Clinical trial NCT05570305: Zibotentan and Dapagliflozin in Patients With Type 2 Diabetes and Elevated Albuminuria
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Kidney Diseases
Keywords: Diabetic Nephropathies
Albuminuria
Chronic kidney disease
Endothelin receptor antagonists
Sodium Glucose Co Transporter 2 inhibitors
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2022-10-06
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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:

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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* 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.

Primary outcomes:
measure: Change from baseline in albuminuria after 4 weeks combined zibotentan and dapagliflozin treatment versus four weeks treatment with zibotentan alone.
timeFrame: 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:
measure: Change in Extracellular Fluid
timeFrame: 4 weeks
measure: Change in bodyweight
timeFrame: 4 weeks
measure: Change in NT-proBNP
timeFrame: 4 weeks
measure: Change in BNP
timeFrame: 4 weeks
measure: Change in Glomerular Filtration Rate (GFR)
timeFrame: 4 weeks
measure: Change in Extracellular volume (ECV)
timeFrame: 4 weeks
measure: Change in hematocrit
timeFrame: 4 weeks
measure: Change in systolic and diastolic blood pressure
timeFrame: 4 weeks
Other outcomes:
measure: Change in renin-angiotensin-aldosterone system (RAAS) markers
timeFrame: 4 weeks
measure: Change in copeptin
timeFrame: 4 weeks
Locations:
city: Aurora
country: United States
facility: Anschutz Medical Campus
state: Colorado
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal Clinical Research Institute
state: Quebec
city: Copenhagen
country: Denmark
facility: Steno Diabetes Center
state: Gentoft
city: Amsterdam
country: Netherlands
facility: Amsterdam Universitair Academisch Centrum
state: Noord Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Edinburgh
country: United Kingdom
facility: Center for Cardiovascular Science
Study officials:
affiliation: University Medical Center Groningen
name: Hiddo J Lambers Heerspink, PhD, PharmD
role: PRINCIPAL_INVESTIGATOR
References: