Zibotentan and Dapagliflozin in Patients With Type 2 Diabetes and Elevated Albuminuria

Chronic Kidney Diseases Clinical Trial

— ZODIAC  

Official title:

A Study to Assess the Effects of the Endothelin Receptor Antagonist Zibotentan and the SGLT2 Inhibitor Dapagliflozin in Patients With Type 2 Diabetes and Elevated Albuminuria: a Randomized Double Blind Cross-Over Trial

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05570305
• Other study ID #: 202100178
• Secondary ID: 2021-001324-18
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: October 6, 2022
• Est. completion date: September 1, 2024

Study information

• Verified date: September 2023
• Source: University Medical Center Groningen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 38
• Est. completion date: September 1, 2024
• Est. primary completion date: April 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Age =18 and =75 years

• Diagnosis of type 2 diabetes

• Hba1c = 6.0%

• 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

• Non-diabetic kidney disease considered to be dominant etiology of albuminuria

• Hba1c > 12.5%

• Urinary protein excretion > 3500 mg/day

• Heart Failure NYHA Class III or IV

• NT-proBNP > 600 pg/ml

• Hemoglobin <9g/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 immunosuppressants according to Investigator's 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 (outlined in section 5.2) 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:

• History of active inflammatory bowel disease within the last six months;

• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;

• Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;

• Pancreatic injury or pancreatitis within the last six months;

• 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;

• 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 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 patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.

Related Conditions & MeSH terms

• Albuminuria
• Chronic Kidney Diseases
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Zibotentan
Zibotentan 1.5 mg once per day as a hard capsule.
• Dapagliflozin
Dapagliflozin 10 mg once per day as a tablet.
• Placebo
Matching placebo.
• Dapagliflozin and Zibotentan
Dapagliflozin 10 mg once per day as a tablet in combination with zibotentan 1.5 mg once per day as a hard capsule.

Locations

Country	Name	City	State
Canada	Montreal Clinical Research Institute	Montreal	Quebec
Canada	Toronto General Hospital	Toronto	Ontario
Denmark	Steno Diabetes Center	Copenhagen	Gentoft
Netherlands	Amsterdam Universitair Academisch Centrum	Amsterdam	Noord Holland
Netherlands	University Medical Center Groningen	Groningen
United Kingdom	Center for Cardiovascular Science	Edinburgh
United States	Anschutz Medical Campus	Aurora	Colorado

Sponsors (2)

Lead Sponsor	Collaborator
University Medical Center Groningen	AstraZeneca

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in renin-angiotensin-aldosterone system (RAAS) markers	Change in RAAS markers in plasma and urine	4 weeks
Other	Change in copeptin	Change in copeptin as a surrogate of vasopressin	4 weeks
Primary	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.	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.
Secondary	Change in Extracellular Fluid	Extracellular Fluid measured by bioimpedance spectroscopy	4 weeks
Secondary	Change in bodyweight	Change in kilograms	4 weeks
Secondary	Change in NT-proBNP	N-terminal B-type natriuretic peptide (NT-proBNP)	4 weeks
Secondary	Change in BNP	B-type natriuretic peptide (BNP)	4 weeks
Secondary	Change in Glomerular Filtration Rate (GFR)	Glomerular Filtration Rate (GFR) using iohexol clearance techniques.	4 weeks
Secondary	Change in Extracellular volume (ECV)	Extracellular volume (ECV) using iohexol clearance techniques.	4 weeks
Secondary	Change in hematocrit	The percentage of red blood cells in blood	4 weeks
Secondary	Change in systolic and diastolic blood pressure	Change in blood pressure as measure in mmHg	4 weeks

External Links

•   New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reduction