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Bosutinib For Autosomal Dominant Polycystic Kidney Disease

Sponsor
Pfizer (Industry)
Overall Status
Completed
CT.gov ID
NCT01233869
Collaborator
(none)
172
Enrollment
67
Locations
3
Arms
44
Duration (Months)
2.6
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This purpose of this study is to determine if bosutinib reduces the rate of kidney enlargement in subjects with autosomal dominant polycystic kidney disease (ADPKD) entering the study with a total kidney volume greater than or equal to 750 cc and eGFR greater than or equal to 60 mL/min/1.73m2.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
172 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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)
Study Start Date :
Dec 1, 2010
Actual Primary Completion Date :
Jul 1, 2014
Actual Study Completion Date :
Aug 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort A

Drug: Bosutinib
Once daily oral dose of 200 mg of bosutinib
Experimental: Cohort B

Drug: Bosutinib
Once daily oral dose of 400 mg of bosutinib transitioned to 200 mg/day
Placebo Comparator: Cohort C

Drug: Placebo
Once daily oral dose of placebo

Outcome Measures

Primary Outcome Measures

  1. Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 [Baseline and Month 25 (end of Initial Treatment Period Visit [ITPV])]

    TKV was measured by centrally evaluated Magnetic Resonance Imaging (MRI).

Secondary Outcome Measures

  1. Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination [Baseline, Month 12, Month 24, Month 25 (end of ITPV), and early termination]

    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.

  2. Time to First Occurrence or Worsening of Hypertension [Baseline up to Month 25 (end of ITPV)]

    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.

  3. Time to First Occurrence or Worsening of Back and/or Flank Pain [Baseline up to Month 25 (end of ITPV)]

    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.

  4. Time to First Occurrence of Gross Hematuria [Baseline up to Month 25 (end of ITPV)]

    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.

  5. Time to First Occurrence of Proteinuria [Baseline up to Month 25 (end of ITPV)]

    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.

  6. Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days [Baseline up to Month 25 (end of ITPV)]

    ESRD is when the kidneys permanently fail to work at a level needed for daily life. No participants developed ESRD during the treatment period, therefore the analysis of the onset of ESRD requiring ≥56 days of dialysis was not performed.

  7. Number of Participants With High Blood Urea Nitrogen (BUN) Levels [Day 15, Months 6, 12, 18, 24, and 25 (end of ITPV)]

    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.

  8. Number of Participants With High Serum Creatinine (SCr) Levels [Day 15, Months 6, 12, 18, 24, and 25 (end of ITPV)]

    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.

  9. Maximum Observed Plasma Concentration (Cmax) of Bosutinib [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)]

  10. Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib [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)]

  11. Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib [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)]

    Area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau=24 hours.

  12. Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib [Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)]

  13. Apparent Oral Clearance (CL/F) of Bosutinib [Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)]

    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.

  14. Apparent Volume of Distribution (Vz/F) of Bosutinib [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)]

    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.

  15. Terminal Elimination Half-Life (t1/2) of Bosutinib [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)]

    t1/2 is the time measured for the plasma concentration to decrease by one half.

  16. Observed Accumulation Ratio (Rac) of Bosutinib [Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)]

    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).

  17. Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 [Baseline and end of ITPV (Month 25)]

    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 (items 13-16); symptoms and problems (items 17-28); effects of kidney disease on daily life subscale (items 29-36). The raw scores are transformed linearly to a range of 0 to 100, with higher scores indicating better quality of life.

Other Outcome Measures

  1. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to 30 days after last study drug administration]

    An AE was any untoward medical occurrence in a participant 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.

  2. Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern [Baseline up to 30 days after last study drug administration]

    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).

  3. Number of Participants With Potentially Clinically Significant Vital Signs Findings [Baseline up to 30 days after last study drug administration]

    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.

  4. Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings [Baseline up to 30 days after last study drug administration]

    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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 50 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  • Males and females, 18 to 50 years old at the time of consent.

  • Documented diagnosis of ADPKD (PKD-1 or PKD-2 genotypes allowed).

  • Total kidney volume ≥ 750 cc, as measured by centrally evaluated MRI.

Exclusion Criteria:

  • eGFR < 60 mL/min/1.73m2.

  • Uncontrolled hypertension (defined as systolic blood pressure ≥140 or diastolic blood pressure ≥90 mm Hg).

