Bosentan Use in Patients With Diabetic Nephropathy

Study Overview
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Brief Summary
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There is little doubt of the necessity for further improvement in the prevention and therapy of end-stage renal disease. Despite the success of ARB in treating diabetic nephropathy, not all patients obtain satisfactory control of blood pressure, albuminuria and decline in renal function. Experimental data have provided us with a rationale for the potential added benefits of ET receptor blockade to the AII inhibition in diabetic renal protection. Considering the nephroprotective effect of bosentan in diabetic rats, clinical studies are warranted to assess whether ET receptor antagonism has additive renoprotective effects on top of AII inhibition.

Official Title
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Effect of Bosentan on Systemic and Renal Inflammatory Markers in Patients With Diabetic Nephropathy on Angiotensin II Receptor Blockers

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: bosentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women ≥ 18 years of age with a body weight of ≥ 40 kg; For female patients, only non-pregnant women who are surgically sterile, postmenopausal or have documented infertility (over 50 years of age and amenorrheic for at least 1 year), or those of childbearing potential using intrauterine devices (IUDs); Patients diagnosed Type 2 diabetes with overt nephropathy (urinary albumin excretion ≥ 300mg/24h); Patients on current treatment with angiotensin II receptor blockers for ≥ 3 months; Patients stable for at least 3 months prior to screening (no change in medications for diabetic nephropathy); Provide written informed consent; Exclusion Criteria: Patients with a history of pulmonary chronic obstructive disease, cardiac failure or coronary artery disease; Patients with documented cancers, acute infections or chronic inflammatory diseases; Patients who are pregnant or breast-feeding; Patients with known hepatic disorders or AST and ∕or ALT upper than normal limit; Patients with hemoglobin or hematocrit that is ≥ 30% below the normal range (patients with secondary polycythemia are permitted); Patients with systolic blood pressure < 110mm Hg; Patients with plasmatic albumin level < 30g/L; Patients with a documented creatinine clearance ≤ 60ml/min; Patients on anticoagulants or anti-inflammatory drugs, including cyclooxygenase inhibitors, AINS, prednisone and immunosuppressive drugs, platelet aggregation inhibitors, except low dose aspirin, ACE inhibitors, antidiabetic agents (rosiglitazone, pioglitazone) and antioxidants (vitamin E)(except statins or low-dose aspirin ≤ 80mg/day); Patients on treatment or planned treatment with another investigational drug; Patients who are receiving an endothelin receptor antagonist, phosphodiesterase type 5 inhibitor, or with a prostanoid (excluding acute administration during a catheterization procedure to test vascular reactivity) within 2 months of inclusion; Patients who are receiving calcineurin-inhibitors (i.e., cyclosporine A and tacrolimus), fluconazole, glibenclamide (glyburide) at inclusion or are expected to receive any of these drugs during the study; Patients with a known hypersensitivity to bosentan or any of the excipients;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Bosentan 62.5mg bid x4 weeks; up-titrated to 125mg bid x12 weeks; | Drug: bosentan<br>* 62.5mg bid x4 weeks, up-titrate to 125mg bid x12 weeks<br>* Other names: Tracleer;|
| Placebo Comparator: 2<br>placebo given bid same as experimental arm; | Drug: bosentan<br>* 62.5mg bid x4 weeks, up-titrate to 125mg bid x12 weeks<br>* Other names: Tracleer;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change from baseline to week 16 in renal inflammation. The following urinary inflammatory/oxidative stress parameters will be measured: - TNF |  | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change from baseline to week 16 in renal functioning. The following renal function parameter will be measured: - 24h UAE; |  | 16 weeks |