E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes Mellitus patients with impaired renal function. Type 2 Diabetes Mellitus patients with normal renal function. Non-diabetic patients with impaired renal function. |
|
E.1.1.1 | Medical condition in easily understood language |
Dapagliflozin to treat T2DM. Previous data indicate beneficial effects on kidney disease. As primary endpoint the study evaluate the effect of treatment on excretion of sodium in urine. |
|
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 |
To investigate change in 24-hr sodium excretion during dapagliflozin treatment between Baseline (average of Days −3 to −1) and average of Days 2 to 4 within each study group in patients with Type 2 Diabetes Mellitus with preserved or impaired renal function and in non diabetics with impaired renal function. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives to be evaluated within each study group during or following dapagliflozin treatment are: • To evaluate the change in 24-hr sodium excretion during dapagliflozin treatment from Baseline to end of treatment, and during follow-up. • To evaluate the change in 24-hr glucose excretion. • To evaluate the change in mean 24-hr systolic blood pressure. • To evaluate the change in plasma volume. • To evaluate the change in extracellular volume. • To evaluate pharmacokinetics of dapagliflozin. • To evaluate the change in 24-hr urine albumin: creatinine ratio (UACR) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Provision of signed and dated, written informed consent prior to any study specific procedures • Female and/or male aged between 18 years and ≤80 years • In the diabetic arms - a diagnosis of Type 2 Diabetes Mellitus with HbA1c ≥6.5% (≥48 mmol/mol) and <10% (<86 mmol/mol); and eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 or between >90 and ≤130 mL/min/1.73m2 for patients aged 59 or younger, between >85 and ≤130 mL/min/1.73m2 for patients aged 60 to 69, and between >75 and ≤130 mL/min/1.73m2 for patients aged 70 or older • In the non-diabetic arm, HbA1c <6.5% (<48 mmol/mol) and an eGFR (CKD-EPI) between ≥25 and ≤50 mL/min/1.73m2 • Patient specific optimal antihypertensive dose of an angiotensin receptor blocker atleast 6 weeks before study treatment • In the diabetic arm (Group 2) an appropriate stable dose of metformin or sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the last 12 weeks prior to study treatment • In the diabetic arm with impaired renal function (Group 1), a stable insulin dosing (intermediate, long-acting, premixed insulin, basal bolus insulin) for the last 12 weeks prior to study treatment as judged by the Investigator. Metformin or sulphonylurea, or metformin+sulphonylurea together with insulin would be accepted, but is not mandatory. If used, stable dose of metformin or sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the last 12 weeks prior to study treatment is required. • Stable urinary sodium excretion on 2 successive 24-hr urinary sodium excretion measurements |
|
E.4 | Principal exclusion criteria |
● Diagnosis of Type 1 Diabetes Mellitus ● Any of the following cardiovascular/vascular diseases within 3 months prior to signing the consent; myocardial infarction, cardiac surgery or revascularization, unstable angina, unstable heart failure, heart failure NYHA Class IV, transient ischemic attack or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia ● Symptoms/complaints suggestive of established neurogenic bladder and/or incomplete bladder emptying. ● History of bladder cancer, diagnosis of polycystic kidney disease, history or current lupus nephritis or unstable or rapidly progressing renal disease ● UACR >1000 mg/g per day at screening ● Current/chronic use of the following medications: any anti-diabetic medication with the exception of metformin, sulphonylurea, insulin (insulin only allowed in Group 1), angiotensin converting enzyme inhibitors, oral glucocorticoids, non-steroidal anti-inflammatory drugs, immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants and monoamine oxidase inhibitors ● Receiving immunosuppressive or other immunotherapy for primary or secondary renal disease within 6 months prior to screening ● Current treatment or treatment within the last 2 weeks prior to screening with diuretics including loop diuretics, thiazides, and mineralocorticoid antagonists |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Average change in 24-hr sodium excretion from average baseline to average values over Day 2 to 4 within each study group. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
•Average change in 24-hr sodium excretion from average Baseline values to average end of treatment values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17). •Average change in 24-hr glucose excretion from average Baseline values to average values at Day 2 to 4; from average Baseline values to average end of treatment values (Day 12 to 14); and from average end of treatment values (Day 12 to 14) to average values during follow-up (Day 15 to 17). •Change in mean 24-hr systolic blood pressure from Baseline to Day 4; from Baseline to end of treatment (Day 13); and from end of treatment (Day 13) to end of follow-up (Day 18). •Change in plasma volume from Baseline to Day 4; from Baseline to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18). •Change in extracellular volume from Baseline to Day 4; from Baseline to end of treatment (Day 14); and from end of treatment (Day 14) to end of follow-up (Day 18) •Dapagliflozin pharmacokinetics on Day 4 and Day 14. •Average change in mean 24-hr UACR from average Baseline to Day 4; and from average Baseline values to average end of treatment values (Day 12 to 14). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day13, Day14, Day17, Day18 |
|
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 | Yes |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 13 |