  • Any previous exposure to the bosutinib test article or receipt of other polycystic kidney disease (PKD) therapies.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Southwest Kidney Institute, PLC Phoenix Arizona United States 85004
2 Southwest Clinical Research Institute, LLC Tempe Arizona United States 85284
3 Southwest Kidney Institute, PLC Tempe Arizona United States 85284
4 Capital Nephrology Clinical Research Sacramento California United States 95825
5 Boise Kidney & Hypertension Institute, PLLC Caldwell Idaho United States 83605
6 Boise Kidney & Hypertension Institute, PLLC Meridian Idaho United States 83642
7 Renal Associates of Baton Rouge Baton Rouge Louisiana United States 70808
8 Tufts Medical Center Boston Massachusetts United States 02111
9 Washington University School of Medicine St. Louis Missouri United States 63110
10 Washington University St. Louis Missouri United States 63110
11 New York University - HHC CTSI Clinical Research Center New York New York United States 10016
12 Doylestown Hospital MRI Doylestown Pennsylvania United States 18901
13 Doylestown Hospital Doylestown Pennsylvania United States 18901
14 Nephrology/Hypertension Specialists Doylestown Pennsylvania United States 18901
15 Renal Associates, PA San Antonio Texas United States 78215
16 San Antonio Kidney Disease Center Physicians Group, P.L.L.C. San Antonio Texas United States 78229
17 University of Virginia Health System - Nephrology Charlottesville Virginia United States 22908
18 University of Virginia Health System Charlottesville Virginia United States 22908
19 The Polyclinic Seattle Washington United States 98104
20 Renal Remission and Hypertension Clinic Silverdale Washington United States 98383
21 Monash Medical Centre Clayton Victoria Australia 3168
22 Toronto General Hospital Toronto Ontario Canada M5G 2N2
23 Hopital du Sacre-Coeur de Montreal Montreal Quebec Canada H4J 1C5
24 Klinika gerontologicka a metabolicka Hradec Kralove Czech Republic 500 05
25 Krajska nemocnice Liberec Liberec 1 Czech Republic 460 63
26 Nemocnice Nove Mesto na Morave Nove Mesto na Morave Czech Republic 592 31
27 Fakultni poliklinika VFN Praha 2 Czech Republic 128 00
28 Vseobecna fakultni nemocnice v Praze Praha 2 Czech Republic 128 08
29 Pharmaceutical Research Associates CZ, s.r.o. Praha 7 Czech Republic 170 00
30 PRA Magyarorszag Kft. Klinikai Farmakologiai Vizsgalohely Budapest Hungary 1077
31 Fovarosi Onkormanyzat Szent Imre Korhaz BSZMI Klinikai Farmakologiai Reszlege Budapest Hungary 1115
32 Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont I.sz.Belgyogyaszati Klinika Szeged Hungary 6720
33 Istituti Ospitalieri di Cremona Cremona Italy 26100
34 A.O. Universitaria Ospedali Riuniti di Foggia Foggia Italy 71100
35 Seoul National University Hospital, Department of Internal Medicine Seoul Korea, Republic of 110-744
36 Samsung Medical Center/Division of Nephrology Seoul Korea, Republic of 135-710
37 Eulji General Hospital Seoul Korea, Republic of 139-872
38 Vilnius University Hospital Santariskiu Clinic, Public Institution, Centre of Nephrology Vilnius Lithuania 08661
39 Spitalul Clinic Republican Chisinau Moldova, Republic of 2025
40 Zaklad Diagnostyki Chorob Serca, II Katedra Kardiologii Gdansk Poland 80-210
41 Klinika Nefrologii, Transplantologii i Chorob Wewnetrznych Gdansk Poland 80-952
42 Specjalistyczny Szpital Zachodni im. Jana Pawla II w Grodzisku Mazowieckim Grodzisk Mazowiecki Poland 05-825
43 Krakowskie Centrum Medyczne NZOZ Krakow Poland 31-501
44 Klinika Nefrologii, Hipertensjologii i Chorob Wewnetrznych Katedry Chorob Wewnetrznych UWM Olsztyn Poland 10-561
45 Pracownia Echokardiografii, Oddzial Kardiologii Olsztyn Poland 10-561
46 Centrum Medyczne Aesculap Radom Poland 26-600
47 Klinika Kardiologii Szczecin Poland 70-111
48 Klinika Nefrologii, Transplantologii i Chorob Wewnetrznych Szczecin Poland 70-111
49 Szpital Powiatowy w Wolominie Wolomin Poland 05-200
50 SPZOZ Akademicki Szpital Kliniczny im. J. Mikulicza - Radeckiego Wroclaw Poland 50-556
51 Spitalul Clinic Municipal Dr. Gavril Curteanu Oradea Oradea jud. Bihor Romania 410469
52 Spitalul Clinic Dr. C. I. Parhon Iasi Iasi jud. Iasi Romania 700503
53 Institutul Clinic Fundeni, Centrul de Medicina Interna-Nefrologie Bucuresti Romania 022328
54 SPITALUL CLINIC JUDETEAN DE URGENTA TIMISOARA ,Clinica de Nefrologie Timisoara Romania 300736
55 Univerzitna nemocnica Bratislava Limbova 5 Bratislava Slovakia 83305
56 SUMMIT CLINICAL RESEARCH, s.r.o., Oddelenie internej mediciny a klinickej farmakologie Bratislava Slovakia 831 01
57 Hospital Universitari de Bellvitge Hospitalet de Llobregat Barcelona Spain 08907
58 Hospital Clinic I Provincial de Barcelona Barcelona Spain 08036
59 Sahlgrenska Universitetssjukhuset, Njurmedicin Goteborg Sweden 413 45
60 Karolinska Universitetssjukhuset Huddinge Stockholm Sweden 141 86
61 Karolinska Universitetssjukhuset Solna Stockholm Sweden 171 76
62 Universitaetsspital Zuerich Zuerich Switzerland 8091
63 Istanbul University, Istanbul Tip Fakultesi Istanbul Capa Turkey 34390
64 Dokuz Eylul Universitesi Hastanesi Ic Hastaliklari Anabilim Dali Izmir Inciralti/ Narlidere Turkey 35340
65 Morriston Hospital Swansea Wales United Kingdom SA6 6NL
66 BHF Glasgow Cardiovascular Research Centre, University of Glasgow Glasgow United Kingdom G12 8TA
67 Renal and Urology Directorate, Leicester General Hospital Leicester United Kingdom LE5 4PW

