Bosutinib For Autosomal Dominant Polycystic Kidney Disease

Polycystic Kidney, Autosomal Dominant Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01233869
• Other study ID #: B1871019
• Secondary ID: 3160A7-22112010-
• Status: Completed
• Phase: Phase 2
• First received: October 28, 2010
• Last updated: February 10, 2016
• Start date: December 2010
• Est. completion date: August 2014

Study information

• Verified date: February 2016
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 172
• Est. completion date: August 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 50 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kidney Diseases
• Polycystic Kidney Diseases
• Polycystic Kidney, Autosomal Dominant

Intervention

Drug:
• Bosutinib
Once daily oral dose of 200 mg of bosutinib
• Bosutinib
Once daily oral dose of 400 mg of bosutinib transitioned to 200 mg/day
• Placebo
Once daily oral dose of placebo

Locations

Country	Name	City	State
Australia	Monash Medical Centre	Clayton	Victoria
Canada	Hopital du Sacre-Coeur de Montreal	Montreal	Quebec
Canada	Toronto General Hospital	Toronto	Ontario
Czech Republic	Klinika gerontologicka a metabolicka	Hradec Kralove
Czech Republic	Krajska nemocnice Liberec	Liberec 1
Czech Republic	Nemocnice Nove Mesto na Morave	Nove Mesto na Morave
Czech Republic	Fakultni poliklinika VFN	Praha 2
Czech Republic	Vseobecna fakultni nemocnice v Praze	Praha 2
Czech Republic	Pharmaceutical Research Associates CZ, s.r.o.	Praha 7
Hungary	Fovarosi Onkormanyzat Szent Imre Korhaz BSZMI Klinikai Farmakologiai Reszlege	Budapest
Hungary	PRA Magyarorszag Kft. Klinikai Farmakologiai Vizsgalohely	Budapest
Hungary	Szegedi Tudomanyegyetem, AOK, Szent-Gyorgyi Albert Klinikai Kozpont I.sz.Belgyogyaszati Klinika	Szeged
Italy	Istituti Ospitalieri di Cremona	Cremona
Italy	A.O. Universitaria Ospedali Riuniti di Foggia	Foggia
Korea, Republic of	Eulji General Hospital	Seoul
Korea, Republic of	Samsung Medical Center/Division of Nephrology	Seoul
Korea, Republic of	Seoul National University Hospital, Department of Internal Medicine	Seoul
Lithuania	Vilnius University Hospital Santariskiu Clinic, Public Institution, Centre of Nephrology	Vilnius
Moldova, Republic of	Spitalul Clinic Republican	Chisinau
Poland	Klinika Nefrologii, Transplantologii i Chorob Wewnetrznych	Gdansk
Poland	Zaklad Diagnostyki Chorob Serca, II Katedra Kardiologii	Gdansk
Poland	Specjalistyczny Szpital Zachodni im. Jana Pawla II w Grodzisku Mazowieckim	Grodzisk Mazowiecki
Poland	Krakowskie Centrum Medyczne NZOZ	Krakow
Poland	Klinika Nefrologii, Hipertensjologii i Chorob Wewnetrznych Katedry Chorob Wewnetrznych UWM	Olsztyn
Poland	Pracownia Echokardiografii, Oddzial Kardiologii	Olsztyn
Poland	Centrum Medyczne Aesculap	Radom
Poland	Klinika Kardiologii	Szczecin
Poland	Klinika Nefrologii, Transplantologii i Chorob Wewnetrznych	Szczecin
Poland	Szpital Powiatowy w Wolominie	Wolomin
Poland	SPZOZ Akademicki Szpital Kliniczny im. J. Mikulicza - Radeckiego	Wroclaw
Romania	Institutul Clinic Fundeni, Centrul de Medicina Interna-Nefrologie	Bucuresti
Romania	Spitalul Clinic Dr. C. I. Parhon Iasi	Iasi	jud. Iasi
Romania	Spitalul Clinic Municipal Dr. Gavril Curteanu Oradea	Oradea	jud. Bihor
Romania	SPITALUL CLINIC JUDETEAN DE URGENTA TIMISOARA ,Clinica de Nefrologie	Timisoara
Slovakia	SUMMIT CLINICAL RESEARCH, s.r.o., Oddelenie internej mediciny a klinickej farmakologie	Bratislava
Slovakia	Univerzitna nemocnica Bratislava	Limbova 5	Bratislava
Spain	Hospital Clinic I Provincial de Barcelona	Barcelona
Spain	Hospital Universitari de Bellvitge	Hospitalet de Llobregat	Barcelona
Sweden	Sahlgrenska Universitetssjukhuset, Njurmedicin	Goteborg
Sweden	Karolinska Universitetssjukhuset Huddinge	Stockholm
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm
Switzerland	Universitaetsspital Zuerich	Zuerich
Turkey	Istanbul University, Istanbul Tip Fakultesi	Istanbul	Capa
Turkey	Dokuz Eylul Universitesi Hastanesi Ic Hastaliklari Anabilim Dali	Izmir	Inciralti/ Narlidere
United Kingdom	BHF Glasgow Cardiovascular Research Centre, University of Glasgow	Glasgow
United Kingdom	Renal and Urology Directorate, Leicester General Hospital	Leicester
United Kingdom	Morriston Hospital	Swansea	Wales
United States	Renal Associates of Baton Rouge	Baton Rouge	Louisiana
United States	Tufts Medical Center	Boston	Massachusetts
United States	Boise Kidney & Hypertension Institute, PLLC	Caldwell	Idaho
United States	University of Virginia Health System	Charlottesville	Virginia
United States	University of Virginia Health System - Nephrology	Charlottesville	Virginia
United States	Doylestown Hospital	Doylestown	Pennsylvania
United States	Doylestown Hospital MRI	Doylestown	Pennsylvania
United States	Nephrology/Hypertension Specialists	Doylestown	Pennsylvania
United States	Boise Kidney & Hypertension Institute, PLLC	Meridian	Idaho
United States	New York University - HHC CTSI Clinical Research Center	New York	New York
United States	Southwest Kidney Institute, PLC	Phoenix	Arizona
United States	Capital Nephrology Clinical Research	Sacramento	California
United States	Renal Associates, PA	San Antonio	Texas
United States	San Antonio Kidney Disease Center Physicians Group, P.L.L.C.	San Antonio	Texas
United States	The Polyclinic	Seattle	Washington
United States	Renal Remission and Hypertension Clinic	Silverdale	Washington
United States	Washington University	St. Louis	Missouri
United States	Washington University School of Medicine	St. Louis	Missouri
United States	Southwest Clinical Research Institute, LLC	Tempe	Arizona
United States	Southwest Kidney Institute, PLC	Tempe	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Czech Republic,  Hungary,  Italy,  Korea, Republic of,  Lithuania,  Moldova, Republic of,  Poland,  Romania,  Slovakia,  Spain,  Sweden,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	Yes
Other	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	Yes
Other	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	Yes
Other	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	Yes
Primary	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])	No
Secondary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No

External Links

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