Comparison of zibotentan/dapagliflozin with dapagliflozin alone in the treatment of chronic kidney disease with high proteinuria

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    What is this study about?

    The study aims to understand how to better treat people with chronic kidney disease (CKD) and high proteinuria. This study is in its third phase and involves multiple centers where participants will be closely monitored. The main goal is to compare the effectiveness, safety, and how well participants tolerate a combination treatment of zibotentan/dapagliflozin versus dapagliflozin alone.

    During this study, participants will be randomly assigned to one of two groups. One group will receive the combination of zibotentan and dapagliflozin, while the other group will receive only dapagliflozin. Both treatments aim to slow down the decline in kidney function, which is a major concern for people with CKD and high proteinuria. The key measure of success for this study is the change in eGFR from baseline, which is a test used to check how well the kidneys are working, specifically by measuring the estimated glomerular filtration rate (eGFR). This will be assessed at the 24-month mark of the study.

    This research is crucial because it could lead to better treatment options for those suffering from CKD and high proteinuria, potentially improving their quality of life and health outcomes.

    Learn more about this Trial

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      Locations

      Where does the clinical trial take place?

      Feldkirch , Austria

      Wien , Austria

      Dobrich , Bulgaria

      Pleven , Bulgaria

      Plovdiv , Bulgaria

      Sofia , Bulgaria

      Stara Zagora , Bulgaria

      Aalborg , Denmark

      Aarhus , Denmark

      Herlev , Denmark

      Herning , Denmark

      Roskilde , Denmark

      La Tronche , France

      Mulhouse , France

      Nice , France

      Nimes , France

      Rouen , France

      St-Priest-en-Jarez , France

      Strasbourg , France

      Tours , France

      Aachen , Germany

      Bad Oeynhausen , Germany

      Berlin , Germany

      Geilenkirchen , Germany

      Hannover , Germany

      Ku00f6ln , Germany

      Ku00f6ln , Germany

      Mainz , Germany

      Mu00fcnchen , Germany

      Bergamo , Italy

      Bologna , Italy

      Foggia , Italy

      Genoa , Italy

      Napoli , Italy

      Pisa , Italy

      Roma , Italy

      Torino , Italy

      Viterbo , Italy

      Amersfoort , Netherlands

      Breda , Netherlands

      Dordrecht , Netherlands

      Bodu00f8 , Norway

      Lu00f8renskog , Norway

      Oslo , Norway

      Stavanger , Norway

      Tromsu00f8 , Norway

      Chrzanu00f3w , Poland

      Krakow , Poland

      Kraku00f3w , Poland

      Lublin , Poland

      Poznau0144 , Poland

      Radom , Poland

      Rzeszu00f3w , Poland

      Szczecin , Poland

      Warszawa , Poland

      u0141u00f3du017a , Poland

      Kosice , Slovakia

      Lucenec , Slovakia

      Presov , Slovakia

      Puchov , Slovakia

      Roznava , Slovakia

      Trebiu0161ov , Slovakia

      Girona , Spain

      L’Hospitalet de Llobregat , Spain

      Lugo , Spain

      Madrid , Spain

      Majadahonda , Spain

      Sevilla , Spain

      Valencia , Spain

      Gu00f6teborg , Sweden

      Linku00f6ping , Sweden

      Ru00e4ttvik , Sweden

      Stockholm , Sweden

      Uppsala , Sweden

      Cardiff , United Kingdom

      Glasgow , United Kingdom

      London , United Kingdom

      London , United Kingdom

      London , United Kingdom

      York , United Kingdom


      Study Steps

      How Complex Will My Study Be and What Phases Will I Go Through?

      Here are the steps and timeline you can expect as a participant:

      1. Screening and Enrollment:
      – Before starting the trial, you will go through a screening process to ensure you meet the eligibility criteria. This includes being at least 18 years of age, having a diagnosis of Chronic Kidney Disease (CKD) with specific eGFR and proteinuria levels, and meeting other health and safety requirements.
      – You must provide signed informed consent before participating in any study-specific procedures.

      2. Randomization:
      – Once enrolled, you will be randomly assigned to one of two groups:
      – Experimental Group: You will receive a daily oral dose of Zibotentan/Dapagliflozin in a fixed-dose combination. The specific dose (dose A or B) will be determined based on your eGFR values.
      – Active Comparator Group:You will receive a daily oral dose of Dapagliflozin alone.

      3. Treatment Period:
      – The treatment will be administered over a period, with the primary completion date estimated to be in June 2027. This suggests that the active phase of the trial, where participants are receiving the treatment and being monitored, could last for several years.
      – During this time, your kidney function, proteinuria levels, blood pressure, and other health indicators will be closely monitored to assess the treatment’s efficacy and safety.

      4. Follow-Up and Assessments:
      – Throughout the trial, you will have regular visits to the study site for health assessments, which include measuring changes in eGFR, urine protein to creatinine ratio (UPCR), albuminuria, and blood pressure from baseline at specified intervals.
      – The primary outcome measure will be evaluated at month 24, indicating a key assessment point for the study’s main objectives.

      5. Completion:
      – The study is estimated to complete in June 2027. At the end of the study, there will be a final assessment of all health outcomes, and you may be involved in follow-up activities to monitor any long-term effects of the treatment.

      It’s important to note that participation in a clinical trial is voluntary, and you can withdraw at any time. The trial team will provide you with all the necessary information and support throughout the study.


      Diseases Under Investigation

      What Conditions Qualify Me for This Study?

      Chronic Kidney Disease With High Proteinuria: This condition involves long-term damage to the kidneys that can get worse over time. It’s often associated with a decrease in kidney function. High proteinuria means there is a significant amount of protein in the urine, which is a sign that the kidneys are not working properly. Proteinuria can lead to further kidney damage and increase the risk of kidney failure.


      Terms and conditions

      What Requirements I Have to Meet To Join This Study?

      When Am I Eligible to Join the Study?

      Here’s a simplified list of the conditions you must meet to join the study, with explanations for any medical terms:

      1. Age 18 or older: You must be at least 18 years old and of legal age to consent to participate in the study where it’s being conducted.
      2. Diagnosis of CKD with specific eGFR and UACR/UPCR levels: You must have chronic kidney disease (CKD), which is defined by having an estimated Glomerular Filtration Rate (eGFR) between 20 and 90 mL/min/1.73 m2, and either a Urine Albumin to Creatinine Ratio (UACR) greater than 700 mg/g or a Urine Protein to Creatinine Ratio (UPCR) greater than 1000 mg/g.
        • eGFR (estimated Glomerular Filtration Rate): This is a test that measures your kidney function and estimates the blood flow through your kidneys. The value indicates how well your kidneys are cleaning your blood.
        • UACR (Urine Albumin to Creatinine Ratio): This test measures the ratio of albumin (a type of protein) to creatinine (a waste product) in your urine. It helps to detect kidney damage.
        • UPCR (Urine Protein to Creatinine Ratio): Similar to UACR, this test measures the ratio of total protein to creatinine in your urine, indicating kidney health.
      3. Negative serum pregnancy test for females: If you are a female participant, you must have a negative blood test for pregnancy at the time of screening.
      4. Birth control for females of childbearing potential: If you are a female capable of becoming pregnant, you must use at least one highly effective method of birth control for at least 3 months before the first dose of the study intervention.
      5. Ability to give informed consent: You must be capable of understanding and willing to sign the informed consent document, which explains the study, its procedures, and its risks.
      6. Consent for optional studies: You must provide consent for optional parts of the study, such as the Study Participant Feedback Questionnaire and the Optional Genomics Initiative Research, if you choose to participate in them.
      7. Stable RAASi therapy: You must be receiving Renin-Angiotensin-Aldosterone System inhibitor (RAASi) therapy, such as ACE inhibitors or ARBs, at the maximum tolerated labeled daily dose, and it must have been stable for at least 4 weeks. RAASi therapy is used to treat high blood pressure and heart failure by relaxing blood vessels and reducing blood volume, which makes it easier for the heart to pump blood.

      These criteria are designed to ensure that participants are suitable for the study and to maintain their safety throughout the trial.

      What Reasons Could Exclude Me from the Study?

      Here is a list of diseases that prevent you from taking part in the study:

      1. Participants with NYHA class III or class IV Congestive Heart Failure (HF) at the time of enrolment. NYHA class III and IV refer to more severe symptoms of heart failure that significantly limit physical activity or occur at rest.
      2. Participants hospitalised for HF during the last 6 months prior to screening.
      3. Evidence of rales or jugular venous distention on physical examination. Rales are a crackling, clicking, or rattling sound in the lungs, and jugular venous distention is swelling of the neck veins, both signs of heart problems.
      4. Participants with type 1 diabetes mellitus.
      5. History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal). Ventricular dysrhythmias are abnormal heart rhythms originating from the lower chambers of the heart, which can be life-threatening.
      6. Blood pressure above 160 mmHg systolic or below 90 mmHg systolic.
      7. Participants hospitalised for heart disease or cardiac procedures or for COVID-19 during the last 3 months prior to screening.
      8. History of solid organ transplantation or bone marrow transplant.
      9. History or ongoing allergy/hypersensitivity, as judged by the Investigator, to SGLT2i therapy (e.g., dapagliflozin, canagliflozin, empagliflozin or other SGLT2 inhibitors) or Endothelin Receptor Antagonists (e.g., ambrisentan, atrasentan, bosentan, or other). SGLT2 inhibitors are a class of medications used to lower blood sugar levels in people with diabetes.
      10. Any condition with a life expectancy of less than 2 years based on investigator´s clinical judgment.
      11. Malignancy within the past 5 years. Exceptions to this criterion include non-melanoma skin cancer and curatively treated cervical carcinoma in situ.
      12. Significant liver disease as judged by the investigator or severe hepatic impairment with AST or ALT > 3 × ULN; or total bilirubin > 2 × ULN at time of screening. AST and ALT are enzymes measured to assess liver function; ULN stands for Upper Limit of Normal.
      13. Known blood-borne diseases.
      14. Clinically significant, unstable, or uncontrolled medical condition as assessed by the Investigator.
      15. Participants on renal replacement therapy or previous kidney transplant.
      16. Known history of drug or alcohol abuse within 12 months of screening.
      17. Participants on treatment with strong or moderate CYP3A4 inducer. CYP3A4 inducers are substances that can increase the activity of the CYP3A4 enzyme, affecting the metabolism of certain drugs.
      18. Participants on systemic immunosuppression therapy other than stable maintenance therapy defined as prednisone 10 mg/day (or equivalent) or less, aziothioprine 100 mg/day or less; MMF 1000 mg/day or less for at least 3 months prior to Visit 1.
      19. Participants treated or expecting to be treated with tolvaptan, any other ERAs, or budesonide (where used to treat IBD or IgAN). ERAs stand for Endothelin Receptor Antagonists, a class of medication.

      These criteria are in place to ensure the safety of participants and the integrity of the study results.


      Investigational Medicinal Product

      What Products Are Being Used in This Study?

      In this study, the drugs involved are:

      1. Zibotentan/Dapagliflozin: This is a combination of two active substances. Zibotentan is an endothelin receptor antagonist, which means it blocks the action of endothelin-1, a molecule that can cause blood vessels to narrow. This can be beneficial in conditions like chronic kidney disease (CKD) where managing blood flow and pressure is important. Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. It works by preventing the kidneys from reabsorbing glucose back into the blood, leading to its excretion through urine. This mechanism can help in controlling blood sugar levels and also has benefits for heart and kidney health. In this study, the combination of zibotentan and dapagliflozin is being investigated for its potential to treat CKD and high proteinuria by offering both vascular and glycemic control.
      2. Dapagliflozin: As mentioned, dapagliflozin is an SGLT2 inhibitor. It helps in reducing blood glucose levels by promoting the excretion of glucose through urine. It is being used alone as a comparator in this study to evaluate the added benefits of combining it with zibotentan for treating CKD and high proteinuria.

      The role of each drug in the study is to assess their effectiveness in slowing the progression of chronic kidney disease and reducing proteinuria, with a focus on comparing the efficacy of the combination therapy against dapagliflozin alone.

      Have the Medicinal Substances Used in the Trial Been Previously Studied in Medicine?

      • Zibotentan/Dapagliflozin: This combination is under investigation in the clinical trial. Zibotentan is known in the medical literature primarily for its potential in treating conditions related to endothelin receptor antagonism. Dapagliflozin is well-known and widely used as a sodium-glucose co-transporter 2 (SGLT2) inhibitor for the treatment of diabetes mellitus type 2.
      • Dapagliflozin: Dapagliflozin is a well-established medication in the medical community. Its efficacy and safety profile are well-documented in medical literature, making it a known entity in medicine.

      Study ID

      CT-EU-00115076

      Recruitment status

      Recruting new patients

      Start of the trial

      8 months ago

      Study phase

      Phase
      III