Sponsors and Collaborators

  • Pfizer

Investigators

  • Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT01233869
Other Study ID Numbers:
  • B1871019
  • 3160A7-2211
  • 2010-023017-65
First Posted:
Nov 3, 2010
Last Update Posted:
Mar 11, 2016
Last Verified:
Feb 1, 2016
Keywords provided by Pfizer
Bosutinib
Autosomal Dominant Polycystic Kidney Disease
Additional relevant MeSH terms:
Arthrogryposis
Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail 172 participants were enrolled in this study, of which 169 received at least 1 dose of study treatment.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Period Title: Initial Treatment Period (24 Months)
STARTED 58 31 24 56
COMPLETED 34 3 22 34
NOT COMPLETED 24 28 2 22
Period Title: Initial Treatment Period (24 Months)
STARTED 34 3 22 34
COMPLETED 34 3 22 34
NOT COMPLETED 0 0 0 0
Period Title: Initial Treatment Period (24 Months)
STARTED 34 3 22 34
COMPLETED 20 0 17 18
NOT COMPLETED 14 3 5 16

Baseline Characteristics

Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo Total
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months. Total of all reporting groups
Overall Participants 58 31 24 56 169
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
37.9
(8.0)
41.3
(4.9)
36.4
(7.8)
38.5
(7.4)
38.5
(7.4)
Sex: Female, Male (Count of Participants)
Female
28
48.3%
14
45.2%
15
62.5%
35
62.5%
92
54.4%
Male
30
51.7%
17
54.8%
9
37.5%
21
37.5%
77
45.6%

Outcome Measures

1. Primary Outcome
Title Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25
Description TKV was measured by centrally evaluated Magnetic Resonance Imaging (MRI).
Time Frame Baseline and Month 25 (end of Initial Treatment Period Visit [ITPV])

Outcome Measure Data

Analysis Population Description
The modified intent-to-treat (mITT) population included all participants who were randomized and received at least 2-weeks' worth of treatment and have at least 1 follow-up MRI assessment that was preceded by a 1-month washout of the study drug; n=the number of participants analyzed at that time point in the respective arms.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 27 6 21 33
Baseline (n=27,6,21,33)
1686.38
(944.30)
1418.96
(629.34)
1487.48
(531.96)
1670.33
(640.69)
CFB at Month 25 (n=23,3,20,30)
85.05
(231.09)
102.45
(257.30)
-6.18
(119.79)
175.36
(191.43)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bosutinib 200 mg/Day, Bosutinib 400 mg/Day, Bosutinib 400/200 mg/Day, Placebo
Comments Statistical Analysis 1 is comparison of annualized rate of kidney enlargement: placebo versus pooled bosutinib.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 3.86
Confidence Interval (2-Sided) 95%
2.02 to 5.74
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Bosutinib 200 mg/Day, Bosutinib 400/200 mg/Day
Comments Statistical Analysis 2 is comparison of annualized rate of kidney enlargement: bosutinib 200 mg/day versus bosutinib 400/200 mg/day.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1234
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 1.83
Confidence Interval (2-Sided) 95%
-0.50 to 4.22
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Bosutinib 200 mg/Day, Placebo
Comments Statistical Analysis 3 is comparison of annualized rate of kidney enlargement: placebo versus bosutinib 200 mg/day.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0050
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 3.06
Confidence Interval (2-Sided) 95%
0.93 to 5.23
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Bosutinib 400 mg/Day, Placebo
Comments Statistical Analysis 4 is comparison of annualized rate of kidney enlargement: placebo versus bosutinib 400 mg/day.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.1336
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 3.41
Confidence Interval (2-Sided) 95%
-1.03 to 8.05
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Bosutinib 400/200 mg/Day, Placebo
Comments Statistical Analysis 5 is comparison of annualized rate of kidney enlargement: placebo versus bosutinib 400/200 mg/day.
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Median Difference (Final Values)
Estimated Value 4.95
Confidence Interval (2-Sided) 95%
2.65 to 7.30
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination
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.
Time Frame Baseline, Month 12, Month 24, Month 25 (end of ITPV), and early termination

Outcome Measure Data

Analysis Population Description
The mITT population included all participants who were randomized and received at least 2 weeks' worth of treatment and have at least 1 post-randomization follow-up MRI assessment; n=the number of participants analyzed at that time point in the respective arms.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
CFB at Month 12 (n=26,4,21,31)
-6.38
(11.60)
-7.56
(11.27)
-11.52
(10.86)
1.30
(9.71)
CFB at Month 24 (n=23,3,20,30)
-8.47
(15.02)
-21.59
(13.74)
-13.16
(13.41)
-7.95
(12.91)
CFB at End of ITPV (n=23,3,20,30)
-5.00
(10.78)
-13.24
(12.45)
-9.92
(14.55)
-2.74
(18.01)
CFB at Early Termination (n=6,3,1,4)
-11.91
(8.79)
0.78
(4.83)
-10.24
(NA)
-2.75
(21.35)
3. Secondary Outcome
Title Time to First Occurrence or Worsening of Hypertension
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.
Time Frame Baseline up to Month 25 (end of ITPV)

