| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage 3 chronic kidney disease |
| Maladie rénale chronique de stade 3 |
|
| E.1.1.1 | Medical condition in easily understood language |
| chronic kidney disease |
| Maladie rénale chronique |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Male diseases of the urinary and reproductive systems [C12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064848 |
| E.1.2 | Term | Chronic kidney disease |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To show that treatment with balcinrenone preserves the beneficial dapagliflozin-driven increase in 24h renal glucose excretion |
| Montrer que le traitement par la balcinrenone préserve l'augmentation bénéfique de l'excrétion rénale de glucose sur 24 heures induite par la dapagliflozine. |
|
| E.2.2 | Secondary objectives of the trial |
Topic 1
To demonstrate that the dapagliflozin-induced increase in urine solute concentration is not altered by balcinrenone
Topic 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, increases the contribution of glucose to osmotic-diuretic volume formation, decreases the contribution of sodium and urea to osmotic-diuretic volume formation, does not change the contribution of potassium to osmotic-diuretic volume formation within 48h, and that this effect persists after 4 weeks and does not change body water content after 4 weeks.
Topic 3
To demonstrate that patients treated with dapagliflozin alone or in combination with balcinrenone show increased plasma copeptin levels and show increased plasma glucagon and reduced plasma insulin levels within 48h and/or after 4 weeks. |
Thème 1:
Démontrer que l'augmentation de la concentration de solutés dans l'urine induite par la dapagliflozine n'est pas modifiée par la balcinrenone.
Thème 2:
Démontrer que le traitement par la dapagliflozine, avec ou sans balcinrenone, réduit la clairance de l'eau libre, augmente la contribution du glucose à la diurèse osmotique, diminue la contribution du sodium et de l'urée à la diurèse osmotique, ne modifie pas la contribution du potassium à la diurèse osmotique dans les 48h et ne modifie pas le contenu en eau de l'organisme après 4 semaines et que ces effet persistent après 4 semaines.
Thème 3:
Démontrer que le traitement par la dapagliflozine, avec ou sans balcinrenone, augmente la concentration plasmatique de copeptine, augmente la concentration plasmatique de glucagon et diminue celle de l'insuline dans les 48h, et que l’effet persiste après 4 semaines.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
• The Nuremberg site will perform metabolomics analyses and evaluation of metabolic longevity switches in erythrocytes
• 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.
Substudies are included in present protocol. |
|
| E.3 | Principal inclusion criteria |
1. Male and female patients over 50 years old
2. Diagnosis of chronic kidney disease, with eGFR ≥30 and ≤60 mL/min/1.73m2
3. Serum/ plasma K+ levels ≥ 3.5 and < 5.0 mmol/L within 2 weeks prior to randomization
4. Serum/plasma Na+ levels within normal reference values within 2 weeks prior to randomization
5. 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
6. No changes in background treatment for at least 3 weeks prior to randomization
7. Body mass index less than 40 kg/m2
8. Negative pregnancy test (urine or serum) for female subjects of childbearing potential and willingness to use a highly effective birth control if of childbearing potential.
9. Willingness to participate and ability to provide signed informed consent |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of type 1 diabetes mellitus
2. Uncontrolled type 2 diabetes mellitus with HbA1C > 10.5% in the most recent medical records
3. Participants with type 2 diabetes mellitus treated with insulin if insulin dosing (intermediate, longâacting, premixed insulin, basal bolus insulin) was not stable in the 12 weeks prior to randomization as judged by the Investigator
4. Patients with systolic blood pressure levels <100 mmHg at the time of enrolment
5. Patients with congestive heart failure NYHA stage IV or hospitalized for decompensation of heart failure in the 3 months prior to screening
6. History of any life-threatening cardiac arrhythmias, or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter
7. Acute coronary syndrome and/or percutaneous cardiac interventions within 3 months prior to screening
8. Unstable or rapidly progressing renal disease
9. Chronic cystitis and recurrent genital or urinary tract infections
10. 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
11. Medical conditions associated with development of hyperkalemia (Addison's disease)
12. Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within 3 months prior to screening
13. Hemoglobin levels below 8.5 g/dL or over 15 g/dL
14. Patients who have received an organ or bone marrow transplant
15. HIV infection
16. Active cancer, history of bladder cancer
17. Patients who have had major surgery in the 3 months prior to screening
18. Patients with muscular dystrophies
19. Patients who have severe comorbid conditions likely to compromise survival or study participation
20. Pregnant and breast-feeding women
21. Medical treatment with either a mineralocorticoid receptor antagonist (MRA) or a sodium-glucose co-transporter-2 inhibitor (SGLT2i) within 3 months prior to screening
22. Medical treatment with potassium binders
23. Medical treatment with strong or moderate CYP3A4 inducers or inhibitors
24. Prior serious hypersensitivity reaction to dapagliflozin (Forxiga®), balcinrenone or to any of their excipients
25. Treatment with cytotoxic therapy, immunosuppressive therapy or other immunotherapy within 6 months prior to screening
26. Unwillingness or other inability to cooperate
27. 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 MRsafe anywhere in the body |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in 24h urine glucose excretion at day 3 and day 28 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| day 3 and day 28 (only day 28 for France) |
|
| E.5.2 | Secondary end point(s) |
Topic 1
• Change from baseline in urine osmolality at day 3 and day 28
Topic 2
• Change from baseline in free water clearance at day 3 and day 28
• Change from baseline in urine glucose fraction at day 3 and day 28
• 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
• Change from baseline in urine potassium fraction at day 3 and day 28
• Change from baseline in muscle water content as measured at 7T MRI at day 28
Topic 3
• Change from baseline in copeptin levels at day 3 and day 28
• Change from baseline in plasma insulin/glucagon ratio at day 3 and day 28 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| day 3 and day 28 (only day 28 for France including muscle water content) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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