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A Study to Investigate the Mechanistic Effects of Dapagliflozin Alone or in Combination With Balcinrenone, Compared to Balcinrenone and Placebo on Body Fluid and Electrolyte Handling and Energy Metabolism in Participants Over 50 Years of Age With Chronic Kidney Disease. (DapaBalci-Leap)

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ClinicalTrials.gov Identifier: NCT05884866
Recruitment Status : Recruiting
First Posted : June 1, 2023
Last Update Posted : November 18, 2023
Sponsor:
Information provided by (Responsible Party):
Adriana Marton, Klinikum Nürnberg

Brief Summary:

The purpose of this study is to investigate the mechanistic effects of dapagliflozin 10 mg, alone or in combination with balcinrenone 150 mg, with balcinrenone 150 mg and placebo, on the way the body handles electrolytes and water content, as well as the effects these interventions may have on energy metabolism in participants with stage 3 chronic kidney disease. The study interventions will be administered orally, daily, in addition to current therapy, for a duration of 28 days. This will allow us to maximize our ability to detect a drug effect while minimizing the drop-out rate that accompanies longer studies. In order to understand the different mechanistic effects of these interventions on energy metabolism, the study will be conducted at two study sites. The study design and treatment allocation, treatment duration as well as sample analysis for evaluation of the primary endpoint will be identical for all participants, at both sites. Therefore, urine and plasma samples for analysis of water and electrolyte handling will be collected from all study participants at both sites.

In addition to the primary endpoint, the main study site (Nuremberg) will conduct a metabolic study to investigate the early- and late-effects of the interventions, while the second site, Marseille, will conduct an imaging sub-study to assess changes at the tissue level before and after treatment.


Condition or disease Intervention/treatment Phase
Chronic Renal Failure Mechanistic Effects of SGLT2 Inhibition and/ or MR Antagonism on Body Fluid and Electrolyte Homeostatis Drug: Dapagliflozin 10mg Tab Drug: Balcinrenone 50mg Capsule Drug: Balcinrenone 100mg Capsule Drug: Dapagliflozin matching Placebo Drug: Balcinrenone 50mg matching Placebo Drug: Balcinrenone 100mg matching Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 4-arm, double-blind, double-dummy, parallel-group
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: double-blind, double-dummy
Primary Purpose: Treatment
Official Title: Natriuretic-ureothelic Adaptation of Body Fluid Homeostasis During SGLT-2 Inhibition and/or Mineralocorticoid Receptor Modulation in Patients With Chronic Kidney Disease. A 4-arm, Double-blind, Double-dummy, Parallel-group, Phase 2 Study to Investigate the Mechanistic Effects of Dapagliflozin, Dapagliflozin + Balcinrenone, Balcinrenone and Placebo on Body Solute and Water Homeostasis and Energy Metabolism in Male and Female Participants Over 50 Years of Age With Chronic Kidney Disease.
Actual Study Start Date : May 8, 2023
Estimated Primary Completion Date : January 31, 2025
Estimated Study Completion Date : January 31, 2025


Arm Intervention/treatment
Active Comparator: Dapagliflozin
1 tablet Dapagliflozin 10 mg + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
Drug: Dapagliflozin 10mg Tab
see arms
Other Name: Forxiga

Drug: Balcinrenone 50mg matching Placebo
see arms

Drug: Balcinrenone 100mg matching Placebo
see arms

Experimental: Balcinrenone
1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg + 1 tablet Dapagliflozin matching Placebo
Drug: Balcinrenone 50mg Capsule
see arms

Drug: Balcinrenone 100mg Capsule
see arms

Drug: Dapagliflozin matching Placebo
see arms

Experimental: Dapagliflozin + Balcinrenone
1 tablet Dapagliflozin 10mg + 1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg
Drug: Dapagliflozin 10mg Tab
see arms
Other Name: Forxiga

Drug: Balcinrenone 50mg Capsule
see arms

Drug: Balcinrenone 100mg Capsule
see arms

Placebo Comparator: Placebo
1 tablet Dapagliflozin matching Placebo + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
Drug: Dapagliflozin matching Placebo
see arms

Drug: Balcinrenone 50mg matching Placebo
see arms

Drug: Balcinrenone 100mg matching Placebo
see arms




Primary Outcome Measures :
  1. To show that treatment with balcinrenone preserves the beneficial dapagliflozin-driven increase in 24h renal glucose excretion [ Time Frame: 28 days ]
    Change from baseline in 24h urine glucose excretion at day 28