Outcome Measure Data

Analysis Population Description
The mITT-2 population included all participants who were randomized and received at least 2 weeks' worth of treatment and have at least 1 post-randomization follow-up MRI assessment (elimination of 1-month washout requirement).
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Number [days]
15
180
90
30
4. Secondary Outcome
Title Time to First Occurrence or Worsening of Back and/or Flank Pain
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.
Time Frame Baseline up to Month 25 (end of ITPV)

Outcome Measure Data

Analysis Population Description
The mITT-2 population included all participants who were randomized and received at least 2 weeks' worth of treatment and have at least 1 post-randomization follow-up MRI assessment (elimination of 1-month washout requirement).
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Number [days]
30
30
270
15
5. Secondary Outcome
Title Time to First Occurrence of Gross Hematuria
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.
Time Frame Baseline up to Month 25 (end of ITPV)

Outcome Measure Data

Analysis Population Description
The mITT-2 population included all participants who were randomized and received at least 2 weeks' worth of treatment and have at least 1 post-randomization follow-up MRI assessment (elimination of 1-month washout requirement).
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Number [days]
330
180
180
45
6. Secondary Outcome
Title Time to First Occurrence of Proteinuria
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.
Time Frame Baseline up to Month 25 (end of ITPV)

Outcome Measure Data

Analysis Population Description
The mITT-2 population included all participants who were randomized and received at least 2 weeks' worth of treatment and have at least 1 post-randomization follow-up MRI assessment (elimination of 1-month washout requirement).
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Number [days]
360
NA
270
540
7. Secondary Outcome
Title Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days
Description ESRD is when the kidneys permanently fail to work at a level needed for daily life. No participants developed ESRD during the treatment period, therefore the analysis of the onset of ESRD requiring ≥56 days of dialysis was not performed.
Time Frame Baseline up to Month 25 (end of ITPV)

Outcome Measure Data

Analysis Population Description
The mITT-2 population included all participants who were randomized and received at least 2 weeks' worth of treatment and have at least 1 post-randomization follow-up MRI assessment (elimination of 1-month washout requirement).
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Number [days]
NA
NA
NA
NA
8. Secondary Outcome
Title Number of Participants With High Blood Urea Nitrogen (BUN) Levels
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.
Time Frame Day 15, Months 6, 12, 18, 24, and 25 (end of ITPV)

Outcome Measure Data

Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of study drug.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Day 15
0
0%
0
0%
2
8.3%
0
0%
Month 6
0
0%
0
0%
0
0%
0
0%
Month 12
0
0%
0
0%
0
0%
0
0%
Month 18
0
0%
0
0%
0
0%
0
0%
Month 24
0
0%
0
0%
1
4.2%
0
0%
End of ITPV
0
0%
0
0%
2
8.3%
0
0%
9. Secondary Outcome
Title Number of Participants With High Serum Creatinine (SCr) Levels
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.
Time Frame Day 15, Months 6, 12, 18, 24, and 25 (end of ITPV)

Outcome Measure Data

Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of study drug.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Day 15
0
0%
1
3.2%
0
0%
0
0%
Month 6
0
0%
0
0%
0
0%
0
0%
Month 12
0
0%
0
0%
0
0%
1
1.8%
Month 18
0
0%
0
0%
0
0%
0
0%
Month 24
0
0%
1
3.2%
1
4.2%
1
1.8%
End of ITPV
0
0%
0
0%
0
0%
1
1.8%
10. Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Bosutinib
Description
Time Frame 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)

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (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.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 58 31 24
Day 1 (n=58,31,24)
32.61
(53)
74.87
(47)
84.57
(56)
Day 15 (n=58,16,22)
68.72
(43)
127.90
(28)
155.00
(31)
11. Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib
Description
Time Frame 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)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 58 31 24
Day 1 (n=58,31,24)
3.00
3.00
4.86
Day 15 (n=58,16,22)
3.95
3.00
5.00
12. Secondary Outcome
Title Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib
Description Area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau=24 hours.
Time Frame 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)

Outcome Measure Data

Analysis Population Description
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.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 58 31 24
Day 1 (n=58,30,24)
437
(48)
1040
(49)
1149
(50)
Day 15 (n=58,16,22)
1059
(45)
2052
(36)
2384
(34)
13. Secondary Outcome
Title Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib
Description
Time Frame Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description
The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 58 16 22
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
25.15
(49)
19.60
(20880)
50.67
(50)
14. Secondary Outcome
Title Apparent Oral Clearance (CL/F) of Bosutinib
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.
Time Frame Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description
The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 58 16 22
Geometric Mean (Geometric Coefficient of Variation) [L/hr]
188.8
(45)
195.0
(36)
167.8
(34)
15. Secondary Outcome
Title Apparent Volume of Distribution (Vz/F) of Bosutinib
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.
Time Frame 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)

Outcome Measure Data

Analysis Population Description
The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest. There was no sufficient data to well-characterize the terminal phase, therefore Vz/F was not reported.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 0 0 0
16. Secondary Outcome
Title Terminal Elimination Half-Life (t1/2) of Bosutinib
Description t1/2 is the time measured for the plasma concentration to decrease by one half.
Time Frame 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)

Outcome Measure Data

Analysis Population Description
The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest. There was no sufficient data to well-characterize the terminal phase, therefore t1/2 was not reported.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 0 0 0
17. Secondary Outcome
Title Observed Accumulation Ratio (Rac) of Bosutinib
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).
Time Frame Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description
The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months.
Measure Participants 58 16 22
Geometric Mean (Geometric Coefficient of Variation) [ratio]
2.452
(36)
2.280
(42)
2.075
(41)
18. Secondary Outcome
Title Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25
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 (items 13-16); symptoms and problems (items 17-28); effects of kidney disease on daily life subscale (items 29-36). The raw scores are transformed linearly to a range of 0 to 100, with higher scores indicating better quality of life.
Time Frame Baseline and end of ITPV (Month 25)

Outcome Measure Data

Analysis Population Description
The mITT-2 population included all participants who were randomized and received at least 2 weeks' worth of treatment and have at least 1 post-randomization follow-up MRI assessment (elimination of 1-month washout); n=the number of participants analyzed in the respective arms.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 42 9 24 43
Burden of Disease: Baseline (n=42,9,24,43)
84.23
(18.48)
84.722
(20.99)
79.43
(24.97)
74.86
(30.21)
Burden of Disease: CFB Month 25 (n=32,3,22,34)
-2.54
(15.70)
-2.08
(9.55)
0.57
(15.90)
1.84
(19.13)
Kidney Disease Effects: Baseline (n=42,9,24,43)
93.30
(8.58)
92.01
(11.06)
91.54
(11.53)
90.41
(14.10)
Kidney Disease Effects: CFB Month 25; n=32,3,22,34
1.07
(5.48)
3.13
(5.41)
-0.57
(9.72)
3.22
(9.50)
SF-12 Mental Health: Baseline (n=42,9,24,43)
54.31
(6.39)
51.11
(12.87)
50.19
(9.28)
51.33
(8.58)
SF-12 Mental Health: CFB Month 25 (n=32,3,22,34)
-1.50
(5.87)
6.55
(6.30)
1.34
(7.35)
0.12
(10.25)
SF-12 Physical Health: Baseline (n=42,9,24,43)
50.52
(6.93)
51.78
(6.40)
49.64
(8.35)
47.17
(10.93)
SF-12 Physical Health: CFB Month 25 (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: CFB Month 25 (n=32,3,22,34)
-2.42
(7.21)
-8.33
(9.19)
-3.75
(8.04)
0.27
(9.31)
19. Other Pre-specified Outcome
Title Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description An AE was any untoward medical occurrence in a participant 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.
Time Frame Baseline up to 30 days after last study drug administration

Outcome Measure Data

Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of study drug.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
AEs
56
96.6%
30
96.8%
23
95.8%
51
91.1%
SAEs
12
20.7%
4
12.9%
6
25%
5
8.9%
20. Other Pre-specified Outcome
Title Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern
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).
Time Frame Baseline up to 30 days after last study drug administration

Outcome Measure Data

Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of study drug.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Number [participants]
53
91.4%
20
64.5%
23
95.8%
43
76.8%
21. Other Pre-specified Outcome
Title Number of Participants With Potentially Clinically Significant Vital Signs Findings
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.
Time Frame Baseline up to 30 days after last study drug administration

Outcome Measure Data

Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of study drug; n=the number of participants analyzed in the respective arms.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
Supine SBP <90 mm Hg (n=2,2,1,4)
0
0%
0
0%
0
0%
0
0%
Sitting SBP <90 mm Hg (n=58,29,24,54)
0
0%
0
0%
1
4.2%
0
0%
Supine DBP <50 mm Hg (n=2,2,1,4)
0
0%
0
0%
0
0%
0
0%
Sitting DBP <50 mm Hg (n=58,29,24,54)
0
0%
1
3.2%
1
4.2%
0
0%
Supine Pulse Rate <40 or >120 bpm(n=2,2,1,4)
0
0%
0
0%
0
0%
0
0%
Sitting Pulse Rate <40 or >120 bpm (n=58,29,24,54)
1
1.7%
0
0%
0
0%
0
0%
Supine SBP ≥30 mm Hg Decrease (n=2,2,1,4)
0
0%
0
0%
1
4.2%
0
0%
Sitting SBP ≥30 mm Hg Decrease (n=58,29,24,54)
2
3.4%
1
3.2%
2
8.3%
2
3.6%
Supine DBP ≥20 mm Hg Decrease (n=2,2,1,4)
0
0%
0
0%
1
4.2%
0
0%
Sitting DBP ≥20 mm Hg Decrease (n=58,29,24,54)
12
20.7%
3
9.7%
3
12.5%
5
8.9%
Supine SBP ≥30 mm Hg Increase (n=2,2,1,4)
0
0%
0
0%
0
0%
0
0%
Sitting SBP ≥30 mm Hg Increase (n=58,29,24,54)
3
5.2%
1
3.2%
3
12.5%
3
5.4%
Supine DBP ≥20 mm Hg Increase (n=2,2,1,4)
0
0%
0
0%
0
0%
0
0%
Sitting DBP ≥20 mm Hg Increase (n=58,29,24,54)
5
8.6%
3
9.7%
5
20.8%
5
8.9%
22. Other Pre-specified Outcome
Title Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
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.
Time Frame Baseline up to 30 days after last study drug administration

