E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061835 |
E.1.2 | Term | Diabetic nephropathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition 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 study the potential protective role of Dapagliflozin on renal disease in patients with Type 2 diabetes and diabetic renal disease. We aim to evaluate in this trial if the combination of Dapagliflozin and Ramipril (an established reno-protective drug) significantly reduces microalbuminuria ( a markers of renal damage) as compared to Ramipril alone in patients with type-2 diabetes with preserved renal function and residual albuminuria despite currently available optimal treatments. |
|
E.2.2 | Secondary objectives of the trial |
Changes in the following will be measured - Central aortic blood pressure and central arterial stiffness; Brachial blood pressure; Plasma renin activity, aldosterone, ACE-2 and Angiotensin 1-7/1-9 levels; Total body water and extracellular fluid volumes by bio-impedance; Highly sensitive CRP; HbA1c, fasting c-peptide, glucose; Lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides); Serum electrolytes (sodium, magnesium, potassium), and renal function (serum creatinine, and estimated GFR; Plasma albumin and liver function tests (ALT, ALP GGT); Serum uric acid, serum calcium, serum phosphate, and haemoglobin; Renal tubular markers L-FABP levels and retinol binding protein; 24 hr urine sodium, urine magnesium, urine uric acid, urine calcium, urine phosphate and urine potassium excretion; Vascular cell adhesion molecule-1, Von Willebrand factor, oxidized low density lipoprotein and endothelin-1; Quality of life (EQOL5)
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male and female patients aged 35 to 75 years with known diagnosis of type-2 diabetes as per ADA criteria (1) with HbA1c ≥ 7% on monotherapy or combination therapy with approved hypoglycaemic agents (e.g. metformin, sulphonylurea, acarbose, or DPP IV inhibitor, insulin, GLP-1 receptor agonist) - Patients with residual albuminuria (defined as a urine albumin creatinine ratio (ACR) >3 mg/mmol in the preceding 12 months) on maximal tolerated dose of ACE-inhibitor or ARB
- preserved renal function [estimated GFR >60 ml/min by 4 variable MDRD equation (23)]
- Patients on a stable dose of ACE-inhibitors or ARB in the preceding 3 months.
- Written informed consent to participate in the study prior to any study procedures; - Ability to communicate and comply with all study requirements.
|
|
E.4 | Principal exclusion criteria |
- Patients with impaired renal function (eGFR<60 ml/min); - Patients with recent (6 months) history of cardiovascular or cerebrovascular disease event; - Patients on thiazolidinediones (e.g. Pioglitazone); - Patients who have started drugs which could affect sodium balance (e.g. diuretics, non steroidal anti-inflammatory drugs (NSAID), cyclo-oxygenase (Cox) 2 inhibitors, beta blockers or Calcium channel antagonists) within the previous month; - Patients with uncontrolled hypertension defined as systolic blood pressure and diastolic blood pressure greater than 160 and 100 mmHg respectively; - Pregnancy and lactating females - Pre-menopausal female patients not using contraception; - Patients with very poorly controlled diabetes defined as HbA1c >12%; - Patients with non diabetic renal disease; - Patients with a history of connective tissue disease or inflammatory arthritis; - Recent ( within 3 months) or current use of SGLT2 receptor blocker; - Patients not willing to use appropriate contraception; - Patients on loop diuretics - Recent history of (within 3 years of screening visit) or active malignancy - Patients with New York Heart Association class 3 or 4 cardiac disease - Abnormal Liver function tests defined as ALT or AST levels >3 times the upper limit of normal at screening - History of hereditary glucose-galactose malabsorption or primary renal glucosuria; - History of one or more severe hypoglycaemic episodes within 6 months of screening; (severe hypoglycaemic episodes is as defined by ADA criteria (24). - Previous hypersensitivity to the active substance or to any of the excipients - Patients with an insufficient understanding of the trial - Patients with a history of DKA or at high risk of DKA (T2DM patients with known low C-peptide (<0.25nmol/l), patients with a history of pancreatitis, patients with conditions that lead to restricted food intake or severe dehydration.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be change albuminuria measured by albumin excretion rate (AER); median of three non-consecutive independent urine collections performed within 10 days of 24 weeks' treatment with Dapagliflozin and Ramipril compared to Ramipril only |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 weeks after treatment with Dapagliflozin and Ramipril compared to Ramipril only. |
|
E.5.2 | Secondary end point(s) |
Changes in the following will be measured - Central aortic blood pressure and central arterial stiffness; Brachial blood pressure; Plasma renin activity, aldosterone, ACE-2 and Angiotensin 1-7/1-9 levels; Total body water and extracellular fluid volumes by bio-impedance; Highly sensitive CRP; HbA1c, fasting c-peptide, glucose; Lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides); Serum electrolytes (sodium, magnesium, potassium), and renal function (serum creatinine, and estimated GFR; Plasma albumin and liver function tests (ALT, ALP GGT); Serum uric acid, serum calcium, serum phosphate, and haemoglobin; Renal tubular markers L-FABP levels and retinol binding protein, soluble Klotho 24 hr urine sodium, urine magnesium, urine uric acid, urine calcium, urine phosphate and urine potassium excretion; Vascular cell adhesion molecule-1, Von Willebrand factor, oxidized low density lipoprotein and endothelin-1; Quality of life (EQOL5)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
24 weeks after treatment with Dapagliflozin and Ramipril compared to Ramipril only. |
|
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) | 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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |