The aim of this study is to test the hypothesis that the effects on albuminuria of combination treatment with the endothelin receptor antagonist zibotentan and SGLT2i dapagliflozin are complimentary and additive while the fluid retaining effects of zibotentan can be mitigated by dapagliflozin.
A double-blind randomized placebo controlled cross-over study will be conducted in male and female subjects with type 2 diabetes aged between 18 and 75 years, urinary albumin:creatinine ratio (UACR) levels between 100 and 3500 mg/g, and an eGFR ≥ 30 ml/min/1.73m2 will be enrolled. Patients with type 1 diabetes or non-diabetic kidney disease will be excluded. The study will consist of a screening visit, a 4-week (up to a maximum of 16-weeks) run-in phase for those subjects not on stable ACEi/ARB treatment. Subjects will be randomly assigned to one of two treatment orders. Each treatment order consists of three treatment periods, separed separated by 4-week wash-out period. Treatment period 1 and 2 take four weeks. The third treatment period last 6 weeks. Participants will be randomized to treatments in addition to receiving background local standard of care (SoC) therapy as follows: 1. Zibotentan 1.5 mg once daily + Dapagliflozin 10 mg once daily. 2. Zibotentan 1.5 mg once daily. 3. Dapagliflozin 10 mg once daily. 4. Placebo once daily.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
42
Zibotentan 1.5 mg once per day as a hard capsule.
Dapagliflozin 10 mg once per day as a tablet.
Matching placebo.
Anschutz Medical Campus
Aurora, Colorado, United States
Toronto General Hospital
Toronto, Ontario, Canada
Montreal Clinical Research Institute
Montreal, Quebec, Canada
Steno Diabetes Center
Copenhagen, Gentoft, Denmark
Change from baseline in albuminuria after 4 weeks combined zibotentan and dapagliflozin treatment versus four weeks treatment with zibotentan alone.
The change in albuminuria as expressed the percentage change of the log-transformed albumin:creatinine ratio in mg/gram. The log-transformation is because of the skewed distribution.
Time frame: The albuminuria will be measured before start of medication intake and after the last intake of medication for each treatment period. This concerns a 4 week time frame.
Change in Extracellular Fluid
Extracellular Fluid measured by bioimpedance spectroscopy
Time frame: 4 weeks
Change in bodyweight
Change in kilograms
Time frame: 4 weeks
Change in NT-proBNP
N-terminal B-type natriuretic peptide (NT-proBNP)
Time frame: 4 weeks
Change in BNP
B-type natriuretic peptide (BNP)
Time frame: 4 weeks
Change in Glomerular Filtration Rate (GFR)
Glomerular Filtration Rate (GFR) using iohexol clearance techniques.
Time frame: 4 weeks
Change in Extracellular volume (ECV)
Extracellular volume (ECV) using iohexol clearance techniques.
Time frame: 4 weeks
Change in hematocrit
The percentage of red blood cells in blood
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Dapagliflozin 10 mg once per day as a tablet in combination with zibotentan 1.5 mg once per day as a hard capsule.
Amsterdam Universitair Academisch Centrum
Amsterdam, North Holland, Netherlands
University Medical Center Groningen
Groningen, Netherlands
Center for Cardiovascular Science
Edinburgh, United Kingdom
Time frame: 4 weeks
Change in systolic and diastolic blood pressure
Change in blood pressure as measure in mmHg
Time frame: 4 weeks