This study investigates how well the combination of the two drugs, zibotentan and dapagliflozin, works for the treatment of chronic kidney disease in patients. We compare the effect of zibotentan and dapagliflozin with the effect of a placebo. The…
ID
Source
Brief title
Condition
- Diabetic complications
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To assess the change from baseline in albuminuria after 4 weeks combined
Zibotentan (ZIBO) and Dapagliflozin (DAPA) treatment versus four weeks
Zibotentan alone in patients with an albumin:creatinine ratio between 100 and
3500 mg/g on stable ACEi or ARB treatment for at least 4 weeks.
Secondary outcome
• To evaluate the effect of a combined zibotentan / dapagliflozin treatment
versus zibotentan only on:
- Extracellular fluid measured by bioimpedance spectroscopy
- Body weight
- NT-proBNP and BNP
Glomerular filtration rate (GFR) and extracellular volume (ECV) using iohexol
clearance techniques.
- Hematocrit
- Systolic and diastolic blood pressure
- fractional lithium excretion
• To assess the effect of zibotentan / dapagliflozin versus zibotentan on
selected neurohormones / biomarkers:
- Renin-angiotensin-aldosterone system markers (plasma and urine)
- Copeptin (surrogate of vasopressin)
Background summary
Dapagliflozin is a medicine that increases the loss of salt and sugar in the
urine. Dapagliflozin reduces urinary protein levels and has been shown to
protect heart and kidney function in patients with type 2 diabetes and chronic
kidney disease. Albuminuria is an important indicator of kidney damage. A
reduction in albuminuria is related to kidney protection.
Zibotentan is a new investigational drug that lowers blood pressure and,
similar to dapagliflozin, reduces albuminuria in patients with type 2 diabetes.
Zibotentan can cause fluid retention and heart failure. Dapagliflozin may
decrease fluid retention due to zibotentan, while the combination of both
zibotentan and dapagliflozin may reduce urinary protein levels more, and
therefore potentially better protect the kidneys, than zibotentan alone.
Study objective
This study investigates how well the combination of the two drugs, zibotentan
and dapagliflozin, works for the treatment of chronic kidney disease in
patients. We compare the effect of zibotentan and dapagliflozin with the effect
of a placebo. The main aim of the study is to investigate whether a combination
of zibotentan and dapagliflozin may have beneficial effects on albuminuria
reduction compared to zibotentan alone. The second aim is to investigate
whether the combination of zibotentan and dapagliflozin has an effect on water
retention compared to zibotentan alone.
Study design
This study has a cross-over design, which means that, depending on the
randomisation schedule, patients will receive successively dapagliflozin,
zibotentan, a combination of dapagliflozin and zibotentan or placebo.
Dapagliflozin is prescribed at a dose of 10 mg/day. Zibotentan is prescribed at
a dose of 1.5 mg/day.
The study consists of a screening visit, a 4-week run-in period (up to a
maximum of 16 weeks) for subjects not receiving stable ACEi/ARB treatment, 2
consecutive double-blind 4-week treatment periods each separated by a 4-week
washout period. The third treatment period lasts 6 weeks.
Patients are randomly assigned to two strata with the order of medications in
periods 1 and 2 within each stratum determined by randomization:
Stratum 1: period 1: zibotentan, period 2: placebo, period 3:
dapagliflozin/placebo and finally the combination of zibotentan and
dapagliflozin
Stratum 2: period 1: dapagliflozin, period 2: zibotentan, period 3:
dapagliflozin/placebo and finally the combination of zibotentan and
dapagliflozin
The above means that there are a total of 8 different randomization options:
the first two treatment periods in each stratum are random, meaning that a
patient can start with zibotentan or placebo in startum 1 and with
dapagliflozin or zibotentan in stratum 2. The third treatment period begins
with 2 weeks of treatment with either dapagliflozin or placebo, which will also
be randomized to place the patient in the dapagliflozin or placebo group.
During the remaining 4 weeks of the third period, all patients will receive the
combination of both zibotentan and dapagliflozin (open-label).
All patients come to the hospital 10 times in 6 months. A visit takes about 4.5
hours. In addition, each patient is called 6 times by the investigator, twice
during each treatment period. The patient is then asked questions about the use
of the medication and adverse events. These phone calls last approximately 15
minutes.
Intervention
Addition of dapagliflozin, zibotentan or a combination of both compared to
placebo in addition to stable background therapy for at least 4 weeks with an
ACEi or ARB according to current guidelines.
Study burden and risks
Patients are at risk for adverse events due to the study drugs dapagliflozin
and zibotentan.
The most relevant potential risks due to dapagliflozin are: urinary tract
infections, genital infections, hypovolemia, electrolyte disturbances and
ketoacidosis. Zibotentan can induce fluid retention, edema, heart failure (in
susceptible patients), nausea, vomiting and dilution anemia.
As with all blood sampling, there is a risk of mild pain, local irritation,
bleeding or bruising (a black and blue mark) at the puncture site. There is a
small risk of light-headedness and/or fainting.
It is possible to have an allergic reaction to the Iohexol kidney function
test, including rashes (hives) and more severe allergic reactions.
It is not expected that the patients will receive treatment benefit from
participation in this mechanistic study.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
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
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 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-001324-18-NL |
| ClinicalTrials.gov | NCT05570305 |
| CCMO | NL77104.042.21 |