Polycystic Kidney, Autosomal Dominant
Conditions
Keywords
Bosutinib, Autosomal Dominant Polycystic Kidney Disease
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.
Interventions
DRUGBosutinib
Once daily oral dose of 200 mg of bosutinib
DRUGPlacebo
Once daily oral dose of placebo
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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) | — |
| 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) | — |
| 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. |
| 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) | — |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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). |
| 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. |
Countries
Australia, Canada, Czechia, Hungary, Italy, Lithuania, Moldova, Poland, Romania, Slovakia, South Korea, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Pre-assignment details
172 participants were enrolled in this study, of which 169 received at least 1 dose of study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Bosutinib 200 mg/Day 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. | 58 |
| Bosutinib 400 mg/Day 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. | 31 |
| Bosutinib 400/200 mg/Day 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. | 24 |
| Placebo 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. | 56 |
| Total | 169 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Extended Treatment Period (46 Months) | Adverse Event | 1 | 0 | 0 | 1 |
| Extended Treatment Period (46 Months) | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Extended Treatment Period (46 Months) | Other | 3 | 0 | 0 | 3 |
| Extended Treatment Period (46 Months) | Withdrawal by Subject | 10 | 3 | 5 | 11 |
| Initial Treatment Period (24 Months) | Adverse Event | 9 | 17 | 0 | 3 |
| Initial Treatment Period (24 Months) | Death | 1 | 0 | 0 | 0 |
| Initial Treatment Period (24 Months) | Not Related to Study Drug | 14 | 11 | 2 | 19 |
Baseline characteristics
| Characteristic | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 37.9 years STANDARD_DEVIATION 8 | 41.3 years STANDARD_DEVIATION 4.9 | 36.4 years STANDARD_DEVIATION 7.8 | 38.5 years STANDARD_DEVIATION 7.4 | 38.5 years STANDARD_DEVIATION 7.4 |
| Sex: Female, Male Female | 28 Participants | 14 Participants | 15 Participants | 35 Participants | 92 Participants |
| Sex: Female, Male Male | 30 Participants | 17 Participants | 9 Participants | 21 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 56 / 58 | 30 / 31 | 23 / 24 | 50 / 56 |
| serious Total, serious adverse events | 12 / 58 | 4 / 31 | 6 / 24 | 5 / 56 |
Outcome results
Primary
Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25
TKV was measured by centrally evaluated Magnetic Resonance Imaging (MRI).
Time frame: Baseline and Month 25 (end of Initial Treatment Period Visit [ITPV])
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib 200 mg/Day | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | Baseline (n=27,6,21,33) | 1686.38 centimeter cube (cm^3) | Standard Deviation 944.3 |
| Bosutinib 200 mg/Day | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | CFB at Month 25 (n=23,3,20,30) | 85.05 centimeter cube (cm^3) | Standard Deviation 231.09 |
| Bosutinib 400 mg/Day | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | CFB at Month 25 (n=23,3,20,30) | 102.45 centimeter cube (cm^3) | Standard Deviation 257.3 |
| Bosutinib 400 mg/Day | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | Baseline (n=27,6,21,33) | 1418.96 centimeter cube (cm^3) | Standard Deviation 629.34 |
| Bosutinib 400/200 mg/Day | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | Baseline (n=27,6,21,33) | 1487.48 centimeter cube (cm^3) | Standard Deviation 531.96 |
| Bosutinib 400/200 mg/Day | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | CFB at Month 25 (n=23,3,20,30) | -6.18 centimeter cube (cm^3) | Standard Deviation 119.79 |
| Placebo | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | Baseline (n=27,6,21,33) | 1670.33 centimeter cube (cm^3) | Standard Deviation 640.69 |
| Placebo | Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 | CFB at Month 25 (n=23,3,20,30) | 175.36 centimeter cube (cm^3) | Standard Deviation 191.43 |
Comparison: Statistical Analysis 1 is comparison of annualized rate of kidney enlargement: placebo versus pooled bosutinib.p-value: <0.000195% CI: [2.02, 5.74]Mixed Models Analysis
Comparison: Statistical Analysis 2 is comparison of annualized rate of kidney enlargement: bosutinib 200 mg/day versus bosutinib 400/200 mg/day.p-value: 0.123495% CI: [-0.5, 4.22]Mixed Models Analysis
Comparison: Statistical Analysis 3 is comparison of annualized rate of kidney enlargement: placebo versus bosutinib 200 mg/day.p-value: 0.00595% CI: [0.93, 5.23]Mixed Models Analysis
