Bosutinib For Autosomal Dominant Polycystic Kidney Disease

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Polycystic Kidney, Autosomal Dominant	Drug: Bosutinib; Drug: Placebo	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	172 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
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 Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Study Start Date :	December 2010
Actual Primary Completion Date :	July 2014
Actual Study Completion Date :	August 2014

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Cohort A	Drug: Bosutinib; Once daily oral dose of 200 mg of bosutinib
Experimental: Cohort B	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

Outcome Measures

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Primary Outcome Measures :

1. 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).

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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) ]
10. 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) ]
11. 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.
12. 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) ]
13. 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.
14. Apparent Volume of Distribution (Vz/F) 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) ]
    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.
15. Terminal Elimination Half-Life (t1/2) 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) ]
    t1/2 is the time measured for the plasma concentration to decrease by one half.
16. Observed Accumulation Ratio (Rac) of Bosutinib [ Time Frame: 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).
17. Change From Baseline in Kidney Disease Quality of Life (KDQoL)-36 Scale Scores at Month 25 [ Time Frame: 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.

Other Outcome Measures:

1. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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.
2. Number of Participants With Laboratory Abnormalities Meeting the Criteria for Potential Clinical Concern [ Time Frame: 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).
3. Number of Participants With Potentially Clinically Significant Vital Signs Findings [ Time Frame: 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.
4. Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings [ Time Frame: 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 50 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Pfizer

Investigators

Study Director:	Pfizer CT.gov Call Center	Pfizer

More Information

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Additional Information:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT01233869 History of Changes
Other Study ID Numbers:	B1871019; 3160A7-2211 ( Other Identifier: Alias Study Number ); 2010-023017-65 ( EudraCT Number )
First Posted:	November 3, 2010
Results First Posted:	October 28, 2015
Last Update Posted:	March 11, 2016
Last Verified:	February 2016

Keywords provided by Pfizer:

Bosutinib; Autosomal Dominant Polycystic Kidney Disease

Additional relevant MeSH terms:

Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Urologic Diseases	Kidney Diseases, Cystic; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn