N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

Study Overview
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Brief Summary
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The study is designed to test if the combination of two potent antioxidant nutritional supplements, N-acetylcysteine and the milk thistle extract silibin, is capable of correcting the shedding of urine protein, the oxidative stress, and the inflammation in patients with type 2 diabetes mellitus and diabetic kidney disease.

Detailed Description
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Oxidative stress and GSH imbalance are major contributors to the pathogenesis of diabetic nephropathy. Current options for the treatment of oxidative stress in diabetic nephropathy are limited and only partially effective, thus interest in the development of new strategies is high. The study intends to test the hypothesis that combined oral supplementation of the antioxidants N-acetylcysteine (NAC) and milk thistle flavonolignan silibin (as silibin-phosphatidylcholine) will reduce proteinuria and urinary and systemic manifestations of oxidative stress and inflammation, which are characteristically observed in patients with type 2 diabetes mellitus and related nephropathy. We expect these effects to be achieved with minimal or no side effects, and with good patient tolerance. The trial is designed as a two-center, double-blind, placebo-controlled, randomized, modified-factorial dose-ranging design, five-arm pilot study in patients with Type 2 diabetes mellitus and advanced diabetic nephropathy with proteinuria. Intervention consists of three-month oral administration of NAC, silibin, and/or respective placebos for three months. Subjects are randomized to the following five intervention arms: (A) placebo; (B) NAC; (C) silibin; (D) NAC + silibin; and (E) NAC + double-dose silibin. The primary outcome measure is urinary excretion of albumin, a marker of glomerular injury. Secondary outcome measures are alpha-1 microglobulin, a marker of tubular injury, and urinary excretion of inflammatory cytokines and C-C chemokines, i.e. markers of renal inflammation. In addition, peripheral blood monocytes from the same patients are analyzed for glutathione (GSH) content and activity of GSH metabolizing enzymes. All outcome measures are monitored in relation to both treatment allocation and prevalent blood and urine levels of the active treatment. Safety and tolerability of this combination treatment are monitored throughout the trial.

Official Title
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N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy.

Conditions
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Diabetic Nephropathies, Proteinuria, Oxidative Stress

Intervention / Treatment
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* Dietary Supplement: N-acetylcysteine
* Dietary Supplement: silibin
* Dietary Supplement: high-dose silibin
* Dietary Supplement: N-acetylcysteine placebo
* Dietary Supplement: silibin placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, age 18-70 years old. Type 2 diabetes mellitus Diabetic nephropathy, as defined by: estimated GFR between 60 and 15 ml/min, presence of proteinuria. Current medical treatment with low dose aspirin Treatment of hypertension with (but not limited to) one diuretic, one beta- blocker and one medication from the classes ARBs or ACE inhibitors. Treatment of hyperglycemia with (but not limited to) glipizide and the medication class insulin. Treatment of hypercholesterolemia with (but not limited to) one medication from the class statins. Exclusion Criteria: Type 1 diabetes mellitus. Glycosylated hemoglobin (HbA1C) > 10% >20% variation in estimated GFR, during last 6 months SBP >170 mmHg or DBP >100 mmHg on medications Other secondary forms of hypertension (endocrine, renovascular) History of intolerance to: Both ACE-I and ARBs; The investigational supplements; Iodinated radiologic contrast material. Known non diabetic renal disease, or history of solid organ transplantation. Hepatitis virus or Human Immunodeficiency virus infections Use of one of the following medications within 2 months prior to enrollment in the study: Metformin. Thiazolidinediones (pioglitazone or rosiglitazone); Prescription-grade vitamin E, vitamin C, systemic steroids, and/or non-steroidal anti-inflammatory agents; Over-the-counter vitamin E, vitamin C, and/or non-steroidal anti-inflammatory agents. Over-the-counter antioxidants supplements including: Lipoic acid, Coenzyme Q10, N-acetyl-cysteine (NAC), Glutathione (GSH), Chromium, Fish-oil extracts (omega-3 fatty acids), Soy extracts (isoflavones), Milk thistle extract (silymarin), Green-tea preparations, Pomegranate extracts, Grape extracts, and Prickly pear extract. Active coronary artery disease or cerebral vascular disease within 3 months prior to signing the informed consent. Hepatic dysfunction as defined by abnormal total bilirubin or liver enzymes (ALT, AST) >2 times upper limit of normal range. Active malignancy. History of drug or alcohol dependency. Psychiatric or neurological condition, preventing aware consent to the study and/or adherence to the study protocol Unwillingness to practice birth control throughout the study. Participation to another clinical study within 1 month prior to signing the informed consent form. Planned move to outside the study area, surgery or radiographic studies utilizing iodine-based contrast material within the next one year

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>N-acetylcysteine placebo + silibin placebo | Dietary Supplement: N-acetylcysteine placebo<br>* excipient orally twice daily for three months<br>* Other names: NAC placebo;Dietary Supplement: silibin placebo<br>* excipient orally twice daily for three months<br>* Other names: silibin-phosphatidylcholine placebo, Siliphos placebo;|
| Experimental: N-acetylcysteine<br>N-acetylcysteine active + silibin placebo | Dietary Supplement: N-acetylcysteine<br>* 600 mg orally twice daily for three months<br>* Other names: NAC;Dietary Supplement: silibin placebo<br>* excipient orally twice daily for three months<br>* Other names: silibin-phosphatidylcholine placebo, Siliphos placebo;|
| Experimental: silibin<br>N-acetylcysteine placebo + silibin active | Dietary Supplement: silibin<br>* 480 mg orally twice daily for three months<br>* Other names: silibin-phosphatidylcholine, Siliphos;Dietary Supplement: N-acetylcysteine placebo<br>* excipient orally twice daily for three months<br>* Other names: NAC placebo;Dietary Supplement: silibin placebo<br>* excipient orally twice daily for three months<br>* Other names: silibin-phosphatidylcholine placebo, Siliphos placebo;|
| Experimental: N-acetycysteine + silibin<br>N-acetylcysteine active + silibin active | Dietary Supplement: N-acetylcysteine<br>* 600 mg orally twice daily for three months<br>* Other names: NAC;Dietary Supplement: silibin<br>* 480 mg orally twice daily for three months<br>* Other names: silibin-phosphatidylcholine, Siliphos;Dietary Supplement: silibin placebo<br>* excipient orally twice daily for three months<br>* Other names: silibin-phosphatidylcholine placebo, Siliphos placebo;|
| Experimental: N-acetylcysteine + high-dose silibin<br>N-acetylcysteine active + high-dose silibin active | Dietary Supplement: N-acetylcysteine<br>* 600 mg orally twice daily for three months<br>* Other names: NAC;Dietary Supplement: high-dose silibin<br>* 960 mg orally twice daily for three months<br>* Other names: silibin-phosphatidylcholine, Siliphos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary Albumin excretion |  | 3-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| urinary alpha-1 microglobulin excretion |  | 3-month | 
| urinary C-C-chemokines excretion |  | 3-month | 
| peripheral blood monocyte glutathione content |  | 3-month | 
| tolerance and safety |  | 3-month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic Nephropathies, Proteinuria, Renal Insufficiency, Chronic, Monocytes, Oxidative stress, Inflammation, Antioxidants, Glutathione, Silymarin, Acetylcysteine, Dietary Supplements, Complementary Therapies