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

NCT05570305 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: 2021001782021-001324-18
• Study Type: interventional
• Target: 42
• Locations: 5 countries
• Sites: 7

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.

Conditions

Chronic Kidney Diseases

Keywords

Diabetic Nephropathies; Albuminuria; Chronic kidney disease; Endothelin receptor antagonists; Sodium Glucose Co Transporter 2 inhibitors

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Change in Extracellular Fluid

  4 weeks

• Change in bodyweight

  4 weeks

• Change in NT-proBNP

  4 weeks

• Change in BNP

  4 weeks

• Change in Glomerular Filtration Rate (GFR)

  4 weeks

Other Outcomes (2)

• Change in renin-angiotensin-aldosterone system (RAAS) markers

  4 weeks

• Change in copeptin

  4 weeks

Study Arms (2)

Treatment order 1

EXPERIMENTAL

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.

Drug: Zibotentan; Drug: Dapagliflozin; Drug: Placebo; Drug: Dapagliflozin and Zibotentan

Treatment order 2

EXPERIMENTAL

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.

Drug: Zibotentan; Drug: Dapagliflozin; Drug: Placebo; Drug: Dapagliflozin and Zibotentan

Interventions

Zibotentan DRUG

Zibotentan 1.5 mg once per day as a hard capsule.

Treatment order 1; Treatment order 2

Dapagliflozin DRUG

Dapagliflozin 10 mg once per day as a tablet.

Treatment order 1; Treatment order 2

Placebo DRUG

Matching placebo.

Treatment order 1; Treatment order 2

Dapagliflozin and Zibotentan 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 1; Treatment order 2

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:

Sponsors & Collaborators

• University Medical Center Groningen: lead
• AstraZeneca: collaborator

Study Sites (7)

Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

Toronto General Hospital

Toronto, Ontario, M5G 2N2, Canada

Location

Montreal Clinical Research Institute

Montreal, Quebec, H2W 1R7, Canada

Location

Steno Diabetes Center

Copenhagen, Gentoft, DK-2820, Denmark

Location

Amsterdam Universitair Academisch Centrum

Amsterdam, North Holland, 1081 HV, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Center for Cardiovascular Science

Edinburgh, EH16 4TJ, United Kingdom

Location

Related 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

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Diabetic Nephropathies; Albuminuria

Interventions

ZD4054; dapagliflozin

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Proteinuria; Urination Disorders; Urological Manifestations; Signs and Symptoms

Study Officials

• Hiddo J Lambers Heerspink, PhD, PharmD

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The first and second treatment period are double-blind, whereas the final and third treatment period (dapagliflozin and zibotentan) is open-label.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2022
• First Posted: October 6, 2022
• Study Start: October 6, 2022
• Primary Completion: March 5, 2025
• Study Completion: March 5, 2025
• Last Updated: April 30, 2025

Record last verified: 2025-04

Locations

NL (2); US (1); CA (2); DK (1); GB (1)