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.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 103
- 试验地点
- 4
- 主要终点
- To show that treatment with balcinrenone preserves the beneficial dapagliflozin-driven increase in 24h renal glucose excretion
研究概览
简要总结
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.
详细描述
The Nuremberg site will perform metabolomics analyses and evaluation of metabolic longevity switches in erythrocytes; participants will be randomly allocated to 1 of the 4 treatment arms, with n=25 participants per arm.
All participants in Nuremberg will undergo 3 study visits: at baseline, day 3 (to study the early effect of the intervention) and at day 28 (for the late metabolic effects). An additional safety study visit will take place at day 7+/-1. A follow-up visit will take place at day 28 +/- 7 after the last dose.
Study procedures: medical examination, height, weight, blood pressure (BP), heart rate (HR), 24h urine collection and analysis, venous blood sampling.
This site will prepare venous blood samples for metabolomic analysis and will perform the erythrocyte isolation protocol for the assessment of erythrocyte metabolism.
The Marseille site will conduct an imaging sub-study to evaluate tissue sodium and water content, and muscle energy metabolism before and after the study intervention; participants will be randomly allocated to 1 of the 4 treatment arms, with n=10 participants per arm.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
double-blind, double-dummy
入排标准
- 年龄范围
- 50 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Balcinrenone
1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg + 1 tablet Dapagliflozin matching Placebo
干预措施: Dapagliflozin matching Placebo (Drug)
Dapagliflozin
1 tablet Dapagliflozin 10 mg + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
干预措施: Dapagliflozin 10mg Tab (Drug)
Dapagliflozin
1 tablet Dapagliflozin 10 mg + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
干预措施: Balcinrenone 50mg matching Placebo (Drug)
Dapagliflozin
1 tablet Dapagliflozin 10 mg + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
干预措施: Balcinrenone 100mg matching Placebo (Drug)
Balcinrenone
1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg + 1 tablet Dapagliflozin matching Placebo
干预措施: Balcinrenone 50mg Capsule (Drug)
Balcinrenone
1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg + 1 tablet Dapagliflozin matching Placebo
干预措施: Balcinrenone 100mg Capsule (Drug)
Dapagliflozin + Balcinrenone
1 tablet Dapagliflozin 10mg + 1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg
干预措施: Dapagliflozin 10mg Tab (Drug)
Dapagliflozin + Balcinrenone
1 tablet Dapagliflozin 10mg + 1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg
干预措施: Balcinrenone 50mg Capsule (Drug)
Dapagliflozin + Balcinrenone
1 tablet Dapagliflozin 10mg + 1 capsule Balcinrenone 50mg + 1 capsule Balcinrenone 100 mg
干预措施: Balcinrenone 100mg Capsule (Drug)
Placebo
1 tablet Dapagliflozin matching Placebo + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
干预措施: Dapagliflozin matching Placebo (Drug)
Placebo
1 tablet Dapagliflozin matching Placebo + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
干预措施: Balcinrenone 50mg matching Placebo (Drug)
Placebo
1 tablet Dapagliflozin matching Placebo + 1 capsule Balcinrenone 50mg matching Placebo + 1 capsule Balcinrenone 100 mg matching Placebo
干预措施: Balcinrenone 100mg matching Placebo (Drug)
结局指标
主要结局
To show that treatment with balcinrenone preserves the beneficial dapagliflozin-driven increase in 24h renal glucose excretion
时间窗: 28 days
Change from baseline in 24h urine glucose excretion at day 28
次要结局
- 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, 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 body water content after 4 weeks(28 days)
- 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(28 days)
- 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(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, does not change the contribution of potassium to osmotic-diuretic volume formation within 48h, and that this effect persists after 4 weeks(28 days)
研究者
Adriana Marton
Principal Investigator
Klinikum Nürnberg