N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Diabetic Nephropathies Proteinuria Oxidative Stress |
Dietary Supplement: N-acetylcysteine Dietary Supplement: silibin Dietary Supplement: high-dose silibin Dietary Supplement: N-acetylcysteine placebo Dietary Supplement: silibin placebo |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy. |
- Urinary Albumin excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]
- urinary alpha-1 microglobulin excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]
- urinary C-C-chemokines excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]
- peripheral blood monocyte glutathione content [ Time Frame: 3-month ] [ Designated as safety issue: No ]
- tolerance and safety [ Time Frame: 3-month ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 225 |
| Study Start Date: | October 2009 |
| Estimated Study Completion Date: | December 2014 |
| Estimated Primary Completion Date: | March 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Placebo Comparator: Placebo
N-acetylcysteine placebo + silibin placebo
|
Dietary Supplement: N-acetylcysteine placebo
excipient orally twice daily for three months
Other Name: NAC placebo
Dietary Supplement: silibin placebo
excipient orally twice daily for three months
Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
|
|
Experimental: N-acetylcysteine
N-acetylcysteine active + silibin placebo
|
Dietary Supplement: N-acetylcysteine
600 mg orally twice daily for three months
Other Name: NAC
Dietary Supplement: silibin placebo
excipient orally twice daily for three months
Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
|
|
Experimental: silibin
N-acetylcysteine placebo + silibin active
|
Dietary Supplement: silibin
480 mg orally twice daily for three months
Other Name: silibin-phosphatidylcholine, Siliphos
Dietary Supplement: N-acetylcysteine placebo
excipient orally twice daily for three months
Other Name: NAC placebo
Dietary Supplement: silibin placebo
excipient orally twice daily for three months
Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
|
|
Experimental: N-acetycysteine + silibin
N-acetylcysteine active + silibin active
|
Dietary Supplement: N-acetylcysteine
600 mg orally twice daily for three months
Other Name: NAC
Dietary Supplement: silibin
480 mg orally twice daily for three months
Other Name: silibin-phosphatidylcholine, Siliphos
Dietary Supplement: silibin placebo
excipient orally twice daily for three months
Other Name: silibin-phosphatidylcholine placebo, Siliphos placebo
|
|
Experimental: N-acetylcysteine + high-dose silibin
N-acetylcysteine active + high-dose silibin active
|
Dietary Supplement: N-acetylcysteine
600 mg orally twice daily for three months
Other Name: NAC
Dietary Supplement: high-dose silibin
960 mg orally twice daily for three months
Other Name: silibin-phosphatidylcholine, Siliphos
|
Detailed Description:
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.
Eligibility| Ages Eligible for Study: | 18 Years to 70 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| Contact: Sriramanan Anandbabu, MBBS/MS | 210-204-8580 | anandbabu@uthscsa.edu |
| Contact: Paolo Fanti, M.D. | 210-567-0880 | fanti@uthscsa.edu |
| United States, Texas | |
| University of Texas Hlth Sci Ctr San Ant | Recruiting |
| San Antonio, Texas, United States, 78229 | |
| Contact: Sriramanan Anandbabu, MBBS/MS 210-204-8580 anandbabu@uthscsa.edu | |
| Contact: Paolo Fanti, M.D. 210-567-0880 fanti@uthscsa.edu | |
| Principal Investigator: Paolo Fanti, M.D. | |
| Principal Investigator: | Paolo Fanti, M.D. | University of Texas |
More Information
No publications provided
| Responsible Party: | The University of Texas Health Science Center at San Antonio |
| ClinicalTrials.gov Identifier: | NCT00915200 History of Changes |
| Other Study ID Numbers: | NIH 1R21AT004490-01A1, 1I01CX000264-01A2 |
| Study First Received: | June 2, 2009 |
| Last Updated: | July 10, 2012 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by The University of Texas Health Science Center at San Antonio:
|
Diabetic Nephropathies Proteinuria Renal Insufficiency, Chronic Monocytes Oxidative stress Inflammation |
Antioxidants Glutathione Silymarin Acetylcysteine Dietary Supplements Complementary Therapies |
Additional relevant MeSH terms:
|
Diabetic Nephropathies Kidney Diseases Proteinuria Urologic Diseases Diabetes Complications Diabetes Mellitus Endocrine System Diseases Urination Disorders Urological Manifestations Signs and Symptoms Acetylcysteine N-monoacetylcystine Silybin |
Antiviral Agents Anti-Infective Agents Therapeutic Uses Pharmacologic Actions Expectorants Respiratory System Agents Free Radical Scavengers Antioxidants Molecular Mechanisms of Pharmacological Action Protective Agents Physiological Effects of Drugs Antidotes |
ClinicalTrials.gov processed this record on May 16, 2013