Outcome Measure Data

Analysis Population Description
The safety analysis population included all participants who received at least 1 dose of study drug; n=the number of participants analyzed in the respective arms.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
Measure Participants 58 31 24 56
PR Interval ≥300 msec (n=58,31,24,56)
0
0%
0
0%
0
0%
0
0%
QRS Complex ≥200 msec (n=58,31,24,56)
0
0%
0
0%
0
0%
0
0%
QTcF Interval 450-<480 msec (n=58,31,24,56)
3
5.2%
2
6.5%
0
0%
6
10.7%
QTcF Interval 480-<500 msec (n=58,31,24,56)
0
0%
0
0%
0
0%
0
0%
QTcF Interval ≥500 msec (n=58,31,24,56)
0
0%
0
0%
0
0%
0
0%
PR Interval ≥25/50% Increase (n=57,28,23,52)
0
0%
0
0%
0
0%
0
0%
QRS Complex ≥25/50% Increase (n=57,28,23,52)
0
0%
0
0%
0
0%
0
0%
QTcF Interval 30-<60 msec Increase (n=57,28,23,52)
4
6.9%
1
3.2%
1
4.2%
5
8.9%
QTcF Interval ≥60 msec Increase (n=57,28,23,52)
0
0%
0
0%
0
0%
0
0%