Comparison: Statistical Analysis 4 is comparison of annualized rate of kidney enlargement: placebo versus bosutinib 400 mg/day.p-value: 0.133695% CI: [-1.03, 8.05]Mixed Models Analysis
Comparison: Statistical Analysis 5 is comparison of annualized rate of kidney enlargement: placebo versus bosutinib 400/200 mg/day.p-value: <0.000195% CI: [2.65, 7.3]Mixed Models Analysis
Secondary
Apparent Oral Clearance (CL/F) of Bosutinib
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)
Population: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 200 mg/Day | Apparent Oral Clearance (CL/F) of Bosutinib | 188.8 L/hr | Geometric Coefficient of Variation 45 |
| Bosutinib 400 mg/Day | Apparent Oral Clearance (CL/F) of Bosutinib | 195.0 L/hr | Geometric Coefficient of Variation 36 |
| Bosutinib 400/200 mg/Day | Apparent Oral Clearance (CL/F) of Bosutinib | 167.8 L/hr | Geometric Coefficient of Variation 34 |
Secondary
Apparent Volume of Distribution (Vz/F) of Bosutinib
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)
Population: 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.
Secondary
Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib 200 mg/Day | Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib | Day 1 (n=58,30,24) | 437 ng*hr/mL | Geometric Coefficient of Variation 48 |
| Bosutinib 200 mg/Day | Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib | Day 15 (n=58,16,22) | 1059 ng*hr/mL | Geometric Coefficient of Variation 45 |
| Bosutinib 400 mg/Day | Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib | Day 1 (n=58,30,24) | 1040 ng*hr/mL | Geometric Coefficient of Variation 49 |
| Bosutinib 400 mg/Day | Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib | Day 15 (n=58,16,22) | 2052 ng*hr/mL | Geometric Coefficient of Variation 36 |
| Bosutinib 400/200 mg/Day | Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib | Day 1 (n=58,30,24) | 1149 ng*hr/mL | Geometric Coefficient of Variation 50 |
| Bosutinib 400/200 mg/Day | Area Under the Concentration-Time Profile From Time 0 to the Dosing Interval (AUCtau) of Bosutinib | Day 15 (n=58,16,22) | 2384 ng*hr/mL | Geometric Coefficient of Variation 34 |
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 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.
Time frame: Baseline, Month 12, Month 24, Month 25 (end of ITPV), and early termination
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib 200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 12 (n=26,4,21,31) | -6.38 mL/min/1.73m^2 | Standard Deviation 11.6 |
| Bosutinib 200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 24 (n=23,3,20,30) | -8.47 mL/min/1.73m^2 | Standard Deviation 15.02 |
| Bosutinib 200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at End of ITPV (n=23,3,20,30) | -5.00 mL/min/1.73m^2 | Standard Deviation 10.78 |
| Bosutinib 200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Early Termination (n=6,3,1,4) | -11.91 mL/min/1.73m^2 | Standard Deviation 8.79 |
| Bosutinib 400 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 24 (n=23,3,20,30) | -21.59 mL/min/1.73m^2 | Standard Deviation 13.74 |
| Bosutinib 400 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at End of ITPV (n=23,3,20,30) | -13.24 mL/min/1.73m^2 | Standard Deviation 12.45 |
| Bosutinib 400 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Early Termination (n=6,3,1,4) | 0.78 mL/min/1.73m^2 | Standard Deviation 4.83 |
| Bosutinib 400 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 12 (n=26,4,21,31) | -7.56 mL/min/1.73m^2 | Standard Deviation 11.27 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at End of ITPV (n=23,3,20,30) | -9.92 mL/min/1.73m^2 | Standard Deviation 14.55 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 24 (n=23,3,20,30) | -13.16 mL/min/1.73m^2 | Standard Deviation 13.41 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Early Termination (n=6,3,1,4) | -10.24 mL/min/1.73m^2 | — |
| Bosutinib 400/200 mg/Day | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 12 (n=26,4,21,31) | -11.52 mL/min/1.73m^2 | Standard Deviation 10.86 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Early Termination (n=6,3,1,4) | -2.75 mL/min/1.73m^2 | Standard Deviation 21.35 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 24 (n=23,3,20,30) | -7.95 mL/min/1.73m^2 | Standard Deviation 12.91 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at Month 12 (n=26,4,21,31) | 1.30 mL/min/1.73m^2 | Standard Deviation 9.71 |
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination | CFB at End of ITPV (n=23,3,20,30) | -2.74 mL/min/1.73m^2 | Standard Deviation 18.01 |
Secondary
Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at 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.
