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

NCT ID: NCT05570305

Last Updated: 2025-04-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-10-06
• Study Completion Date: 2025-03-05

Brief 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.

Detailed 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.

Conditions

Chronic Kidney Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment order 1

Subjects will start with 4 weeks of placebo in treatment period one, then 4 weeks of zibotentan during treatment period two. The order of the first two treatment periods is random which means that patients can start with either placebo or zibotentan. Then in treatment period three, patients are randomized to either either placebo or dapagliflozin for 2 weeks followed immediately by 4 weeks of both zibotentan and dapagliflozin. Between treatment periods there is a 4-week wash-out.

Group Type: EXPERIMENTAL

Zibotentan

Intervention Type: DRUG

Zibotentan 1.5 mg once per day as a hard capsule.

Dapagliflozin

Intervention Type: DRUG

Dapagliflozin 10 mg once per day as a tablet.

Placebo

Intervention Type: DRUG

Matching placebo.

Dapagliflozin and Zibotentan

Intervention Type: DRUG

Dapagliflozin 10 mg once per day as a tablet in combination with zibotentan 1.5 mg once per day as a hard capsule.

Treatment order 2

Subjects will start with 4 weeks of dapagliflozine in treatment period one, then 4 weeks of zibotentan during treatment period two. The order of the first two treatment periods is random which means that patients can start with either dapagliflozine or zibotentan. Then in treatment period three, patients are randomized to either either placebo or dapagliflozin for 2 weeks followed immediately by 4 weeks of both zibotentan and dapagliflozin. Between treatment periods there is a 4-week wash-out.

Group Type: EXPERIMENTAL

Zibotentan

Intervention Type: DRUG

Zibotentan 1.5 mg once per day as a hard capsule.

Dapagliflozin

Intervention Type: DRUG

Dapagliflozin 10 mg once per day as a tablet.

Placebo

Intervention Type: DRUG

Matching placebo.

Dapagliflozin and Zibotentan

Intervention Type: DRUG

Dapagliflozin 10 mg once per day as a tablet in combination with zibotentan 1.5 mg once per day as a hard capsule.

Interventions

Zibotentan

Zibotentan 1.5 mg once per day as a hard capsule.

Intervention Type: DRUG

Dapagliflozin

Dapagliflozin 10 mg once per day as a tablet.

Intervention Type: DRUG

Placebo

Matching placebo.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Eligibility 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

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 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

University Medical Center Groningen

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hiddo J Lambers Heerspink, PhD, PharmD

Role: PRINCIPAL_INVESTIGATOR

University Medical Center Groningen

Locations

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

Amsterdam Universitair Academisch Centrum

Amsterdam, North Holland, Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Center for Cardiovascular Science

Edinburgh, , United Kingdom

Countries

United States; Canada; Denmark; Netherlands; United Kingdom

Related Links

https://doi.org/10.1016/j.kint.2020.09.026

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

Other Identifiers

2021-001324-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

202100178

Identifier Type: -

Identifier Source: org_study_id