A multicenter, randomized, double-blind, placebo-controlled study of the safety, effectiveness, and pharmacokinetics of bosutinib versus placebo in subjects with polycystic kidney disease
- Conditions
- Autosomal Dominant Polycystic Kidney Disease (ADPKD)MedDRA version: 14.1Level: LLTClassification code 10036046Term: Polycystic kidney, autosomal dominantSystem Organ Class: 100000004850Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
- Registration Number
- EUCTR2010-023017-65-CZ
- Lead Sponsor
- Pfizer Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 190
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
2. Males and females, aged =18 years to 50 years at the time of consent.
3. Documented diagnosis of ADPKD by renal ultrasound cyst criteria based on the Unified Criteria for Ultrasonographic Diagnosis of ADPKD. A family history of ADPKD is not required to support diagnosis by ultrasound criteria. Alternatively, the diagnosis of ADPKD may be based on PKD 1 or PKD 2 genotype findings as documented in the medical record.
4. Total kidney volume =750 cc, as measured by centrally evaluated MRI.
5. Left ventricular ejection fraction by echocardiogram or MUGA =50% at screening.
6. All women of childbearing potential must have two negative pregnancy test results before administration of study drug. Women of childbearing potential must agree to use two highly effective methods of contraception as described in the protocol for at least 14 days prior to the first dose of study medication and continue until 28 days after dosing. A subject is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children and is sexually active.
7. Men willing to use two highly effective methods of contraception as described in the protocol throughout the active treatment phase of the study and for 28 days after the last dose of study drug. Any pregnancy that occurs in the female partner of a male subject in the study must be reported if it occurs at any time during the active treatment phase of the study or for 28 days after the last dose of study drug.
8. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 190
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range
Subjects presenting with any of the following will not be included in the study:
1. Weight <40 kg or >125 kg.
2. Women who are pregnant or breastfeeding or women who intend to become pregnant during their participation in the study.
3. Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2
4. Abnormal urinalysis showing cellular casts.
5. Biopsy proven renal disease other than ADPKD.
6. Chronic back and/or flank pain requiring daily or near daily pain medication over the preceding month.
7. Documented renal vascular disease.
8. Documented systemic illness with renal involvement.
9. Creatine supplements within 3 months of the baseline visit.
10. Uncontrolled hypertension (defined as systolic blood pressure =140 or diastolic blood pressure =90 mm Hg).
11. Uncontrolled diabetes mellitus as evidenced by screening assessments and/or recent medical record.
12. Medical history or diagnosis of immunodeficiency.
13. Autoimmune disease not in remission or requiring ongoing treatment with immunosuppressive medication.
14. Increased ALT and/or AST >2.5 x the upper limit of normal.
15. Total bilirubin >2 x the upper limit of normal (unless associated with Gilbert’s syndrome).
16. Grade 2 or higher abnormalities of serum sodium [sodium >150 or <130 mmol/l].
17. Uncorrected hypomagnesemia or hypokalemia [serum magnesium or serum potassium < lower limit of normal].
18. Grade 2 or higher elevation of serum potassium or serum magnesium [serum potassium >5.5 or serum magnesium >3.0 mg/dl (or >1.23 mmol/l)].
19. Hemoglobin <9.0 gm/dl.
20. Platelet count <100,000/microliter.
21. Congenital absence of a kidney or prior surgical resection of a kidney for any reason.
22. Clinically significant or unstable cardiac disease (eg, unstable angina, recent myocardial infarction, clinically significant arrhythmia requiring treatment, uncontrolled congestive heart failure, etc).
23. Subjects with any pre dose corrected QT interval (QTc) =450 msec based on any one of the machine read tracing using Fridericia’s formulae obtained at screening. Any decision to retest a subject must first be discussed with the Pfizer Medical Monitor. If a repeat QTcF interval obtained pre-dose is =450 msec, the subject is excluded from enrollment.
24. History of prolonged QTc interval or additional risk factors for Torsade de Pointes (eg, heart failure, hypokalemia, family history of long QT syndrome).
25. History or evidence of infection with hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
26. Past or present malignancy (with the exception of adequately treated, localized basal cell or squamous cell carcinoma of the skin).
27. Use of any investigational drug or investigational biologic compound within 4 weeks prior to the screening visit or during the screening period.
28. Participation in any interventional studies within 4 weeks prior to the screening visit and/or during study participation.
29. Any previous exposure to the bosutinib study drug, including previous participation in a bosutinib clinical study, or receipt of other therapies intended to modify the progression of polycystic kidney disease (supportive care measures excepted).
30. Contraindication(s) to undergoing magnetic resonance imaging (MRI).
31. Mental illness that could interfere with the subject’s ability to comply with the protocol.
32. Ongoing treatment with Digoxin.
33. Ongoing treatment with strong P Glycoprotein inhibitors or ind
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: ? To demonstrate that bosutinib reduces the rate of kidney enlargement in subjects with autosomal dominant polycystic kidney disease (ADPKD) entering the study with total kidney volume (TKV) =750 cc and eGFR =60 mL/min/1.73m2.<br>;Secondary Objective: ? To investigate the effect of treatment with bosutinib on renal function compared with placebo.<br>? To determine the time to first occurrence (or worsening) of clinical measures of disease activity.<br>? To evaluate the plasma PK of bosutinib.<br>? To evaluate the effect of treatment with bosutinib on subject-reported, disease specific quality of life compared with placebo.<br>? To investigate the progression of eGFR over the course of the study;Primary end point(s): • Annualized rate (%) of kidney enlargement relative to placebo.<br>;Timepoint(s) of evaluation of this end point: 25 Months
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • The following clinical parameters to assess disease progression will be evaluated:<br>• Rate of decline of estimated Glomerular Filtration Rate (eGFR) relative to placebo will be investigated.<br>• Time to first occurrence or worsening of hypertension, defined as the need for increased dose of or need for additional anti hypertensive medication.<br>• Time to first occurrence or worsening of back and/or flank pain.<br>• Time to first occurrence of gross hematuria.<br>• Time to first occurrence of proteinuria.<br>• Onset of end stage renal disease requiring dialysis =56 days.<br>• Renal function evaluations to include blood urea nitrogen and serum creatinine.<br>• Pharmcokinetic parameters of bosutinib including Cmax, tmax, AUCtau, Cmin, Clearance, Vz/F, t1/2, and R.<br>• Quality of Life measured by the Kidney Disease Quality of Life (KDQoL 36) questionnaire.;Timepoint(s) of evaluation of this end point: 25 Months