Time frame: Baseline and end of ITPV (Month 25)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: Baseline (n=42,9,24,43) | 84.23 units on a scale | Standard Deviation 18.48 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: CFB Month 25 (n=32,3,22,34) | -2.54 units on a scale | Standard Deviation 15.7 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: Baseline (n=42,9,24,43) | 93.30 units on a scale | Standard Deviation 8.58 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: CFB Month 25; n=32,3,22,34 | 1.07 units on a scale | Standard Deviation 5.48 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: Baseline (n=42,9,24,43) | 54.31 units on a scale | Standard Deviation 6.39 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: CFB Month 25 (n=32,3,22,34) | -1.50 units on a scale | Standard Deviation 5.87 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: Baseline (n=42,9,24,43) | 50.52 units on a scale | Standard Deviation 6.93 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: CFB Month 25 (n=32,3,22,34) | -0.28 units on a scale | Standard Deviation 5.81 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: Baseline (n=42,9,24,43) | 93.13 units on a scale | Standard Deviation 6.96 |
| Bosutinib 200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: CFB Month 25 (n=32,3,22,34) | -2.42 units on a scale | Standard Deviation 7.21 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: Baseline (n=42,9,24,43) | 92.01 units on a scale | Standard Deviation 11.06 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: Baseline (n=42,9,24,43) | 93.69 units on a scale | Standard Deviation 7.35 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: CFB Month 25; n=32,3,22,34 | 3.13 units on a scale | Standard Deviation 5.41 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: Baseline (n=42,9,24,43) | 51.11 units on a scale | Standard Deviation 12.87 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: CFB Month 25 (n=32,3,22,34) | 6.55 units on a scale | Standard Deviation 6.3 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: Baseline (n=42,9,24,43) | 51.78 units on a scale | Standard Deviation 6.4 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: CFB Month 25 (n=32,3,22,34) | -8.33 units on a scale | Standard Deviation 9.19 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: CFB Month 25 (n=32,3,22,34) | -7.59 units on a scale | Standard Deviation 7.63 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: Baseline (n=42,9,24,43) | 84.722 units on a scale | Standard Deviation 20.99 |
| Bosutinib 400 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: CFB Month 25 (n=32,3,22,34) | -2.08 units on a scale | Standard Deviation 9.55 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: CFB Month 25 (n=32,3,22,34) | -2.33 units on a scale | Standard Deviation 8.16 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: Baseline (n=42,9,24,43) | 49.64 units on a scale | Standard Deviation 8.35 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: CFB Month 25 (n=32,3,22,34) | -3.75 units on a scale | Standard Deviation 8.04 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: Baseline (n=42,9,24,43) | 79.43 units on a scale | Standard Deviation 24.97 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: CFB Month 25; n=32,3,22,34 | -0.57 units on a scale | Standard Deviation 9.72 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: CFB Month 25 (n=32,3,22,34) | 1.34 units on a scale | Standard Deviation 7.35 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: Baseline (n=42,9,24,43) | 90.72 units on a scale | Standard Deviation 9.31 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: CFB Month 25 (n=32,3,22,34) | 0.57 units on a scale | Standard Deviation 15.9 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: Baseline (n=42,9,24,43) | 50.19 units on a scale | Standard Deviation 9.28 |
| Bosutinib 400/200 mg/Day | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: Baseline (n=42,9,24,43) | 91.54 units on a scale | Standard Deviation 11.53 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: Baseline (n=42,9,24,43) | 51.33 units on a scale | Standard Deviation 8.58 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: CFB Month 25 (n=32,3,22,34) | 2.32 units on a scale | Standard Deviation 8.34 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Mental Health: CFB Month 25 (n=32,3,22,34) | 0.12 units on a scale | Standard Deviation 10.25 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: CFB Month 25 (n=32,3,22,34) | 0.27 units on a scale | Standard Deviation 9.31 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | SF-12 Physical Health: Baseline (n=42,9,24,43) | 47.17 units on a scale | Standard Deviation 10.93 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: CFB Month 25 (n=32,3,22,34) | 1.84 units on a scale | Standard Deviation 19.13 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: Baseline (n=42,9,24,43) | 90.41 units on a scale | Standard Deviation 14.1 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Kidney Disease Effects: CFB Month 25; n=32,3,22,34 | 3.22 units on a scale | Standard Deviation 9.5 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Burden of Disease: Baseline (n=42,9,24,43) | 74.86 units on a scale | Standard Deviation 30.21 |
| Placebo | Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 | Symptoms/Problems: Baseline (n=42,9,24,43) | 90.86 units on a scale | Standard Deviation 9.29 |
Secondary
Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib
Time frame: Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose)
