Clinical Trial: Bosutinib For Autosomal Dominant Polycystic Kidney Disease

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

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.

Detailed Summary:
Sponsor: Pfizer

Current Primary Outcome: Change From Baseline (CFB) in Total Kidney Volume (TKV) at Month 25 [ Time Frame: Baseline and Month 25 (end of Initial Treatment Period Visit [ITPV]) ]

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


Original Primary Outcome:

  • Annualized rate (%) of kidney enlargement relative to placebo [ Time Frame: 24 months ]
  • Safety endpoints to include incidence of AEs and SAEs, changes in laboratory test results, including ECGs, and changes in vital signs [ Time Frame: 24 months ]


Current Secondary Outcome:

  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Months 12, 24, 25 and Early Termination [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Number of Participants With High Serum Creatinine (SCr) Levels [ Time Frame: 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.
  • 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 [ 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 time tau, the dosing interval, where tau=24 hours.
  • 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 [ Time Frame: 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.


    Original Secondary Outcome:

    • Effect of treatment with bosutinib on renal function evaluations including blood urea nitrogen and serum and urine creatinine. [ Time Frame: 24 months ]
    • Time to first occurence (or worsening) of clinical measures of disease activity [ Time Frame: 24 months ]
    • Serum concentrations of bosutinib will be measured, PK parameters (Cmax, Tmax, AUCt, Cl/F, Vz/F, t1/2 and R) will be calculated [ Time Frame: 24 months ]
    • Subject-reported, disease specific quality of life [ Time Frame: 24 months ]
    • Demonstrate that reduction in the rate of kidney enlargement is predictive of a reduction in rate of decline of eGFR by evaluating total kidney volume and rate of decline of eGFR after 24 months and up to 72 months of treatment respectively. [ Time Frame: 72 months ]


    Information By: Pfizer

    Dates:
    Date Received: October 28, 2010
    Date Started: December 2010
    Date Completion:
    Last Updated: February 10, 2016
    Last Verified: February 2016