The Effects of Bindarit in Diabetic Nephropathy

• Urinary Monocyte Chemoattractant protein (MCP-1/CCL2)(pg/ml) levels in the overnight urine specimen. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Relative change (per cent change) in Urinary MCP-1 levels from the baseline.
• Serum lipids [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Relative change (per cent change) in total cholesterol, cholesterol HDL, triglycerides, apolipoprotein-A, apolipoprotein-B from the baseline.
• Safety and tolerability of bindarit in association of irbesartan. [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Changes in anthropometrics, laboratory parameters and vital signs from the baseline. Number of adverse events.
• Albuminuria remission rates [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Rate of remission from macro to microalbuminuria and from micro to normoalbuminuria.

The purpose of this study is to determine whether bindarit is effective to reduce albuminuria, compared to placebo, in nephropathic patients treated with irbesartan, as a background therapy.

This is a pilot phase II, double-blind, multicentre, randomized, placebo-controlled, parallel groups study in patients with DN undergoing irbesartan therapy.

According to screening urinary albumin excretion, at baseline and before randomization, all patients will be categorized into 2 strata:

Stratum 1: microalbuminuria (20 to 200 μg/min, in at least 2 of 3 consecutive overnight urine samples collected at the screening) Stratum 2: macroalbuminuria (>200 μg/min, in at least 2 of 3 consecutive overnight urine samples collected at the screening).

Within each stratum, patients will be randomly allocated on a 1:1 basis to the 2 treatment arms (after one month induction period):

• bindarit 600MG twice a day
• placebo All patients will be treated with irbesartan 300 mg/day as background therapy. After 12 months of treatment albuminuria will be evaluated as primary endopoint.

• Drug: Bindarit
  dosage form:tablet dosage:2x300 mg frequency:b.i.d duration:12 weeks
  Other Name: AF2838
• Drug: Placebo
  dosage form: tablet dosage: n.a. frequency: 2xplacebo b.i.d duration:12 weeks
  Other Name: Placebo

• Experimental: Bindarit
  Patients treated with bindarit 2x300 mg bid plus irbesartan 2x150 mg once a day for 12 weeks
  Intervention: Drug: Bindarit
• Placebo Comparator: Placebo
  patients treated with placebo 2 tablets bid plus irbesartan 2x150 mg once a day for 12 weeks
  Intervention: Drug: Placebo

INCLUSION CRITERIA

• male and female patients with no limitation of race, aged 30 to 70 years;
• Type 2 diabetes defined as: > 30 years of age at diagnosis; insulin not required within 6 months of initial diagnosis; no history of diabetic ketoacidosis; currently treated with diet, oral hypoglycemics or insulin [Brenner 2000];
• microalbuminuria defined as urinary albumin excretion, 20 to 200 µg/min in at least 2 of 3 overnight urine samples or macroalbuminuria defined as urinary albumin excretion, > 200 µg/min in at least 2 of 3 overnight urine samples, confirmed in the baseline collection; should baseline albuminuria data not to be available, the patient may be conditionally treated;
• glycosylated haemoglobin (Hb A1c) <12% at Screening [Brenner 2000];
• serum creatinine ≤ 3 mg/dL at Screening;
• normotensive patients or hypertensive patients on stable antihypertensive therapy over the last 3 months and without specific contraindications to angiotensin antagonist therapy;
• female patients of childbearing potential required to have a negative pregnancy test and use an approved birth control method;
• patients legally able to give written informed consent to the trial (signed and dated by the patient).

EXCLUSION CRITERIA

Patients cannot enter the trial under the following circumstances:

• patients hypersensitive or allergic to ARBs or bindarit or its components, or with a positive history for drug allergy;
• Type 1 diabetes [Brenner 2000];
• history of non diabetic renal disease, including renal artery stenosis [Brenner 2000];
• history of heart failure before enrolment [Brenner 2000];
• acute myocardial infarction, coronary artery bypass grafting within the past one month [Brenner 2000];
• cerebral vascular accident or coronary angioplasty within the past six months month [Brenner 2000];
• Transient Ischemic Attacks (TIA) in the past 12 months [Brenner 2000];
• primary aldosteronism or pheocromocytoma [Brenner 2000];
• severe uncontrolled hypertension (sitting diastolic blood pressure > 115 and/or sitting systolic blood pressure> 220 mm Hg) in the previous 6 months;
• chronic use of corticosteroids, non-steroidal anti-inflammatory drugs, immunosuppressive drugs, MAO inhibitors;
• patients under the influence of alcohol or narcotics;
• patients treated with experimental drugs in the previous 4 weeks.