Secondary Outcome Measures :
  1. To demonstrate that the dapagliflozin induced increase in urine solute concentration is not altered by balcinrenone [ Time Frame: 28 days ]
    Change from baseline in urine osmolality at day 3 and day 28

  2. To demonstrate that treatment with dapagliflozin, with or without balcinrenone reduces free-water clearance within 48h, and further urine concentration is observed after 4 weeks [ Time Frame: 28 days ]
    Change from baseline in free water clearance at day 3 and day 28

  3. To demonstrate that treatment with dapagliflozin, with or without balcinrenone, increases the contribution of glucose to osmoticdiuretic volume formation within 48h, and that this effect persists after 4 weeks [ Time Frame: 28 days ]
    Change from baseline in urine glucose fraction at day 3 and day 28

  4. To demonstrate that treatment with dapagliflozin, with or without balcinrenone, decreases the contribution of sodium and urea to osmotic-diuretic volume formation within 48h, and that this effect persists after 4 weeks [ Time Frame: 28 days ]
    Change from baseline in urine sodium fraction at day 3 and day 28; Change from baseline in urine urea fraction at day 3 and day 28

  5. To demonstrate that treatment with dapagliflozin, with or without balcinrenone, does not change the contribution of potassium to osmotic-diuretic volume formation within 48h, and that this effect persists after 4 weeks [ Time Frame: 28 days ]
    Change from baseline in urine potassium fraction at day 3 and day 28

  6. To demonstrate that treatment with dapagliflozin with or without balcinrenone does not change body water content after 4 weeks [ Time Frame: 28 days ]
    Change from baseline in muscle water content as measured at 7T MRI at day 28

  7. To demonstrate that patients treated with dapagliflozin alone or in combination with balcinrenone show increased plasma copeptin levels within 48h and/or after 4 weeks [ Time Frame: 28 days ]
    Change from baseline in copeptin levels at day 3 and day 28

  8. To demonstrate that patients treated with dapagliflozin alone or in combination balcinrenone show increased plasma glucagon and reduced plasma insulin levels within 48h and/or after 4 weeks [ Time Frame: 28 days ]
    Change from baseline in plasma insulin/glucagon ratio at day 3 and day 28


Other Outcome Measures:
  1. To demonstrate that treatment with dapagliflozin and/or balcinrenone for 4 weeks does not change tissue Na+ content as measured with MRI at 7T [ Time Frame: 28 days ]
    Change from baseline in tissue Na+ content at day 28

  2. To demonstrate that treatment with dapagliflozin with or without balcinrenone will increase muscle nitrogen transfer and induce pH changes during the rest-exercise-recovery period [ Time Frame: 28 days ]
    Change from baseline in pH levels levels at day 28 as quantified with 31P spectroscopy at 3T MRI

  3. To test the hypothesis that parallel to RAAS activation, patients treated with dapagliflozin show increased 24h urine cortisol excretion independent of parallel balcinrenone treatment [ Time Frame: 28 days ]
    Change from baseline in 24h urine cortisol levels at day 3 and day 28



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of chronic kidney disease, with eGFR ≥30 and ≤60 mL/min/1.73m2
  • Serum/ plasma K+ levels ≥ 3.5 and < 5.0 mmol/L OR within normal laboratory ranges when these are provided, within 2 weeks prior to randomization
  • Serum/plasma Na+ levels within normal reference values within 2 weeks prior to randomization
  • If participants have type 2 diabetes mellitus, treatment with metformin, sulphonylureas, DPP4 inhibitors or any combinations of these agents with or without insulin would be accepted but is not mandatory. If used, stable dose of metformin, sulphonylureas, or DPP4 inhibitors or their combination as anti-diabetic therapy for the 12 weeks prior to randomization is required
  • No changes in background treatment for at least 3 weeks prior to randomization
  • Body mass index less than 40 kg/m2
  • Negative pregnancy test (urine or serum) for female subjects of childbearing potential and willingness to use a highly effective birth control (see Appendix 4) if of childbearing potential.
  • Willingness to participate and ability to provide signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

  • Diagnosis of type 1 diabetes mellitus
  • Uncontrolled type 2 diabetes mellitus with HbA1C > 10.5% in the most recent medical records
  • Participants with type 2 diabetes mellitus treated with insulin if insulin dosing (intermediate, long-acting, premixed insulin, basal bolus insulin) was not stable in the 12 weeks prior to randomization as judged by the Investigator
  • Patients with systolic blood pressure levels <100 mmHg at the time of enrolment
  • Patients with congestive heart failure NYHA stage IV or hospitalized for decompensation of heart failure in the 3 months prior to screening
  • History of any life-threatening cardiac arrhythmias, or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter
  • Acute coronary syndrome and/or percutaneous cardiac interventions within 3 months prior to screening
  • Unstable or rapidly progressing renal disease
  • Chronic cystitis and recurrent genital or urinary tract infections
  • Significant hepatic disease, including hepatitis and/or liver cirrhosis (Child-Pugh class A-C), or AST or ALT > 2 × ULN (upper limit of normal); or total bilirubin levels (TBL) > 2 × ULN; or serum albumin levels < 3.5 g/dL
  • Medical conditions associated with development of hyperkalemia (Addison's disease)
  • Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within 3 months prior to screening
  • Hemoglobin levels below 8.5 g/dL or over 15 g/dL OR over the normal laboratory ranges, when these are provided
  • Patients who have received an organ transplant at any time or bone marrow transplant in the previous 10 years
  • HIV infection
  • Active cancer, history of bladder cancer
  • Patients who have had major surgery in the 3 months prior to screening
  • Patients with muscular dystrophies
  • Patients who have severe comorbid conditions likely to compromise survival or study participation
  • Pregnant and breast-feeding women
  • Medical treatment with either a mineralocorticoid receptor antagonist (MRA) or a sodium-glucose co-transporter-2 inhibitor (SGLT2i) within 3 months prior to screening
  • Medical treatment with potassium binders
  • Medical treatment with strong or moderate CYP3A4 inducers or inhibitors
  • Prior serious hypersensitivity reaction to dapagliflozin (Forxiga®), balcinrenone or to any of their excipients
  • Treatment with cytotoxic therapy, immunosuppressive therapy or other immunotherapy within 6 months prior to screening
  • Unwillingness or other inability to cooperate
  • For patients undergoing MRI scans, presence of implanted devices (surgical clips, heart pacemakers or defibrillators, cochlear implants), iron-based tattoos, any other pieces of metal or devices that are not MR-safe anywhere in the body

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05884866


Contacts
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Contact: Dominik Zaremba +499113985403 dominik.zaremba@klinikum-nuernberg.de

Locations
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France
Assistance Publique-Hopitaux de Marseille (AP-HM) Recruiting
Marseille, France, 13005
Contact: Joelle Rakotomavo    +33 491381338    joelle.rakotomavo@ap-hm.fr   
Principal Investigator: Stephane Burtey, MD         
Germany
Klinikum Nuernberg Recruiting
Nuremberg, Bavaria, Germany, 90419
Contact: Adriana Marton, MD       adriana.marton@klinikum-nuernberg.de   
Contact: Dominik Zaremba, MD    +4917681673788    dominik.zaremba@klinikum-nuernberg.de   
Principal Investigator: Adriana Marton, MD         
Sub-Investigator: Roland Veelken, Prof.         
Sub-Investigator: Dominik Zaremba, MD         
Sponsors and Collaborators
Klinikum Nürnberg
Investigators
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Principal Investigator: Adriana Marton, MD Klinikum Nuernberg
Publications:

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Responsible Party: Adriana Marton, Principal Investigator, Klinikum Nürnberg
ClinicalTrials.gov Identifier: NCT05884866    
Other Study ID Numbers: CT114-2022-01
2022-002721-99 ( EudraCT Number )
First Posted: June 1, 2023    Key Record Dates
Last Update Posted: November 18, 2023
Last Verified: November 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Adriana Marton, Klinikum Nürnberg:
Chronic kidney disease
Water conservation
SGLT2 inhibitors, dapagliflozin
MR antagonists, balcinrenone
Amino acids
Energy metabolism
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Kidney Failure, Chronic
Urologic Diseases
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Male Urogenital Diseases
Renal Insufficiency
Chronic Disease
Disease Attributes
Pathologic Processes
Dapagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs