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

Sponsor

University Medical Center Groningen (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT05570305

Collaborator

AstraZeneca (Industry)

Enrollment

Locations

Arms

10.8

Anticipated Duration (Months)

6.3

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

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:

Zibotentan 1.5 mg once daily + Dapagliflozin 10 mg once daily.
Zibotentan 1.5 mg once daily.
Dapagliflozin 10 mg once daily.
Placebo once daily.

Study Design

Study Type:

Interventional

Anticipated 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 :

Oct 6, 2022

Anticipated Primary Completion Date :

Sep 1, 2023

Anticipated Study Completion Date :

Sep 1, 2023

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.

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

Change from baseline in albuminuria after 4 weeks combined zibotentan and dapagliflozin treatment versus four weeks treatment with zibotentan alone. [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

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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
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 as per the treating physician's judgment.
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 4.2) within 6 weeks of screening will not be allowed.
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 evidence of such abuse as indicated by the laboratory assays conducted during the screening 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

	Site	City	State	Country	Postal Code
1	Anschutz Medical Campus	Aurora	Colorado	United States	80045
2	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2N2
3	Montreal Clinical Research Institute	Montreal	Quebec	Canada	H2W 1R7
4	Steno Diabetes Center	Copenhagen	Gentoft	Denmark	DK-2820
5	Amsterdam Universitair Academisch Centrum	Amsterdam	Noord Holland	Netherlands	1081 HV
6	Center for Cardiovascular Science	Edinburgh		United Kingdom	EH16 4TJ