A Study to Assess the Effects of the Endothelin Receptor Antagonist Zibotentan and the SGLT2 Inhibitor Dapagliflozin in Patients elevated Albuminuria: a Randomized Double Blind Cross-Over Trial
- Conditions
- diabetic kidney diseasediabetic nephropathy1001265310029149
- Registration Number
- NL-OMON54022
- Lead Sponsor
- niversitair Medisch Centrum Groningen
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 12
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
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 albuminexcretion > 3500 mg/day Heart Failure NYHA
Class III or IV NT-proBNP > 600 pg/ml 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 as per the treating physician*s
judgment. 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 will not be allowed. 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 Severe hepatic impairment
History of epilepsy syndrome History of severe hypersensitivity or
contraindications to dapagliflozin 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 evidence of
such abuse as indicated by the laboratory assays conducted during the screening
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.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>To assess the change from baseline in albuminuria after 4 weeks combined<br /><br>Zibotentan (ZIBO) and Dapagliflozin (DAPA) treatment versus four weeks<br /><br>Zibotentan alone in patients with an albumin:creatinine ratio between 100 and<br /><br>3500 mg/g on stable ACEi or ARB treatment for at least 4 weeks.</p><br>
- Secondary Outcome Measures
Name Time Method <p>• To evaluate the effect of a combined zibotentan / dapagliflozin treatment<br /><br>versus zibotentan only on:<br /><br>- Extracellular fluid measured by bioimpedance spectroscopy<br /><br>- Body weight<br /><br>- NT-proBNP and BNP<br /><br>Glomerular filtration rate (GFR) and extracellular volume (ECV) using iohexol<br /><br>clearance techniques.<br /><br>- Hematocrit<br /><br>- Systolic and diastolic blood pressure<br /><br>- fractional lithium excretion<br /><br><br /><br>• To assess the effect of zibotentan / dapagliflozin versus zibotentan on<br /><br>selected neurohormones / biomarkers:<br /><br>- Renin-angiotensin-aldosterone system markers (plasma and urine)<br /><br>- Copeptin (surrogate of vasopressin)</p><br>