Population: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 200 mg/Day | Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib | 25.15 ng/mL | Geometric Coefficient of Variation 49 |
| Bosutinib 400 mg/Day | Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib | 19.60 ng/mL | Geometric Coefficient of Variation 20880 |
| Bosutinib 400/200 mg/Day | Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib | 50.67 ng/mL | Geometric Coefficient of Variation 50 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Bosutinib
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)
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib 200 mg/Day | Maximum Observed Plasma Concentration (Cmax) of Bosutinib | Day 1 (n=58,31,24) | 32.61 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 53 |
| Bosutinib 200 mg/Day | Maximum Observed Plasma Concentration (Cmax) of Bosutinib | Day 15 (n=58,16,22) | 68.72 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 43 |
| Bosutinib 400 mg/Day | Maximum Observed Plasma Concentration (Cmax) of Bosutinib | Day 1 (n=58,31,24) | 74.87 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 47 |
| Bosutinib 400 mg/Day | Maximum Observed Plasma Concentration (Cmax) of Bosutinib | Day 15 (n=58,16,22) | 127.90 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 28 |
| Bosutinib 400/200 mg/Day | Maximum Observed Plasma Concentration (Cmax) of Bosutinib | Day 1 (n=58,31,24) | 84.57 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 56 |
| Bosutinib 400/200 mg/Day | Maximum Observed Plasma Concentration (Cmax) of Bosutinib | Day 15 (n=58,16,22) | 155.00 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 31 |
Secondary
Number of Participants With High Blood Urea Nitrogen (BUN) Levels
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)
Population: The safety analysis population included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib 200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Day 15 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 6 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 12 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 18 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 24 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | End of ITPV | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | End of ITPV | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 18 | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Day 15 | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 12 | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 6 | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 24 | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 6 | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 12 | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 18 | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | End of ITPV | 2 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 24 | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Day 15 | 2 participants |
| Placebo | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 24 | 0 participants |
| Placebo | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | End of ITPV | 0 participants |
| Placebo | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 6 | 0 participants |
| Placebo | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 18 | 0 participants |
| Placebo | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Day 15 | 0 participants |
| Placebo | Number of Participants With High Blood Urea Nitrogen (BUN) Levels | Month 12 | 0 participants |
Secondary
Number of Participants With High Serum Creatinine (SCr) Levels
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)
Population: The safety analysis population included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib 200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Day 15 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 6 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 12 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 18 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 24 | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | End of ITPV | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | End of ITPV | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 18 | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Day 15 | 1 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 12 | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 6 | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 24 | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 6 | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 12 | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 18 | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | End of ITPV | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Month 24 | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With High Serum Creatinine (SCr) Levels | Day 15 | 0 participants |
| Placebo | Number of Participants With High Serum Creatinine (SCr) Levels | Month 24 | 1 participants |
| Placebo | Number of Participants With High Serum Creatinine (SCr) Levels | End of ITPV | 1 participants |
| Placebo | Number of Participants With High Serum Creatinine (SCr) Levels | Month 6 | 0 participants |
| Placebo | Number of Participants With High Serum Creatinine (SCr) Levels | Month 18 | 0 participants |
| Placebo | Number of Participants With High Serum Creatinine (SCr) Levels | Day 15 | 0 participants |
| Placebo | Number of Participants With High Serum Creatinine (SCr) Levels | Month 12 | 1 participants |
Secondary
Observed Accumulation Ratio (Rac) of Bosutinib