Adverse Events

Time Frame Baseline up to 30 days after last study drug administration
Adverse Event Reporting 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 participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
Arm/Group Title Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Arm/Group Description Participants 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, participants who entered the Extended Treatment Period (ETP) continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received bosutinib 400 mg tablet orally QD in the morning with food for 24 months in the ITP. All participants 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. Participants 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, participants who entered the ETP continued to receive bosutinib 200 mg orally QD for up to 46 months. Participants received placebo tablet orally QD in the morning with food for 24 months in the ITP. After a 30-day washout period, participants who entered the ETP continued to receive placebo matched bosutinib QD for up to 46 months.
All Cause Mortality
Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN)
Serious Adverse Events
Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 12/58 (20.7%) 4/31 (12.9%) 6/24 (25%) 5/56 (8.9%)
Blood and lymphatic system disorders
Anaemia 0/58 (0%) 0/31 (0%) 1/24 (4.2%) 0/56 (0%)
Cardiac disorders
Ventricular extrasystoles 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Gastrointestinal disorders
Abdominal pain 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Peptic ulcer 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Subileus 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Hepatobiliary disorders
Hepatitis acute 0/58 (0%) 1/31 (3.2%) 0/24 (0%) 0/56 (0%)
Infections and infestations
Appendicitis 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Gastroenteritis 0/58 (0%) 1/31 (3.2%) 0/24 (0%) 0/56 (0%)
Hepatitis C 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 1/56 (1.8%)
Pneumonia 0/58 (0%) 1/31 (3.2%) 0/24 (0%) 0/56 (0%)
Pyelonephritis acute 0/58 (0%) 0/31 (0%) 1/24 (4.2%) 0/56 (0%)
Renal cyst infection 0/58 (0%) 0/31 (0%) 0/24 (0%) 1/56 (1.8%)
Sepsis 2/58 (3.4%) 0/31 (0%) 1/24 (4.2%) 0/56 (0%)
Urinary tract infection 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Investigations
Alanine aminotransferase increased 2/58 (3.4%) 1/31 (3.2%) 0/24 (0%) 0/56 (0%)
Amylase increased 0/58 (0%) 1/31 (3.2%) 0/24 (0%) 0/56 (0%)
Aspartate aminotransferase increased 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Lipase increased 0/58 (0%) 1/31 (3.2%) 0/24 (0%) 0/56 (0%)
Musculoskeletal and connective tissue disorders
Osteonecrosis 0/58 (0%) 0/31 (0%) 0/24 (0%) 1/56 (1.8%)
Sacroiliitis 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Spondylitis 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Nervous system disorders
Intracranial aneurysm 0/58 (0%) 0/31 (0%) 1/24 (4.2%) 0/56 (0%)
Syncope 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Psychiatric disorders
Insomnia 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Psychosomatic disease 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Renal and urinary disorders
Calculus ureteric 0/58 (0%) 0/31 (0%) 1/24 (4.2%) 0/56 (0%)
Haematuria 0/58 (0%) 0/31 (0%) 0/24 (0%) 1/56 (1.8%)
Renal cyst haemorrhage 1/58 (1.7%) 1/31 (3.2%) 1/24 (4.2%) 0/56 (0%)
Renal cyst ruptured 0/58 (0%) 1/31 (3.2%) 0/24 (0%) 1/56 (1.8%)
Renal failure acute 0/58 (0%) 1/31 (3.2%) 0/24 (0%) 0/56 (0%)
Renal haemorrhage 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Reproductive system and breast disorders
Cervix disorder 0/28 (0%) 0/14 (0%) 1/15 (6.7%) 0/35 (0%)
Other (Not Including Serious) Adverse Events
Bosutinib 200 mg/Day Bosutinib 400 mg/Day Bosutinib 400/200 mg/Day Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 56/58 (96.6%) 30/31 (96.8%) 23/24 (95.8%) 50/56 (89.3%)
Blood and lymphatic system disorders
Anaemia 7/58 (12.1%) 4/31 (12.9%) 5/24 (20.8%) 2/56 (3.6%)
Eosinophilia 3/58 (5.2%) 0/31 (0%) 1/24 (4.2%) 0/56 (0%)
Cardiac disorders
Pericardial effusion 2/58 (3.4%) 1/31 (3.2%) 2/24 (8.3%) 0/56 (0%)
Gastrointestinal disorders
Abdominal distension 3/58 (5.2%) 2/31 (6.5%) 2/24 (8.3%) 3/56 (5.4%)
Abdominal pain 4/58 (6.9%) 8/31 (25.8%) 2/24 (8.3%) 7/56 (12.5%)
Abdominal pain upper 5/58 (8.6%) 7/31 (22.6%) 8/24 (33.3%) 5/56 (8.9%)
Constipation 2/58 (3.4%) 2/31 (6.5%) 1/24 (4.2%) 1/56 (1.8%)
Diarrhoea 26/58 (44.8%) 26/31 (83.9%) 18/24 (75%) 11/56 (19.6%)
Dyspepsia 6/58 (10.3%) 2/31 (6.5%) 3/24 (12.5%) 3/56 (5.4%)
Gastrooesophageal reflux disease 0/58 (0%) 0/31 (0%) 0/24 (0%) 3/56 (5.4%)
Nausea 21/58 (36.2%) 15/31 (48.4%) 13/24 (54.2%) 9/56 (16.1%)
Vomiting 6/58 (10.3%) 11/31 (35.5%) 9/24 (37.5%) 4/56 (7.1%)
General disorders
Asthenia 1/58 (1.7%) 1/31 (3.2%) 3/24 (12.5%) 1/56 (1.8%)
Chest pain 1/58 (1.7%) 2/31 (6.5%) 0/24 (0%) 0/56 (0%)
Fatigue 4/58 (6.9%) 8/31 (25.8%) 2/24 (8.3%) 6/56 (10.7%)
Influenza-like illness 2/58 (3.4%) 1/31 (3.2%) 3/24 (12.5%) 6/56 (10.7%)
Oedema peripheral 2/58 (3.4%) 1/31 (3.2%) 1/24 (4.2%) 3/56 (5.4%)
Pain 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 3/56 (5.4%)
Pyrexia 2/58 (3.4%) 3/31 (9.7%) 2/24 (8.3%) 1/56 (1.8%)
Hepatobiliary disorders
Hepatocellular injury 3/58 (5.2%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Immune system disorders
Hypersensitivity 2/58 (3.4%) 1/31 (3.2%) 0/24 (0%) 3/56 (5.4%)
Infections and infestations
Bronchitis 3/58 (5.2%) 2/31 (6.5%) 2/24 (8.3%) 3/56 (5.4%)
Cystitis 0/58 (0%) 0/31 (0%) 3/24 (12.5%) 1/56 (1.8%)
Gastroenteritis viral 0/58 (0%) 0/31 (0%) 1/24 (4.2%) 3/56 (5.4%)
Influenza 2/58 (3.4%) 0/31 (0%) 1/24 (4.2%) 3/56 (5.4%)
Nasopharyngitis 12/58 (20.7%) 3/31 (9.7%) 8/24 (33.3%) 8/56 (14.3%)
Pharyngitis 0/58 (0%) 0/31 (0%) 3/24 (12.5%) 4/56 (7.1%)
Rhinitis 2/58 (3.4%) 0/31 (0%) 2/24 (8.3%) 2/56 (3.6%)
Sinusitis 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 3/56 (5.4%)
Upper respiratory tract infection 6/58 (10.3%) 4/31 (12.9%) 7/24 (29.2%) 7/56 (12.5%)
Urinary tract infection 8/58 (13.8%) 2/31 (6.5%) 2/24 (8.3%) 8/56 (14.3%)
Vaginal infection 1/28 (3.6%) 0/14 (0%) 0/15 (0%) 3/35 (8.6%)
Viral infection 2/58 (3.4%) 0/31 (0%) 1/24 (4.2%) 3/56 (5.4%)
Vulvovaginal mycotic infection 1/28 (3.6%) 0/14 (0%) 1/15 (6.7%) 1/35 (2.9%)
Injury, poisoning and procedural complications
Excoriation 3/58 (5.2%) 0/31 (0%) 1/24 (4.2%) 0/56 (0%)
Investigations
Alanine aminotransferase increased 18/58 (31%) 16/31 (51.6%) 12/24 (50%) 4/56 (7.1%)
Amylase increased 2/58 (3.4%) 4/31 (12.9%) 3/24 (12.5%) 1/56 (1.8%)
Aspartate aminotransferase increased 17/58 (29.3%) 11/31 (35.5%) 6/24 (25%) 3/56 (5.4%)
Blood creatine phosphokinase increased 11/58 (19%) 3/31 (9.7%) 6/24 (25%) 5/56 (8.9%)
Blood creatinine increased 2/58 (3.4%) 1/31 (3.2%) 2/24 (8.3%) 2/56 (3.6%)
Blood lactate dehydrogenase increased 0/58 (0%) 2/31 (6.5%) 0/24 (0%) 0/56 (0%)
Blood phosphorus decreased 0/58 (0%) 2/31 (6.5%) 0/24 (0%) 0/56 (0%)
Gamma-glutamyltransferase increased 4/58 (6.9%) 0/31 (0%) 0/24 (0%) 0/56 (0%)
Haemoglobin decreased 0/58 (0%) 0/31 (0%) 2/24 (8.3%) 0/56 (0%)
Lipase increased 5/58 (8.6%) 6/31 (19.4%) 6/24 (25%) 3/56 (5.4%)
Weight increased 0/58 (0%) 2/31 (6.5%) 3/24 (12.5%) 0/56 (0%)
Metabolism and nutrition disorders
Decreased appetite 2/58 (3.4%) 4/31 (12.9%) 4/24 (16.7%) 0/56 (0%)
Hypophosphataemia 2/58 (3.4%) 0/31 (0%) 2/24 (8.3%) 1/56 (1.8%)
Musculoskeletal and connective tissue disorders
Arthralgia 5/58 (8.6%) 0/31 (0%) 1/24 (4.2%) 5/56 (8.9%)
Back pain 9/58 (15.5%) 2/31 (6.5%) 1/24 (4.2%) 8/56 (14.3%)
Flank pain 10/58 (17.2%) 5/31 (16.1%) 0/24 (0%) 5/56 (8.9%)
Muscle spasms 3/58 (5.2%) 1/31 (3.2%) 0/24 (0%) 3/56 (5.4%)
Musculoskeletal pain 3/58 (5.2%) 1/31 (3.2%) 2/24 (8.3%) 2/56 (3.6%)
Myalgia 0/58 (0%) 0/31 (0%) 0/24 (0%) 3/56 (5.4%)
Pain in extremity 1/58 (1.7%) 0/31 (0%) 0/24 (0%) 3/56 (5.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma 0/28 (0%) 0/14 (0%) 1/15 (6.7%) 0/35 (0%)
Nervous system disorders
Dizziness 7/58 (12.1%) 2/31 (6.5%) 4/24 (16.7%) 3/56 (5.4%)
Dysgeusia 0/58 (0%) 2/31 (6.5%) 0/24 (0%) 0/56 (0%)
Headache 9/58 (15.5%) 3/31 (9.7%) 2/24 (8.3%) 12/56 (21.4%)
Psychiatric disorders
Insomnia 3/58 (5.2%) 1/31 (3.2%) 0/24 (0%) 1/56 (1.8%)
Renal and urinary disorders
Haematuria 4/58 (6.9%) 3/31 (9.7%) 1/24 (4.2%) 4/56 (7.1%)
Proteinuria 1/58 (1.7%) 0/31 (0%) 2/24 (8.3%) 3/56 (5.4%)
Renal failure acute 2/58 (3.4%) 1/31 (3.2%) 2/24 (8.3%) 0/56 (0%)
Reproductive system and breast disorders
Amenorrhoea 0/28 (0%) 0/14 (0%) 1/15 (6.7%) 0/35 (0%)
Cervical dysplasia 0/28 (0%) 0/14 (0%) 1/15 (6.7%) 0/35 (0%)
Menorrhagia 1/28 (3.6%) 0/14 (0%) 1/15 (6.7%) 1/35 (2.9%)
Metrorrhagia 1/28 (3.6%) 0/14 (0%) 1/15 (6.7%) 0/35 (0%)
Ovarian cyst 0/28 (0%) 1/14 (7.1%) 0/15 (0%) 1/35 (2.9%)
Vaginal inflammation 0/28 (0%) 0/14 (0%) 1/15 (6.7%) 1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Cough 2/58 (3.4%) 3/31 (9.7%) 3/24 (12.5%) 4/56 (7.1%)
Oropharyngeal pain 5/58 (8.6%) 2/31 (6.5%) 1/24 (4.2%) 2/56 (3.6%)
Skin and subcutaneous tissue disorders
Acne 4/58 (6.9%) 0/31 (0%) 0/24 (0%) 1/56 (1.8%)
Alopecia 2/58 (3.4%) 1/31 (3.2%) 3/24 (12.5%) 3/56 (5.4%)
Dermatitis allergic 2/58 (3.4%) 0/31 (0%) 2/24 (8.3%) 0/56 (0%)
Pruritis 1/58 (1.7%) 2/31 (6.5%) 1/24 (4.2%) 1/56 (1.8%)
Rash maculo-papular 0/58 (0%) 2/31 (6.5%) 0/24 (0%) 0/56 (0%)
Vascular disorders
Hypertension 8/58 (13.8%) 3/31 (9.7%) 5/24 (20.8%) 9/56 (16.1%)
Hypotension 1/58 (1.7%) 0/31 (0%) 3/24 (12.5%) 0/56 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

Name/Title Pfizer ClinicalTrials.gov Call Center
Organization Pfizer, Inc.
Phone 1-800-718-1021
Email ClinicalTrials.gov_Inquiries@pfizer.com
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT01233869
Other Study ID Numbers:
  • B1871019
  • 3160A7-2211
  • 2010-023017-65
First Posted:
Nov 3, 2010
Last Update Posted:
Mar 11, 2016
Last Verified:
Feb 1, 2016