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

Primary Purpose

Chronic Kidney Diseases

Status
Enrolling by invitation
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Zibotentan
Dapagliflozin
Placebo
Dapagliflozin and Zibotentan
Sponsored by
University Medical Center Groningen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Kidney Diseases focused on measuring Diabetic Nephropathies, Albuminuria, Chronic kidney disease, Endothelin receptor antagonists, Sodium Glucose Co Transporter 2 inhibitors

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • Anschutz Medical Campus
  • Toronto General Hospital
  • Montreal Clinical Research Institute
  • Steno Diabetes Center
  • Amsterdam Universitair Academisch Centrum
  • University Medical Center Groningen
  • Center for Cardiovascular Science

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Treatment order 1

Treatment order 2

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Full Information

First Posted
October 5, 2022
Last Updated
September 28, 2023
Sponsor
University Medical Center Groningen
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT05570305
Brief Title
Zibotentan and Dapagliflozin in Patients With Type 2 Diabetes and Elevated Albuminuria
Acronym
ZODIAC
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
October 6, 2022 (Actual)
Primary Completion Date
April 1, 2024 (Anticipated)
Study Completion Date
September 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Medical Center Groningen
Collaborators
AstraZeneca

4. Oversight

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
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Kidney Diseases
Keywords
Diabetic Nephropathies, Albuminuria, Chronic kidney disease, Endothelin receptor antagonists, Sodium Glucose Co Transporter 2 inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
38 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment order 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Treatment order 2
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Zibotentan
Intervention Description
Zibotentan 1.5 mg once per day as a hard capsule.
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin
Intervention Description
Dapagliflozin 10 mg once per day as a tablet.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo.
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin and Zibotentan
Intervention Description
Dapagliflozin 10 mg once per day as a tablet in combination with zibotentan 1.5 mg once per day as a hard capsule.
Primary Outcome Measure Information:
Title
Change from baseline in albuminuria after 4 weeks combined zibotentan and dapagliflozin treatment versus four weeks treatment with zibotentan alone.
Description
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.
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.
Secondary Outcome Measure Information:
Title
Change in Extracellular Fluid
Description
Extracellular Fluid measured by bioimpedance spectroscopy
Time Frame
4 weeks
Title
Change in bodyweight
Description
Change in kilograms
Time Frame
4 weeks
Title
Change in NT-proBNP
Description
N-terminal B-type natriuretic peptide (NT-proBNP)
Time Frame
4 weeks
Title
Change in BNP
Description
B-type natriuretic peptide (BNP)
Time Frame
4 weeks
Title
Change in Glomerular Filtration Rate (GFR)
Description
Glomerular Filtration Rate (GFR) using iohexol clearance techniques.
Time Frame
4 weeks
Title
Change in Extracellular volume (ECV)
Description
Extracellular volume (ECV) using iohexol clearance techniques.
Time Frame
4 weeks
Title
Change in hematocrit
Description
The percentage of red blood cells in blood
Time Frame
4 weeks
Title
Change in systolic and diastolic blood pressure
Description
Change in blood pressure as measure in mmHg
Time Frame
4 weeks
Other Pre-specified Outcome Measures:
Title
Change in renin-angiotensin-aldosterone system (RAAS) markers
Description
Change in RAAS markers in plasma and urine
Time Frame
4 weeks
Title
Change in copeptin
Description
Change in copeptin as a surrogate of vasopressin
Time Frame
4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hiddo J Lambers Heerspink, PhD, PharmD
Organizational Affiliation
University Medical Center Groningen
Official's Role
Principal Investigator
Facility Information:
Facility Name
Anschutz Medical Campus
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Toronto General Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2N2
Country
Canada
Facility Name
Montreal Clinical Research Institute
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H2W 1R7
Country
Canada
Facility Name
Steno Diabetes Center
City
Copenhagen
State/Province
Gentoft
ZIP/Postal Code
DK-2820
Country
Denmark
Facility Name
Amsterdam Universitair Academisch Centrum
City
Amsterdam
State/Province
Noord Holland
ZIP/Postal Code
1081 HV
Country
Netherlands
Facility Name
University Medical Center Groningen
City
Groningen
Country
Netherlands
Facility Name
Center for Cardiovascular Science
City
Edinburgh
ZIP/Postal Code
EH16 4TJ
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Links:
URL
https://doi.org/10.1016/j.kint.2020.09.026
Description
New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reduction

Learn more about this trial

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

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