N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

Study Overview
=================
Brief Summary
-----------------
The study is done to find out whether the combined use of the nutritional supplements N-acetylcysteine and Siliphos (milk thistle extract) corrects the shedding of urine protein and oxidative damage (damage to cells and organs often compared to fast aging) in patients with Type 2 Diabetes Mellitus (T2DM) and diabetic kidney disease.

Detailed Description
-----------------
Oxidative stress and glutathione (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 T2DM and related nephropathy. The investigators 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 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
-----------------
Correction of Glutathione Deficiency for Treatment of Diabetic Nephropathy

Conditions
-----------------
Diabetic Nephropathy, Proteinuria, Oxidative Stress

Intervention / Treatment
-----------------
* Drug: N-acetylcysteine placebo and silibin placebo
* Drug: N-acetylcysteine active and silibin placebo
* Drug: N-acetylcysteine placebo and silibin active
* Drug: N-acetylcysteine active and silibin active
* Drug: N-acetylcysteine active + high-dose silibin active


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females age 18-76 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 Angiotensin Receptor Blockers (ARBs) or Angiotensin Converting Enzyme inhibitors (ACE-I) 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 Systolic Blood Pressure >170 mmHg or Diastolic Blood Pressure >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) Phenytoin Warfarin 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 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
-----------------
Minimum Age: 18 Years
Maximum Age: 76 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Urinary Albumin Excretion | Urine albumin to creatinine ratio was assessed at the end of run in period and after 3 months administration of study intervention. | Baseline and 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin-A1c | Hemoglobin A1C was assessed at the end of the run in period and after 3 months of administration of study interventions. Here is delta HgA1C is reported between the two periods | Baseline and 3 months | 
| Urinary Alpha-1 Microglobulin, Inflammatory Cytokines and C-C Chemokines | Urinary alpha-1 microglobulin, inflammatory cytokines and C-C chemokines were never measured and analyzed. | Baseline and 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
silymarin, glutathione, diabetic nephropathies, oxidative stress, N-acetylcysteine, protein tholation