Bosutinib For Autosomal Dominant Polycystic Kidney Disease - Full Text View

Purpose

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	Intervention	Phase
Polycystic Kidney, Autosomal Dominant	Drug: Bosutinib Drug: Placebo	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, 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)

Resource links provided by NLM:

Genetics Home Reference related topics: polycystic kidney disease

MedlinePlus related topics: Kidney Diseases

Drug Information available for: Bosutinib

U.S. FDA Resources

Further study details as provided by Pfizer:

Primary Outcome Measures:

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]) ] [ Designated as safety issue: No ]
TKV was measured by centrally evaluated Magnetic Resonance Imaging (MRI).

Secondary Outcome Measures:

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 ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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) ] [ Designated as safety issue: No ]
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.
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) ] [ Designated as safety issue: No ]
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.
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) ] [ Designated as safety issue: No ]
t1/2 is the time measured for the plasma concentration to decrease by one half.
Observed Accumulation Ratio (Rac) of Bosutinib [ Time Frame: Day 15 (pre-dose and 1, 2, 3, 4, 6, 8 and 24 hours post-dose) ] [ Designated as safety issue: No ]
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).
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) ] [ Designated as safety issue: No ]
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:

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 ] [ Designated as safety issue: Yes ]
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.
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 ] [ Designated as safety issue: Yes ]
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).
Number of Participants With Potentially Clinically Significant Vital Signs Findings [ Time Frame: Baseline up to 30 days after last study drug administration ] [ Designated as safety issue: Yes ]
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.
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Findings [ Time Frame: Baseline up to 30 days after last study drug administration ] [ Designated as safety issue: Yes ]
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.


Enrollment:	172
Study Start Date:	December 2010
Study Completion Date:	August 2014
Primary Completion Date:	July 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

Eligibility


Ages Eligible for Study:	18 Years to 50 Years (Adult)
Genders Eligible for Study:	Both
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01233869

Show 67 Study Locations

Sponsors and Collaborators

Pfizer

Investigators


Study Director:	Pfizer CT.gov Call Center	Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. This link exits the ClinicalTrials.gov site


Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT01233869 History of Changes
Other Study ID Numbers:	B1871019 3160A7-2211 2010-023017-65
Study First Received:	October 28, 2010
Results First Received:	August 26, 2015
Last Updated:	February 10, 2016
Health Authority:	United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on September 23, 2016