes meeting potential clinical concern included: PR interval greater than or equal to (≥)300 milliseconds (msec) or ≥25% increase when baseline is greater than (>)200 msec and ≥50% increase when baseline is less than or equal to (≤)200 msec; QRS interval ≥200 msec or ≥25%/50% increase from baseline; and QTcF ≥450 msec or ≥30 msec increase.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after last study drug administration
    End point values
    		 Bosutinib 200 mg/day Bosutinib 400 mg/day Bosutinib 400/200 mg/day Placebo
    Number of subjects analysed
    58
    31
    24
    56
    Units: subjects
        PR >=300 msec (n=58,31,24,56)
    0
    0
    0
    0
        QRS >=200 msec (n=58,31,24,56)
    0
    0
    0
    0
        QTcF 450-<480 msec (n=58,31,24,56)
    3
    2
    0
    6
        QTcF 480-<500 msec (n=58,31,24,56)
    0
    0
    0
    0
        QTcF >=500 msec (n=58,31,24,56)
    0
    0
    0
    0
        PR >=25/50% Increase (n=57,28,23,52)
    0
    0
    0
    0
        QRS >=25/50% Increase (n=57,28,23,52)
    0
    0
    0
    0
        QTcF 30/60 msec Increase (n=57,28,23,52)
    4
    1
    1
    5
        QTcF >=60 msec Increase (n=57,28,23,52)
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after last study drug administration
    Adverse event reporting additional description
    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 subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Bosutinib 200 mg/day
    Reporting group description
    		 Subjects received bosutinib 200 mg tablet orally once daily (QD) in the morning with food for 24 months in the Initial Treatment Period (ITP). After a 30-day washout period, subjects who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Bosutinib 400/200 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg and were dose-reduced to 200 mg tablet (based on protocol amendment) orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, subjects who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.

    Reporting group title
    Bosutinib 400 mg/day
    Reporting group description
    		 Subjects received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All subjects were dose-reduced during the ITP based on a protocol amendment. Those who remained active in the study at the time of the amendment are represented in the bosutinib 400/200 mg/day group.

    Serious adverse events
    		 Bosutinib 200 mg/day Bosutinib 400/200 mg/day Placebo Bosutinib 400 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 58 (20.69%)
    6 / 24 (25.00%)
    5 / 56 (8.93%)
    4 / 31 (12.90%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial aneurysm
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervix disorder
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychosomatic disease
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cyst haemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cyst ruptured
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal haemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sacroiliitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bosutinib 200 mg/day Bosutinib 400/200 mg/day Placebo Bosutinib 400 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 58 (96.55%)
    23 / 24 (95.83%)
    51 / 56 (91.07%)
    30 / 31 (96.77%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 58 (13.79%)
    5 / 24 (20.83%)
    9 / 56 (16.07%)
    3 / 31 (9.68%)
         occurrences all number
    14
    9
    17
    3
    Hypotension
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 24 (12.50%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    3
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 24 (12.50%)
    1 / 56 (1.79%)
    1 / 31 (3.23%)
         occurrences all number
    1
    3
    1
    1
    Chest pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    2
    Fatigue
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 24 (8.33%)
    6 / 56 (10.71%)
    8 / 31 (25.81%)
         occurrences all number
    4
    2
    8
    9
    Influenza-like illness
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 24 (12.50%)
    6 / 56 (10.71%)
    1 / 31 (3.23%)
         occurrences all number
    3
    4
    10
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 24 (4.17%)
    3 / 56 (5.36%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    4
    1
    Pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Pyrexia
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 24 (8.33%)
    1 / 56 (1.79%)
    3 / 31 (9.68%)
         occurrences all number
    2
    2
    1
    3
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    3
    1
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cervical dysplasia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Menorrhagia
