E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The study will include adult male and female patients with an early stage of chronic kidney disease (CKD stage G1A2/G2A2) and prediabetes |
|
E.1.1.1 | Medical condition in easily understood language |
The study will include adult male and female patients with an early stage of chronic kidney disease (CKD stage G1A2/G2A2) and prediabetes |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
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 |
The primary objective is to test if kidney damage can be improved |
|
E.2.2 | Secondary objectives of the trial |
• Reduction in estimated glomerular filtration rate (eGFR) and measured GFR (mGFR) as well as slopes over time of eGFR and mGFR • insulin secretion and insulin sensitivity • progress to T2DM as defined as a HbA1c ≥ 6.5 • remission of prediabetes as defined by HbA1c <5.7 % and in the oGTT a fasting glucose <100 mg/dl and 2 h glucose <140 mg/dl • body weight, body mass index (BMI) and body composition • resolution of CKD • arterial blood pressure • left ventricular mass index and systolic and diastolic myocardial function
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• • Male, female or intersexual diverse patients aged 35 and 75 years (including) • Patients assigned to high risk for diabetes clusters 3, 5 and 6 according to Wagner et al., 2021 who have signs of early kidney disease (urinary albumin-to-creatinine ratio (uACR) 30mg/g - 300 mg/g, CKD stage G1A2/G2A2) • Prediabetes (defined by one of the following: FG > 100 mg/dL, HbA1c > 5,6 or 2h OGTT glucose > 140 mg/dL) • BMI ≥ 20 kg/m2 • TSH within normal range • Ability to understand and follow study-related instructions • Negative pregnancy test for premenopausal women (blood) • Patients who are receiving thyroid replacement therapy must be on a stable treatment (i.e. TSH within normal range) regimen for at least 3 months prior to the screening visit (V-10) • Patients who are receiving antihypertensive medication such as mineralocorticoid receptor antagonists must be on a stable treatment regimen (i.e. no hospital admission due to excessive hypertension and stable dosing) for at least 6 weeks prior to the screening visit (V-10) • Patients who are treated with antihypertensive medication such as ACE inhibitors and AT1 receptor antagonists, thiazides as well as loop diuretics must be on stable treatment (i.e. no hospital admission due to excessive hypertension and stable dosing) for at least 2 weeks • Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. • Patients will not be included in the study if, in the opinion of the investigator, participation will lead to an unacceptable risk to the subjects’ safety or well-being
|
|
E.4 | Principal exclusion criteria |
• • Manifest diabetes mellitus • eGFR (as calculated by the CKD-EPI equation) < 60 ml/min/1.73 m2 • all glucose altering medications (including current therapy with dapagliflozin or empagliflozin or any other SGLT2-Inhibitor) • Symptomatic chronic congestive heart disease • New diuretic or antihypertensive medication or dosing changes within the last 2 weeks, for aldosterone antagonists within the last 6 weeks • known or suspected orthostatic proteinuria • any acute severe or chronic severe illness, including the following: malignant disease ongoing or < 5 years ago, unstable cardiovascular disease or procedure within 3 months prior to enrolment or expected to require coronary revascularisation procedure • history of or current therapy for congestive heart failure (NYHA III and IV), pacemaker or aortic stenosis > II° • acute pancreatic disease (i.e. elevated lipase 3x ULN) • rapidly progressing renal disease or anuria • known HIV infection or positive HIV test at screening • history of or planned organ transplantation • history or presence of inflammatory bowel disease or other severe gastrointestinal diseases, particularly those which may impact gastric emptying, such as gastroparesis or pyloric stenosis • relevant hepatic disease, including, but not limited to, acute hepatitis, chronic active hepatitis, or severe hepatic insufficiency, including patients with alanine aminotransferase and/or aspartate aminotransferase > 3 x upper limit of normal and/or total bilirubin (TB) > 2 mg/dL (> 34.2 μmol/L) (patients with TB > 2 mg/dL [> 34.2 μmol/L] and documented Gilbert’s syndrome will be allowed to participate). • treatment with glucocorticoids • antibiotic treatment within the last 4 weeks • History of ketoacidosis • history of repeated urogenital infection • hemoglobinopathies, haemolytic anaemia, or chronic anaemia (haemoglobin concentration < 12.0 g/dL) • presence of psychiatric disorder or intake of antidepressant or antipsychotic agents • Positive Screening for a severe depression (BDI ≥29) • history of hypersensitivity to the study drug or its ingredients • allergy to iodine contrast dye • more than 5% weight loss in the last 3 months • Pregnant or breastfeeding women • Subject (male, female or intersexualdiverse) is not willing to use highly effective contraceptive methods during treatment and for 14 days (male or female) after the end of treatment (highly effective methods are defined as: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence). • Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success. • Current participation in other interventional clinical trials or treatment with other IMPs within five times the half-life of the drug • Previous therapy with dapagliflozin or other drugs that can potentially lead to overlapping toxicities within five times the half-life of the drug • Patients who do not want to be informed about accidental findings • Any other clinical condition that would jeopardize subjects’ safety or well-being while participating in this clinical trial • Patients will not be included in the study if, in the opinion of the investigator, participation leads to an unacceptable risk to their safety and well-being • Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success • In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. • Current participation in other interventional clinical trials or previous treatment with other IMPs within five times the half-life of the drug • Previous therapy with dapagliflozin or other drugs that can potentially lead to overlapping toxicities within five times the half-life of the drug
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
mean of baseline-adjusted uACR measurements (V2-V6) with dapagliflozin in comparison to treatment with placebo |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
mean of baseline-adjusted uACR measurements (V2-V6) with dapagliflozin in comparison to treatment with placebo |
|
E.5.2 | Secondary end point(s) |
mean of baseline-adjusted uACR measurements (V2-V6) with dapagliflozin in comparison to treatment with placebo |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
mean of baseline-adjusted uACR measurements (V2-V6) with dapagliflozin in comparison to treatment with placebo |
|
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 | No |
E.6.4 | Safety | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |