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.

NCT05884866 | Completed Phase 2

• 2 other identifiers: CT114-2022-012022-002721-99
• Study Type: interventional
• Target: 103
• Locations: 2 countries
• Sites: 2

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.

Conditions

Chronic Renal Failure; Mechanistic Effects of SGLT2 Inhibition and/ or MR Antagonism on Body Fluid and Electrolyte Homeostatis; Chronic Kidney Disease Stage 3; Electrolyte and Fluid Balance Conditions

Keywords

Chronic kidney disease; Water conservation; SGLT2 inhibitors, dapagliflozin; MR antagonists, balcinrenone; Amino acids; Energy metabolism

Outcome Measures

Primary Outcomes (1)

• To show that treatment with balcinrenone preserves the beneficial dapagliflozin-driven increase in 24h renal glucose excretion

  Change from baseline in 24h urine glucose excretion at day 28

  28 days

Secondary Outcomes (8)

• To demonstrate that the dapagliflozin induced increase in urine solute concentration is not altered by balcinrenone

  28 days

• 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

  28 days

• 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

  28 days

• 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

  28 days

• 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

  28 days

Other Outcomes (3)

• To demonstrate that treatment with dapagliflozin and/or balcinrenone for 4 weeks does not change tissue Na+ content as measured with MRI at 7T

  28 days

• 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

  28 days

• To test the hypothesis that parallel to RAAS activation, patients treated with dapagliflozin show increased 24h urine cortisol excretion independent of parallel balcinrenone treatment

  28 days

Study Arms (4)

Dapagliflozin

ACTIVE COMPARATOR

1 tablet Dapagliflozin 10 mg + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo

Drug: Dapagliflozin 10mg Tab; Drug: Balcinrenone 50mg matching Placebo; Drug: Balcinrenone 100mg matching Placebo

Balcinrenone

EXPERIMENTAL

1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg + 1 tablet Dapagliflozin matching Placebo

Drug: Balcinrenone 50mg Capsule; Drug: Balcinrenone 100mg Capsule; Drug: Dapagliflozin matching Placebo

Dapagliflozin + Balcinrenone

EXPERIMENTAL

1 tablet Dapagliflozin 10mg + 1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg

Drug: Dapagliflozin 10mg Tab; Drug: Balcinrenone 50mg Capsule; Drug: Balcinrenone 100mg Capsule

Placebo

PLACEBO COMPARATOR

1 tablet Dapagliflozin matching Placebo + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo

Drug: Dapagliflozin matching Placebo; Drug: Balcinrenone 50mg matching Placebo; Drug: Balcinrenone 100mg matching Placebo

Interventions

Dapagliflozin 10mg Tab DRUG

see arms

Also known as: Forxiga

Dapagliflozin; Dapagliflozin + Balcinrenone

Balcinrenone 50mg Capsule DRUG

see arms

Balcinrenone; Dapagliflozin + Balcinrenone

Balcinrenone 100mg Capsule DRUG

see arms

Balcinrenone; Dapagliflozin + Balcinrenone

Dapagliflozin matching Placebo DRUG

see arms

Balcinrenone; Placebo

Balcinrenone 50mg matching Placebo DRUG

see arms

Dapagliflozin; Placebo

Balcinrenone 100mg matching Placebo DRUG

see arms

Dapagliflozin; Placebo

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Klinikum Nürnberg: lead

Study Sites (2)

Assistance Publique-Hopitaux de Marseille (AP-HM)

Marseille, 13005, France

Location

Klinikum Nuernberg

Nuremberg, Bavaria, 90419, Germany

Location

Related Publications (4)

• Marton A, Kaneko T, Kovalik JP, Yasui A, Nishiyama A, Kitada K, Titze J. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol. 2021 Jan;17(1):65-77. doi: 10.1038/s41581-020-00350-x. Epub 2020 Oct 1.

  PMID: 33005037 BACKGROUND

• Kovarik JJ, Morisawa N, Wild J, Marton A, Takase-Minegishi K, Minegishi S, Daub S, Sands JM, Klein JD, Bailey JL, Kovalik JP, Rauh M, Karbach S, Hilgers KF, Luft F, Nishiyama A, Nakano D, Kitada K, Titze J. Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure. Acta Physiol (Oxf). 2021 May;232(1):e13629. doi: 10.1111/apha.13629. Epub 2021 Mar 7.

  PMID: 33590667 BACKGROUND

• Wild J, Jung R, Knopp T, Efentakis P, Benaki D, Grill A, Wegner J, Molitor M, Garlapati V, Rakova N, Marko L, Marton A, Mikros E, Munzel T, Kossmann S, Rauh M, Nakano D, Kitada K, Luft F, Waisman A, Wenzel P, Titze J, Karbach S. Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. Acta Physiol (Oxf). 2021 May;232(1):e13628. doi: 10.1111/apha.13628. Epub 2021 Feb 23.

  PMID: 33590724 BACKGROUND

• Kitada K, Daub S, Zhang Y, Klein JD, Nakano D, Pedchenko T, Lantier L, LaRocque LM, Marton A, Neubert P, Schroder A, Rakova N, Jantsch J, Dikalova AE, Dikalov SI, Harrison DG, Muller DN, Nishiyama A, Rauh M, Harris RC, Luft FC, Wassermann DH, Sands JM, Titze J. High salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation. J Clin Invest. 2017 May 1;127(5):1944-1959. doi: 10.1172/JCI88532. Epub 2017 Apr 17.

  PMID: 28414295 BACKGROUND

MeSH Terms

Conditions

Kidney Failure, Chronic; Renal Insufficiency, Chronic

Interventions

dapagliflozin

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Adriana Marton, MD

  Klinikum Nuernberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: double-blind, double-dummy
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 4-arm, double-blind, double-dummy, parallel-group

Study Record Dates

• First Submitted: May 9, 2023
• First Posted: June 1, 2023
• Study Start: July 13, 2023
• Primary Completion: December 29, 2025
• Study Completion: January 28, 2026
• Last Updated: April 27, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: 2 years after article publication with no end date
• Access Criteria: Access will be granted upon reasonable request, provided that interested researchers have a scientific hypothesis for which they submit a methodologically sound proposal, including clearly defined research hypothesis and a statistical analysis plan. To gain access, data requesters must comply with applicable ethical and data protection regulations. Proposals should be directed to the Principal Investigator (Adriana Marton) and/or Data Manager (Jens Titze) via email.

Locations

FR (1); DE (1)