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

• ClinicalTrials.gov Identifier: NCT05570305
• Recruitment Status: Enrolling by invitation
• First Posted: October 6, 2022
• Last Update Posted: September 29, 2023
• Sponsor: University Medical Center Groningen
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Hiddo Lambers Heerspink, University Medical Center Groningen

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Diseases	Drug: Zibotentan; Drug: Dapagliflozin; Drug: Placebo; Drug: Dapagliflozin and Zibotentan	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The first and second treatment period are double-blind, whereas the final and third treatment period (dapagliflozin and zibotentan) is open-label.
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 6, 2022
• Estimated Primary Completion Date: April 1, 2024
• Estimated Study Completion Date: September 1, 2024

Arms and Interventions

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: Zibotentan; Zibotentan 1.5 mg once per day as a hard capsule.; Drug: Dapagliflozin; Dapagliflozin 10 mg once per day as a tablet.; Drug: Placebo; Matching placebo.; 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: Zibotentan; Zibotentan 1.5 mg once per day as a hard capsule.; Drug: Dapagliflozin; Dapagliflozin 10 mg once per day as a tablet.; Drug: Placebo; Matching placebo.; 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.

Outcome Measures

Primary Outcome Measures :

1. Change from baseline in albuminuria after 4 weeks combined zibotentan and dapagliflozin treatment versus four weeks treatment with zibotentan alone. [ Time Frame: 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. ]
   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.

Secondary Outcome Measures :

1. Change in Extracellular Fluid [ Time Frame: 4 weeks ]
   Extracellular Fluid measured by bioimpedance spectroscopy
2. Change in bodyweight [ Time Frame: 4 weeks ]
   Change in kilograms
3. Change in NT-proBNP [ Time Frame: 4 weeks ]
   N-terminal B-type natriuretic peptide (NT-proBNP)
4. Change in BNP [ Time Frame: 4 weeks ]
   B-type natriuretic peptide (BNP)
5. Change in Glomerular Filtration Rate (GFR) [ Time Frame: 4 weeks ]
   Glomerular Filtration Rate (GFR) using iohexol clearance techniques.
6. Change in Extracellular volume (ECV) [ Time Frame: 4 weeks ]
   Extracellular volume (ECV) using iohexol clearance techniques.
7. Change in hematocrit [ Time Frame: 4 weeks ]
   The percentage of red blood cells in blood
8. Change in systolic and diastolic blood pressure [ Time Frame: 4 weeks ]
   Change in blood pressure as measure in mmHg

Other Outcome Measures:

1. Change in renin-angiotensin-aldosterone system (RAAS) markers [ Time Frame: 4 weeks ]
   Change in RAAS markers in plasma and urine
2. Change in copeptin [ Time Frame: 4 weeks ]
   Change in copeptin as a surrogate of vasopressin

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Colorado

Anschutz Medical Campus

Aurora, Colorado, United States, 80045

Canada, Ontario

Toronto General Hospital

Toronto, Ontario, Canada, M5G 2N2

Canada, Quebec

Montreal Clinical Research Institute

Montreal, Quebec, Canada, H2W 1R7

Denmark

Steno Diabetes Center

Copenhagen, Gentoft, Denmark, DK-2820

Netherlands

Amsterdam Universitair Academisch Centrum

Amsterdam, Noord Holland, Netherlands, 1081 HV

University Medical Center Groningen

Groningen, Netherlands

United Kingdom

Center for Cardiovascular Science

Edinburgh, United Kingdom, EH16 4TJ

Sponsors and Collaborators

University Medical Center Groningen

AstraZeneca

Investigators

• Principal Investigator: Hiddo J Lambers Heerspink, PhD, PharmD; University Medical Center Groningen

More Information

Additional Information:

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

• Responsible Party: Hiddo Lambers Heerspink, Professor at the Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen
• ClinicalTrials.gov Identifier: NCT05570305
• Other Study ID Numbers: 202100178; 2021-001324-18 ( EudraCT Number )
• First Posted: October 6, 2022
• Last Update Posted: September 29, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Keywords provided by Hiddo Lambers Heerspink, University Medical Center Groningen:

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

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Albuminuria; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Proteinuria; Urination Disorders; Urological Manifestations; Dapagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs