Bosutinib For Autosomal Dominant Polycystic Kidney Disease

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Of The Safety, Clinical Activity And Pharmacokinetics Of Bosutinib (PF-05208763) Versus Placebo In Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Conditions
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Polycystic Kidney, Autosomal Dominant

Intervention / Treatment
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* Drug: Bosutinib
* Drug: Bosutinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br> | Drug: Bosutinib<br>* Once daily oral dose of 200 mg of bosutinib<br>|
| Experimental: Cohort B<br> | Drug: Bosutinib<br>* Once daily oral dose of 400 mg of bosutinib transitioned to 200 mg/day<br>|
| Placebo Comparator: Cohort C<br> | Drug: Placebo<br>* Once daily oral dose of placebo<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Day 15, Months 6, 12, 18, 24, and 25 (end of 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 | Area under the concentration-time profile from time 0 to time tau, the dosing interval, where tau=24 hours. | 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 |  | 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. | 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. | 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. | 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). | 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. | Baseline and end of ITPV (Month 25) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bosutinib, Autosomal Dominant Polycystic Kidney Disease