A Phase 2 interventional study of Bosutinib and Bosutinib in Polycystic Kidney, Autosomal Dominant, sponsored by Pfizer. Completed at 67 sites in 17 countries. Open to participants aged 18 Years to 50 Years. Per ClinicalTrials.gov, last updated 2016-03-11.
Sponsored by Pfizer · Phase 2, Interventional, and Treatment
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.
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Exclusion Criteria:
Drug: Bosutinib
Drug: Bosutinib
Drug: Placebo
Once daily oral dose of 200 mg of bosutinib
Once daily oral dose of 400 mg of bosutinib transitioned to 200 mg/day
Once daily oral dose of placebo
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])
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
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
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
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
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
| Milestone | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Started | 58 | 31 | 24 | 56 |
| Completed | 34 | 3 | 22 | 34 |
| Not completed | 24 | 28 | 2 | 22 |
| Withdrew: Death | 1 | 0 | 0 | 0 |
| Withdrew: Adverse event | 9 | 17 | 0 | 3 |
| Withdrew: Not related to study drug | 14 | 11 | 2 | 19 |
| Milestone | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Started | 34 | 3 | 22 | 34 |
| Completed | 34 | 3 | 22 | 34 |
| Not completed | 0 | 0 | 0 | 0 |
| Milestone | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Started | 34 | 3 | 22 | 34 |
| Completed | 20 | 0 | 17 | 18 |
| Not completed | 14 | 3 | 5 | 16 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 1 |
| Withdrew: Withdrawal by subject | 10 | 3 | 5 | 11 |
| Withdrew: Other | 3 | 0 | 0 | 3 |
| Withdrew: Adverse event | 1 | 0 | 0 | 1 |
TKV was measured by centrally evaluated Magnetic Resonance Imaging (MRI).
| centimeter cube (cm^3) | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| 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 |
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.
| mL/min/1.73m^2 | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| 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 |
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.
| days | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Time to First Occurrence or Worsening of Hypertension | 15 | 180 | 90 | 30 |
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.
| days | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Time to First Occurrence or Worsening of Back and/or Flank Pain | 30 | 30 | 270 | 15 |
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.
| days | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Time to First Occurrence of Gross Hematuria | 330 | 180 | 180 | 45 |
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.
| days | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Time to First Occurrence of Proteinuria | 360 | NA | 270 | 540 |
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.
| days | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Time to First Occurrence of End-Stage Renal Disease (ESRD) Requiring Dialysis >=56 Days | NA | NA | NA | NA |
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.
| participants | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Day 15 | 0 | 0 | 2 | 0 |
| Month 6 | 0 | 0 | 0 | 0 |
| Month 12 | 0 | 0 | 0 | 0 |
| Month 18 | 0 | 0 | 0 | 0 |
| Month 24 | 0 | 0 | 1 | 0 |
| End of ITPV | 0 | 0 | 2 | 0 |
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.
| participants | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Day 15 | 0 | 1 | 0 | 0 |
| Month 6 | 0 | 0 | 0 | 0 |
| Month 12 | 0 | 0 | 0 | 1 |
| Month 18 | 0 | 0 | 0 | 0 |
| Month 24 | 0 | 1 | 1 | 1 |
| End of ITPV | 0 | 0 | 0 | 1 |
| nanograms per milliliter (ng/mL) | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day |
|---|---|---|---|
| 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 |
| hours | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day |
|---|---|---|---|
| Day 1 (n=58,31,24) | 3.00 (1.00 to 24.00) | 3.00 (2.80 to 23.80) | 4.86 (1.00 to 5.25) |
| Day 15 (n=58,16,22) | 3.95 (0.00 to 25.60) | 3.00 (1.00 to 8.00) | 5.00 (1.00 to 8.12) |
Area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau=24 hours.
| ng*hr/mL | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day |
|---|---|---|---|
| Day 1 (n=58,30,24) | 437 ± 48 | 1040 ± 49 | 1149 ± 50 |
| Day 15 (n=58,16,22) | 1059 ± 45 | 2052 ± 36 | 2384 ± 34 |
| ng/mL | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day |
|---|---|---|---|
| Lowest Concentration Observed During the Dosing Interval (Cmin) of Bosutinib | 25.15 ± 49 | 19.60 ± 20880 | 50.67 ± 50 |
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.
| L/hr | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day |
|---|---|---|---|
| Apparent Oral Clearance (CL/F) of Bosutinib | 188.8 ± 45 | 195.0 ± 36 | 167.8 ± 34 |
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.
No measurements were reported for this outcome.
t1/2 is the time measured for the plasma concentration to decrease by one half.
No measurements were reported for this outcome.
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).
| ratio | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day |
|---|---|---|---|
| Observed Accumulation Ratio (Rac) of Bosutinib | 2.452 ± 36 | 2.280 ± 42 | 2.075 ± 41 |
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.
| units on a scale | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| 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 |
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.
| participants | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| AEs | 56 | 30 | 23 | 51 |
| SAEs | 12 | 4 | 6 | 5 |
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).
| participants | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern | 53 | 20 | 23 | 43 |
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.
| participants | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Supine SBP <90 mm Hg (n=2,2,1,4) | 0 | 0 | 0 | 0 |
| Sitting SBP <90 mm Hg (n=58,29,24,54) | 0 | 0 | 1 | 0 |
| Supine DBP <50 mm Hg (n=2,2,1,4) | 0 | 0 | 0 | 0 |
| Sitting DBP <50 mm Hg (n=58,29,24,54) | 0 | 1 | 1 | 0 |
| Supine Pulse Rate <40 or >120 bpm(n=2,2,1,4) | 0 | 0 | 0 | 0 |
| Sitting Pulse Rate <40 or >120 bpm (n=58,29,24,54) | 1 | 0 | 0 | 0 |
| Supine SBP ≥30 mm Hg Decrease (n=2,2,1,4) | 0 | 0 | 1 | 0 |
| Sitting SBP ≥30 mm Hg Decrease (n=58,29,24,54) | 2 | 1 | 2 | 2 |
| Supine DBP ≥20 mm Hg Decrease (n=2,2,1,4) | 0 | 0 | 1 | 0 |
| Sitting DBP ≥20 mm Hg Decrease (n=58,29,24,54) | 12 | 3 | 3 | 5 |
| Supine SBP ≥30 mm Hg Increase (n=2,2,1,4) | 0 | 0 | 0 | 0 |
| Sitting SBP ≥30 mm Hg Increase (n=58,29,24,54) | 3 | 1 | 3 | 3 |
| Supine DBP ≥20 mm Hg Increase (n=2,2,1,4) | 0 | 0 | 0 | 0 |
| Sitting DBP ≥20 mm Hg Increase (n=58,29,24,54) | 5 | 3 | 5 | 5 |
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.
| participants | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| PR Interval ≥300 msec (n=58,31,24,56) | 0 | 0 | 0 | 0 |
| QRS Complex ≥200 msec (n=58,31,24,56) | 0 | 0 | 0 | 0 |
| QTcF Interval 450-<480 msec (n=58,31,24,56) | 3 | 2 | 0 | 6 |
| QTcF Interval 480-<500 msec (n=58,31,24,56) | 0 | 0 | 0 | 0 |
| QTcF Interval ≥500 msec (n=58,31,24,56) | 0 | 0 | 0 | 0 |
| PR Interval ≥25/50% Increase (n=57,28,23,52) | 0 | 0 | 0 | 0 |
| QRS Complex ≥25/50% Increase (n=57,28,23,52) | 0 | 0 | 0 | 0 |
| QTcF Interval 30-<60 msec Increase (n=57,28,23,52) | 4 | 1 | 1 | 5 |
| QTcF Interval ≥60 msec Increase (n=57,28,23,52) | 0 | 0 | 0 | 0 |
Collected over Baseline up to 30 days after last study drug administration. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Bosutinib 200 mg/Day | — | 12/58 (20.7%) | 56/58 (96.6%) |
| Bosutinib 400 mg/Day | — | 4/31 (12.9%) | 30/31 (96.8%) |
| Bosutinib 400/200 mg/Day | — | 6/24 (25%) | 23/24 (95.8%) |
| Placebo | — | 5/56 (8.9%) | 50/56 (89.3%) |
| Event | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| Cervix disorderReproductive system and breast disorders | 0/28 | 0/14 | 1/15 | 0/35 |
| AnaemiaBlood and lymphatic system disorders | 0/58 | 0/31 | 1/24 | 0/56 |
| Pyelonephritis acuteInfections and infestations | 0/58 | 0/31 | 1/24 | 0/56 |
| SepsisInfections and infestations | 2/58 | 0/31 | 1/24 | 0/56 |
| Intracranial aneurysmNervous system disorders | 0/58 | 0/31 | 1/24 | 0/56 |
| Calculus uretericRenal and urinary disorders | 0/58 | 0/31 | 1/24 | 0/56 |
| Renal cyst haemorrhageRenal and urinary disorders | 1/58 | 1/31 | 1/24 | 0/56 |
| Alanine aminotransferase increasedInvestigations | 2/58 | 1/31 | 0/24 | 0/56 |
| Hepatitis acuteHepatobiliary disorders | 0/58 | 1/31 | 0/24 | 0/56 |
| GastroenteritisInfections and infestations | 0/58 | 1/31 | 0/24 | 0/56 |
| Event | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo |
|---|---|---|---|---|
| DiarrhoeaGastrointestinal disorders | 26/58 | 26/31 | 18/24 | 11/56 |
| NauseaGastrointestinal disorders | 21/58 | 15/31 | 13/24 | 9/56 |
| Alanine aminotransferase increasedInvestigations | 18/58 | 16/31 | 12/24 | 4/56 |
| VomitingGastrointestinal disorders | 6/58 | 11/31 | 9/24 | 4/56 |
| Aspartate aminotransferase increasedInvestigations | 17/58 | 11/31 | 6/24 | 3/56 |
| Abdominal pain upperGastrointestinal disorders | 5/58 | 7/31 | 8/24 | 5/56 |
| NasopharyngitisInfections and infestations | 12/58 | 3/31 | 8/24 | 8/56 |
| Upper respiratory tract infectionInfections and infestations | 6/58 | 4/31 | 7/24 | 7/56 |
| Abdominal painGastrointestinal disorders | 4/58 | 8/31 | 2/24 | 7/56 |
| FatigueGeneral disorders | 4/58 | 8/31 | 2/24 | 6/56 |
The safety population included all participants who received at least 1 dose of study medication.
| Age, Continuous(years) | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo | Total |
|---|---|---|---|---|---|
| Mean | 37.9 ± 8.0 | 41.3 ± 4.9 | 36.4 ± 7.8 | 38.5 ± 7.4 | 38.5 ± 7.4 |
| Sex: Female, Male(Participants) | Bosutinib 200 mg/Day | Bosutinib 400 mg/Day | Bosutinib 400/200 mg/Day | Placebo | Total |
|---|---|---|---|---|---|
| Female | 28 | 14 | 15 | 35 | 92 |
| Male | 30 | 17 | 9 | 21 | 77 |
This study is completed, as verified in Feb 2016. You cannot join it, but the record below documents what was studied.
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