Bosutinib For Autosomal Dominant Polycystic Kidney Disease

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)

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.

Study Overview

• Status: Completed
• Conditions: Polycystic Kidney, Autosomal Dominant
• Intervention / Treatment: Drug: Bosutinib; Drug: Bosutinib; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 172
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	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.	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.	Baseline up to 30 days after last study drug administration

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Tesar V, Ciechanowski K, Pei Y, Barash I, Shannon M, Li R, Williams JH, Levisetti M, Arkin S, Serra A. Bosutinib versus Placebo for Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2017 Nov;28(11):3404-3413. doi: 10.1681/ASN.2016111232. Epub 2017 Aug 24.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: October 28, 2010
• First Submitted That Met QC Criteria: November 2, 2010
• First Posted (Estimate): November 3, 2010

Study Record Updates

• Last Update Posted (Estimate): March 11, 2016
• Last Update Submitted That Met QC Criteria: February 10, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Bosutinib; Autosomal Dominant Polycystic Kidney Disease
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Arthrogryposis
• Other Study ID Numbers: B1871019; 3160A7-2211 (Other Identifier: Alias Study Number); 2010-023017-65 (EudraCT Number)