Zibotentan and Dapagliflozin in Patients With Type 2 Diabetes and Elevated Albuminuria (ZODIAC)

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Drug: Placebo; Drug: Zibotentan; Drug: Dapagliflozin; Drug: Dapagliflozin and Zibotentan

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.

• Study Type: Interventional
• Enrollment (Estimated): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2W 1R7
      • Montreal Clinical Research Institute
• Denmark
  • Gentoft
    • Copenhagen, Gentoft, Denmark, DK-2820
      • Steno Diabetes center
• Netherlands
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands, 1081 HV
      • Amsterdam Universitair Academisch Centrum
• United Kingdom
  • Edinburgh, United Kingdom, EH16 4TJ
    • Center for Cardiovascular Science
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Anschutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Placebo; Matching placebo.; Drug: Zibotentan; Zibotentan 1.5 mg once per day as a hard capsule.; Drug: Dapagliflozin; Dapagliflozin 10 mg once per day as a tablet.; 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.
Experimental: 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.	Drug: Placebo; Matching placebo.; Drug: Zibotentan; Zibotentan 1.5 mg once per day as a hard capsule.; Drug: Dapagliflozin; Dapagliflozin 10 mg once per day as a tablet.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Extracellular Fluid	Extracellular Fluid measured by bioimpedance spectroscopy	4 weeks
Change in bodyweight	Change in kilograms	4 weeks
Change in NT-proBNP	N-terminal B-type natriuretic peptide (NT-proBNP)	4 weeks
Change in BNP	B-type natriuretic peptide (BNP)	4 weeks
Change in Glomerular Filtration Rate (GFR)	Glomerular Filtration Rate (GFR) using iohexol clearance techniques.	4 weeks
Change in Extracellular volume (ECV)	Extracellular volume (ECV) using iohexol clearance techniques.	4 weeks
Change in hematocrit	The percentage of red blood cells in blood	4 weeks
Change in systolic and diastolic blood pressure	Change in blood pressure as measure in mmHg	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in renin-angiotensin-aldosterone system (RAAS) markers	Change in RAAS markers in plasma and urine	4 weeks
Change in copeptin	Change in copeptin as a surrogate of vasopressin	4 weeks

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Hiddo J Lambers Heerspink, PhD, PharmD, University Medical Center Groningen

Publications and helpful links

Helpful 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

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2022
• Primary Completion (Estimated): April 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: October 5, 2022
• First Submitted That Met QC Criteria: October 5, 2022
• First Posted (Actual): October 6, 2022

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 28, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Chronic kidney disease; Diabetic Nephropathies; Albuminuria; Endothelin receptor antagonists; Sodium Glucose Co Transporter 2 inhibitors
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Urological Manifestations; Disease Attributes; Renal Insufficiency; Urination Disorders; Proteinuria; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Albuminuria; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 202100178; 2021-001324-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No