Chronic Kidney DiseasesPhase 2ZODIACNCT05570305
Zibotentan and Dapagliflozin in Patients With Type 2 Diabetes and Elevated Albuminuria
A Phase 2 study testing Zibotentan, Dapagliflozin and Dapagliflozin and Zibotentan in people with Chronic Kidney Diseases, run by University Medical Center Groningen at 7 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Chronic Kidney Diseases
- What is being tested?
- Zibotentan, Dapagliflozin and Dapagliflozin and Zibotentan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 42 participants
- Where
- 7 sitesin 5 countries
- Study dates
- 6 Oct 2022to 5 Mar 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 31Show fewer
- 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.
Trial locations and contacts
7 sites in 5 countries.
7 sites in 5 countries
Canada2 sites
Montreal Clinical Research Institute
Montreal, Quebec, H2W 1R7
Toronto General Hospital
Toronto, Ontario, M5G 2N2
Netherlands2 sites
Amsterdam Universitair Academisch Centrum
Amsterdam, North Holland, 1081 HV
University Medical Center Groningen
Groningen
United Kingdom1 site
Center for Cardiovascular Science
Edinburgh, EH16 4TJ
About this study
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
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.
Read the 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.
- Conditions
- Chronic Kidney Diseases
- Being tested
- Zibotentan, Dapagliflozin, Placebo, Dapagliflozin and Zibotentan
- Keywords
- Diabetic Nephropathies, Albuminuria, Chronic kidney disease, Endothelin receptor antagonists, Sodium Glucose Co Transporter 2 inhibitors
- Medical subject headings
- Renal Insufficiency, Chronic, Diabetic Nephropathies, Albuminuria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZibotentanDrug
Zibotentan 1.5 mg once per day as a hard capsule.
DapagliflozinDrug
Dapagliflozin 10 mg once per day as a tablet.
PlaceboDrug
Matching placebo.
Dapagliflozin and ZibotentanDrug
Dapagliflozin 10 mg once per day as a tablet in combination with zibotentan 1.5 mg once per day as a hard capsule.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Zibotentan; Drug: Dapagliflozin; Drug: Placebo; Drug: Dapagliflozin and Zibotentan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Extracellular Fluid measured by bioimpedance spectroscopy
Measured: 4 weeks
Change in bodyweight
Change in kilograms
Measured: 4 weeks
Change in NT-proBNP
N-terminal B-type natriuretic peptide (NT-proBNP)
Measured: 4 weeks
Change in BNP
B-type natriuretic peptide (BNP)
Measured: 4 weeks
Change in Glomerular Filtration Rate (GFR)
Glomerular Filtration Rate (GFR) using iohexol clearance techniques.
Measured: 4 weeks
Change in Extracellular volume (ECV)
Extracellular volume (ECV) using iohexol clearance techniques.
Measured: 4 weeks
Change in hematocrit
The percentage of red blood cells in blood
Measured: 4 weeks
Change in systolic and diastolic blood pressure
Change in blood pressure as measure in mmHg
Measured: 4 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2022
- Study start6 Oct 2022
- Primary completion5 Mar 2025
- Study completion5 Mar 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Kidney DiseasesStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
- Investigators
- Hiddo J Lambers Heerspink, PhD, PharmD, Principal investigator, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05570305
- Sponsor's protocol ID
- 202100178
- Other IDs
- 2021-001324-18
- Acronym
- ZODIAC
- Status last verified
- Apr 2025
- First submitted
- 5 Oct 2022
- Last updated
- 30 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Hu S, Lee K, He JC, Fan Y. Current Landscape and Emerging Therapeutic Targets in Diabetic Kidney Disease. Clin J Am Soc Nephrol. 2026 Mar 10. doi: 10.2215/CJN.0000001053. Online ahead of print.
PubMed 41805697
Study at a glance
From the registry record, last updated by the sponsor on 30 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05570305
- Acronym / sponsor ID
- ZODIAC / 202100178
- Conditions
- Chronic Kidney Diseases
- Keywords
- Diabetic Nephropathies, Albuminuria, Chronic kidney disease, Endothelin receptor antagonists, Sodium Glucose Co Transporter 2 inhibitors
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 6 Oct 2022 (actual)
- Primary completion
- 5 Mar 2025 (actual)
- Study completion
- 5 Mar 2025 (actual)
- First posted
- 6 Oct 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Treatment order 1 | Experimental | Drug: Zibotentan, Drug: Dapagliflozin, Drug: Placebo, Drug: Dapagliflozin and ZibotentanSubjects 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. |
| Treatment order 2 | Experimental | Drug: Zibotentan, Drug: Dapagliflozin, Drug: Placebo, Drug: Dapagliflozin and ZibotentanSubjects 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (31 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZibotentanZibotentan 1.5 mg once per day as a hard capsule. | Drug | Treatment order 1, Treatment order 2 |
| DapagliflozinDapagliflozin 10 mg once per day as a tablet. | Drug | Treatment order 1, Treatment order 2 |
| PlaceboMatching placebo. | Drug | Treatment order 1, Treatment order 2 |
| Dapagliflozin and ZibotentanDapagliflozin 10 mg once per day as a tablet in combination with zibotentan 1.5 mg once per day as a hard capsule. | Drug | Treatment order 1, Treatment order 2 |
Primary outcome
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.
8 secondary outcomes
Change in Extracellular Fluid
Time frame: 4 weeks
Change in bodyweight
Time frame: 4 weeks
Change in NT-proBNP
Time frame: 4 weeks
Change in BNP
Time frame: 4 weeks
Change in Glomerular Filtration Rate (GFR)
Time frame: 4 weeks
Change in Extracellular volume (ECV)
Time frame: 4 weeks
Change in hematocrit
Time frame: 4 weeks
Change in systolic and diastolic blood pressure
Time frame: 4 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Apr 2025.
- Derived from this study: PubMed 41805697Hu S, Lee K, He JC, Fan Y. Current Landscape and Emerging Therapeutic Targets in Diabetic Kidney Disease. Clin J Am Soc Nephrol. 2026 Mar 10. doi: 10.2215/CJN.0000001053. Online ahead of print.
- New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reductionLink provided by the sponsor.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hiddo J Lambers Heerspink, PhD, PharmD principal investigator
University Medical Center Groningen
7 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Zibotentan, Dapagliflozin and Dapagliflozin and Zibotentan in people with Chronic Kidney Diseases, run by University Medical Center Groningen at 7 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Canada, Netherlands, United States, Denmark, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05570305, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Apr 2025.