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)
Population: The PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 200 mg/Day | Observed Accumulation Ratio (Rac) of Bosutinib | 2.452 ratio | Geometric Coefficient of Variation 36 |
| Bosutinib 400 mg/Day | Observed Accumulation Ratio (Rac) of Bosutinib | 2.280 ratio | Geometric Coefficient of Variation 42 |
| Bosutinib 400/200 mg/Day | Observed Accumulation Ratio (Rac) of Bosutinib | 2.075 ratio | Geometric Coefficient of Variation 41 |
Secondary
Terminal Elimination Half-Life (t1/2) of Bosutinib
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)
Population: 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.
Secondary
Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib 200 mg/Day | Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days | NA days |
| Bosutinib 400 mg/Day | Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days | NA days |
| Bosutinib 400/200 mg/Day | Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days | NA days |
| Placebo | Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days | NA days |
Secondary
Time to First Occurrence of Gross Hematuria
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib 200 mg/Day | Time to First Occurrence of Gross Hematuria | 330 days |
| Bosutinib 400 mg/Day | Time to First Occurrence of Gross Hematuria | 180 days |
| Bosutinib 400/200 mg/Day | Time to First Occurrence of Gross Hematuria | 180 days |
| Placebo | Time to First Occurrence of Gross Hematuria | 45 days |
Secondary
Time to First Occurrence of Proteinuria
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib 200 mg/Day | Time to First Occurrence of Proteinuria | 360 days |
| Bosutinib 400 mg/Day | Time to First Occurrence of Proteinuria | NA days |
| Bosutinib 400/200 mg/Day | Time to First Occurrence of Proteinuria | 270 days |
| Placebo | Time to First Occurrence of Proteinuria | 540 days |
Secondary
Time to First Occurrence or Worsening of Back and/or Flank Pain
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib 200 mg/Day | Time to First Occurrence or Worsening of Back and/or Flank Pain | 30 days |
| Bosutinib 400 mg/Day | Time to First Occurrence or Worsening of Back and/or Flank Pain | 30 days |
| Bosutinib 400/200 mg/Day | Time to First Occurrence or Worsening of Back and/or Flank Pain | 270 days |
| Placebo | Time to First Occurrence or Worsening of Back and/or Flank Pain | 15 days |
Secondary
Time to First Occurrence or Worsening of Hypertension
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib 200 mg/Day | Time to First Occurrence or Worsening of Hypertension | 15 days |
| Bosutinib 400 mg/Day | Time to First Occurrence or Worsening of Hypertension | 180 days |
| Bosutinib 400/200 mg/Day | Time to First Occurrence or Worsening of Hypertension | 90 days |
| Placebo | Time to First Occurrence or Worsening of Hypertension | 30 days |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib
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)
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosutinib 200 mg/Day | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib | Day 15 (n=58,16,22) | 3.95 hours |
| Bosutinib 200 mg/Day | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib | Day 1 (n=58,31,24) | 3.00 hours |
| Bosutinib 400 mg/Day | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib | Day 1 (n=58,31,24) | 3.00 hours |
| Bosutinib 400 mg/Day | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib | Day 15 (n=58,16,22) | 3.00 hours |
| Bosutinib 400/200 mg/Day | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib | Day 1 (n=58,31,24) | 4.86 hours |
| Bosutinib 400/200 mg/Day | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Bosutinib | Day 15 (n=58,16,22) | 5.00 hours |
Other Pre-specified
Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern
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
Population: The safety analysis population included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib 200 mg/Day | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 53 participants |
| Bosutinib 400 mg/Day | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 20 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 23 participants |
| Placebo | Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 43 participants |
Other Pre-specified
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=58,31,24,56) | 3 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥200 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥300 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec Increase (n=57,28,23,52) | 4 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥500 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥60 msec Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥500 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥200 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥300 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=58,31,24,56) | 2 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec Increase (n=57,28,23,52) | 1 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥60 msec Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥300 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥200 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥500 msec (n=58,31,24,56) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec Increase (n=57,28,23,52) | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥60 msec Increase (n=57,28,23,52) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 480-<500 msec (n=58,31,24,56) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 450-<480 msec (n=58,31,24,56) | 6 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥60 msec Increase (n=57,28,23,52) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval 30-<60 msec Increase (n=57,28,23,52) | 5 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QRS Complex ≥200 msec (n=58,31,24,56) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥25/50% Increase (n=57,28,23,52) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | QTcF Interval ≥500 msec (n=58,31,24,56) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings | PR Interval ≥300 msec (n=58,31,24,56) | 0 participants |
