Patients with elevated Albuminuria MedDRA version: 27.1 Level: PT Classification code 10061835 Term: Diabetic nephropathy System Organ Class: 10038359 - Renal and urinary disorders MedDRA version: 27.0 Level: PT Classification code 10016807 Term: Fluid retention System Organ Class: 10027433 - Metabolism and nutrition disorders MedDRA version: 20.0 Level: PT Classification code 10001580 Term: Albuminuria System Organ Class: 10038359 - Renal and urinary disorders
Conditions
Interventions
Product Name: zibotentan
Product Code: ZD4054
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ZIBOTENTAN
CAS Number: 186497-07-4
Current Sponsor code: ZD4054
Concentration unit: mg milligram(s
Sponsors
University Medical Center Groningen
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Age =18 and =75 years Urinary albumin:creatinine ratio > 100 mg/g and = 3500 mg/g in a first morning void urine collection eGFR = 30 mL/min/1.73m2 On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization Willing to sign informed consent 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 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 8
Exclusion criteria
Exclusion criteria: . Diagnosis of type 1 diabetes . Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease requiring significant immunosuppression, autosomal dominant or autosomal recessive polycystic kidney disease . Hba1c > 12.5% . Urinary albumin excretion > 3500 mg/day . Heart Failure NYHA Class III or IV . NT-proBNP > 600 pg/ml . Hemoglobin < 9 g/dL . Acute coronary syndrome event within the preceding 6 months . Severe peripheral edema according to investigators opinion . Women of childbearing potential (WOCBP). WOCBP is defined as women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal . Pregnancy or breastfeeding . Indication for high dose immunosuppressants according to Investigators opinion . Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin within the last 5 years. . Use of the co-interventional treatments within 6 weeks of screening. . Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following: o History of active inflammatory bowel disease within the last six months; o Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; o Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months; o Pancreatic injury or pancreatitis within the last six months; o Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at the screening visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt; o Evidence of urinary obstruction or difficulty in voiding at screening o Severe hepatic impairment o History of epilepsy syndrome o History of severe hypersensitivity or contraindications to dapagliflozin o History of hypersensitivity or contraindications to iodinated contrast media .Subject who, in the assessment of the investigator, may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data . Participation in any clinical investigation within 3 months prior to initial dosing. . Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing . History of drug or alcohol abuse within the 12 months prior to dosing, or according to investigator’s assessment. . History of noncompliance to medical regimens or unwillingness to comply with the study protocol. . Any surgical or medical condition, which in the opinion of the investigator, may place the subject at higher risk from his/her participation in the study, or is likely to prevent the subject from complying with the requirements of the study or completing the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the change from baseline in albuminuria after 4 weeks combined zibotentan (ZIBO) and dapagliflozin (DAPA) treatment versus four weeks treatment with ZIBO alone in patients an albumin: creatinine ratio between 100 and 3500 mg/g on stable ACEi or ARB treatment for at least 4 weeks. ;Secondary Objective: To assess the effect of combined ZIBO/DAPA treatment versus ZIBO alone on: o Extracellular Fluid measured by bioimpedance spectroscopy o Body weight o NT-proBNP and BNP o Glomerular Filtration Rate (GFR) and extracellular volume (ECV) using iohexol clearance techniques. o Hematocrit o Systolic and diastolic blood pressure o Fractional lithium excretion To assess the effect of ZIBO/DAPA versus ZIBO on selected neurohormones/biomarkers: o Renin-angiotensin-aldosterone system markers (plasma and urine) o Copeptin (surrogate of vasopressin) ;Primary end point(s): Geometric mean ratio of three consecutive albumin:creatinine ratio derived from a first morning void collection;Timepoint(s) of evaluation of this end point: Week 22 of the trial (end of treatment period 3) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Extracelluar volume measured by bioimpedance spectroscopy Body weight NT-proBNP and BNP Glomerular Filtration Rate (GFR) using iohexol clearance. hematocrit Systolic and diastolic blood pressure Fractional Lithium excretion Renin-angiotensin-aldosterone system markers (plasma and urine) Copeptin (surrogate marker of vasopressin);Timepoint(s) of evaluation of this end point: Week 22 of the trial (end of treatment period 3) | — |
Countries
Canada, Denmark, Netherlands, United Kingdom, United States
Contacts
Public ContactHiddo Lambers Heerspink
University Medical Center Groningen
Outcome results
None listed