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 24 (4.17%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Metrorrhagia
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Ovarian cyst
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    1
    Vaginal inflammation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 24 (12.50%)
    4 / 56 (7.14%)
    3 / 31 (9.68%)
         occurrences all number
    4
    3
    5
    3
    Oropharyngeal pain
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 24 (4.17%)
    2 / 56 (3.57%)
    2 / 31 (6.45%)
         occurrences all number
    5
    1
    4
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    1 / 31 (3.23%)
         occurrences all number
    4
    0
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 58 (31.03%)
    12 / 24 (50.00%)
    4 / 56 (7.14%)
    16 / 31 (51.61%)
         occurrences all number
    42
    21
    4
    35
    Amylase increased
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 24 (12.50%)
    1 / 56 (1.79%)
    4 / 31 (12.90%)
         occurrences all number
    5
    5
    1
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 58 (29.31%)
    6 / 24 (25.00%)
    3 / 56 (5.36%)
    11 / 31 (35.48%)
         occurrences all number
    26
    8
    3
    19
    Blood creatine phosphokinase increased
         subjects affected / exposed
    11 / 58 (18.97%)
    6 / 24 (25.00%)
    5 / 56 (8.93%)
    3 / 31 (9.68%)
         occurrences all number
    19
    14
    9
    5
    Blood creatinine increased
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 24 (8.33%)
    2 / 56 (3.57%)
    1 / 31 (3.23%)
         occurrences all number
    2
    4
    2
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    4
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    7
    0
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 24 (8.33%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Lipase increased
         subjects affected / exposed
    5 / 58 (8.62%)
    6 / 24 (25.00%)
    3 / 56 (5.36%)
    6 / 31 (19.35%)
         occurrences all number
    12
    6
    6
    15
    Weight increased
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 24 (12.50%)
    0 / 56 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    3
    0
    3
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 24 (8.33%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    2
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 58 (12.07%)
    4 / 24 (16.67%)
    3 / 56 (5.36%)
    2 / 31 (6.45%)
         occurrences all number
    7
    5
    3
    2
    Dysgeusia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    Headache
         subjects affected / exposed
    9 / 58 (15.52%)
    2 / 24 (8.33%)
    12 / 56 (21.43%)
    3 / 31 (9.68%)
         occurrences all number
    12
    6
    48
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 58 (12.07%)
    5 / 24 (20.83%)
    2 / 56 (3.57%)
    4 / 31 (12.90%)
         occurrences all number
    11
    11
    2
    5
    Eosinophilia
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 24 (4.17%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 24 (8.33%)
    3 / 56 (5.36%)
    2 / 31 (6.45%)
         occurrences all number
    3
    2
    3
    3
    Abdominal pain
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 24 (8.33%)
    7 / 56 (12.50%)
    8 / 31 (25.81%)
         occurrences all number
    8
    2
    15
    15
    Abdominal pain upper
         subjects affected / exposed
    5 / 58 (8.62%)
    8 / 24 (33.33%)
    5 / 56 (8.93%)
    7 / 31 (22.58%)
         occurrences all number
    6
    11
    11
    11
    Constipation
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 24 (4.17%)
    1 / 56 (1.79%)
    2 / 31 (6.45%)
         occurrences all number
    2
    1
    1
    2
    Diarrhoea
         subjects affected / exposed
    26 / 58 (44.83%)
    18 / 24 (75.00%)
    11 / 56 (19.64%)
    26 / 31 (83.87%)
         occurrences all number
    42
    44
    18
    59
    Dyspepsia
         subjects affected / exposed
    6 / 58 (10.34%)
    3 / 24 (12.50%)
    3 / 56 (5.36%)
    2 / 31 (6.45%)
         occurrences all number
    7
    4
    4
    21
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Nausea
         subjects affected / exposed
    21 / 58 (36.21%)
    13 / 24 (54.17%)
    9 / 56 (16.07%)
    15 / 31 (48.39%)
         occurrences all number
    30
    22
    15
    26
    Vomiting
         subjects affected / exposed
    6 / 58 (10.34%)
    9 / 24 (37.50%)
    4 / 56 (7.14%)
    11 / 31 (35.48%)
         occurrences all number
    6
    17
    4
    15
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 24 (0.00%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Alopecia
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 24 (12.50%)
    3 / 56 (5.36%)
    1 / 31 (3.23%)
         occurrences all number
    2
    4
    4
    1
    Dermatitis allergic
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 24 (8.33%)
    0 / 56 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Pruritis
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 24 (4.17%)
    1 / 56 (1.79%)
    2 / 31 (6.45%)
         occurrences all number
    1
    1
    1
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    0 / 56 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 24 (4.17%)
    4 / 56 (7.14%)
    3 / 31 (9.68%)
         occurrences all number
    4
    1
    5
    4
    Proteinuria
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 24 (8.33%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Renal failure acute
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 24 (8.33%)
    0 / 56 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    3
    5
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 24 (4.17%)
    5 / 56 (8.93%)
    0 / 31 (0.00%)
         occurrences all number
    8
    2
    6
    0
    Back pain
         subjects affected / exposed
    9 / 58 (15.52%)
    1 / 24 (4.17%)
    8 / 56 (14.29%)
    2 / 31 (6.45%)
         occurrences all number
    13
    1
    9
    3
    Flank pain
         subjects affected / exposed
    10 / 58 (17.24%)
    0 / 24 (0.00%)
    5 / 56 (8.93%)
    5 / 31 (16.13%)
         occurrences all number
    21
    0
    7
    6
    Muscle spasms
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    1 / 31 (3.23%)
         occurrences all number
    4
    0
    3
    4
    Musculoskeletal pain
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 24 (8.33%)
    2 / 56 (3.57%)
    1 / 31 (3.23%)
         occurrences all number
    4
    2
    2
    1
    Myalgia
         subjects affected / exposed
    0 / 58 (0.00%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Pain in extremity
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 24 (8.33%)
    3 / 56 (5.36%)
    2 / 31 (6.45%)
         occurrences all number
    3
    2
    3
    2
    Cystitis
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 24 (12.50%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 24 (4.17%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    6
    0
    Nasopharyngitis
         subjects affected / exposed
    12 / 58 (20.69%)
    8 / 24 (33.33%)
    8 / 56 (14.29%)
    3 / 31 (9.68%)
         occurrences all number
    29
    13
    14
    3
    Influenza
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 24 (4.17%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Pharyngitis
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 24 (12.50%)
    4 / 56 (7.14%)
    0 / 31 (0.00%)
         occurrences all number
    0
    3
    9
    0
    Rhinitis
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 24 (8.33%)
    2 / 56 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    2
    3
    3
    0
    Sinusitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 58 (10.34%)
    7 / 24 (29.17%)
    7 / 56 (12.50%)
    4 / 31 (12.90%)
         occurrences all number
    10
    9
    11
    5
    Urinary tract infection
         subjects affected / exposed
    8 / 58 (13.79%)
    2 / 24 (8.33%)
    8 / 56 (14.29%)
    2 / 31 (6.45%)
         occurrences all number
    14
    7
    12
    2
    Vaginal infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 24 (0.00%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Viral infection
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 24 (4.17%)
    3 / 56 (5.36%)
    0 / 31 (0.00%)
         occurrences all number
    2
    2
    3
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 24 (4.17%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 24 (16.67%)
    0 / 56 (0.00%)
    4 / 31 (12.90%)
         occurrences all number
    3
    4
    0
    5
    Hypophosphataemia
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 24 (8.33%)
    1 / 56 (1.79%)
    0 / 31 (0.00%)
         occurrences all number
    2
    5
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2012
    Reduced sample size from 275 subjects to 190 subjects. Changed secondary objectives to investigation of eGFR over the study and removed demonstration that a reduction in rate of kidney enlargement is predictive of a reduction in decline in eGFR.
    07 Oct 2013
    Reduced dose for Cohort B from 400 mg/day to 200 mg/day and removed the matching placebo for subjects in the 200 mg/day cohort.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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