Other Pre-specified
Number of Participants With Potentially Clinically Significant Vital Signs Findings
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Decrease (n=58,29,24,54) | 2 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=2,2,1,4) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm(n=2,2,1,4) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Increase (n=58,29,24,54) | 5 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP <90 mm Hg (n=58,29,24,54) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Decrease (n=58,29,24,54) | 12 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting Pulse Rate <40 or >120 bpm (n=58,29,24,54) | 1 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=2,2,1,4) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Increase (n=58,29,24,54) | 3 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Decrease (n=2,2,1,4) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Decrease (n=2,2,1,4) | 0 participants |
| Bosutinib 200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP <50 mm Hg (n=58,29,24,54) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=2,2,1,4) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Decrease (n=58,29,24,54) | 1 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Decrease (n=2,2,1,4) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Decrease (n=58,29,24,54) | 3 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=2,2,1,4) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP <50 mm Hg (n=58,29,24,54) | 1 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Increase (n=58,29,24,54) | 3 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm(n=2,2,1,4) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Increase (n=58,29,24,54) | 1 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting Pulse Rate <40 or >120 bpm (n=58,29,24,54) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP <90 mm Hg (n=58,29,24,54) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Decrease (n=2,2,1,4) | 0 participants |
| Bosutinib 400 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Increase (n=58,29,24,54) | 5 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=2,2,1,4) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP <90 mm Hg (n=58,29,24,54) | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=2,2,1,4) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP <50 mm Hg (n=58,29,24,54) | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm(n=2,2,1,4) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting Pulse Rate <40 or >120 bpm (n=58,29,24,54) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Decrease (n=2,2,1,4) | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Decrease (n=58,29,24,54) | 2 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Decrease (n=2,2,1,4) | 1 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Decrease (n=58,29,24,54) | 3 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Increase (n=58,29,24,54) | 3 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Decrease (n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP <90 mm Hg (n=58,29,24,54) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP ≥30 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting Pulse Rate <40 or >120 bpm (n=58,29,24,54) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine Pulse Rate <40 or >120 bpm(n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine SBP <90 mm Hg (n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Increase (n=58,29,24,54) | 3 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP <50 mm Hg (n=58,29,24,54) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP <50 mm Hg (n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Increase (n=58,29,24,54) | 5 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Decrease (n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Supine DBP ≥20 mm Hg Increase (n=2,2,1,4) | 0 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting DBP ≥20 mm Hg Decrease (n=58,29,24,54) | 5 participants |
| Placebo | Number of Participants With Potentially Clinically Significant Vital Signs Findings | Sitting SBP ≥30 mm Hg Decrease (n=58,29,24,54) | 2 participants |
Other Pre-specified
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
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
Population: The safety analysis population included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib 200 mg/Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 56 participants |
| Bosutinib 200 mg/Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 12 participants |
| Bosutinib 400 mg/Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 participants |
| Bosutinib 400 mg/Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 30 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 6 participants |
| Bosutinib 400/200 mg/Day | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 23 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 51 participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 5 participants |