N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy - Full Text View

Sponsors and Collaborators:	The University of Texas Health Science Center at San Antonio The University of Texas Health Science Center, Houston
Information provided by:	The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier:	NCT00915200

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 II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy.

Resource links provided by NLM:

MedlinePlus related topics: Antioxidants Diabetes Diabetic Kidney Problems Dietary Supplements Diets Urine and Urination

Drug Information available for: silybin Acetylcysteine Lecithin

U.S. FDA Resources

Further study details as provided by The University of Texas Health Science Center at San Antonio:

Primary Outcome Measures:

Urinary Albumin excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

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:	150
Study Start Date:	October 2009
Estimated Study Completion Date:	September 2012
Estimated Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo: Placebo Comparator N-acetylcysteine placebo + silibin placebo	Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months Dietary Supplement: silibin placebo excipient orally twice daily for three months
N-acetylcysteine: Experimental N-acetylcysteine active + silibin placebo	Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months Dietary Supplement: silibin placebo excipient orally twice daily for three months
silibin: Experimental N-acetylcysteine placebo + silibin active	Dietary Supplement: silibin 480 mg orally twice daily for three months Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months Dietary Supplement: silibin placebo excipient orally twice daily for three months
N-acetycysteine + silibin: Experimental N-acetylcysteine active + silibin active	Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months Dietary Supplement: silibin 480 mg orally twice daily for three months Dietary Supplement: silibin placebo excipient orally twice daily for three months
N-acetylcysteine + high-dose silibin: Experimental N-acetylcysteine active + high-dose silibin active	Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months Dietary Supplement: high-dose silibin 960 mg orally twice daily for three months

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

Criteria

Inclusion Criteria:

Type 2 diabetes mellitus
Diabetic nephropathy, as defined by:
- estimated GFR between 60 and 15 ml/min,
- presence of proteinuria, and
- presence of diabetic microvascular disease, as indicated by retinopathy.
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) > 9%
Hemoglobin < 10. 5 g/dl
>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:
- 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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00915200

Contacts

Contact: Subrata D. Nath, Ph.D.	210-358-7306	nath@uthscsa.edu
Contact: Paolo Fanti, M.D.	210-567-0880	fanti@uthscsa.edu

Locations

United States, Texas
University of Texas Hlth Sci Ctr Houston
Houston, Texas, United States, 77030
University of Texas Hlth Sci Ctr San Ant
San Antonio, Texas, United States, 78229

Sponsors and Collaborators

The University of Texas Health Science Center at San Antonio

The University of Texas Health Science Center, Houston

Investigators

Principal Investigator:

Paolo Fanti, M.D.

University of Texas

More Information

No publications provided

Responsible Party:	University of Texas Hlth Sci Ctr San Ant ( Paolo Fanti, M.D., Associate Professor of Medicine )
Study ID Numbers:	NIH 1R21AT004490-01A1, NIH Award Number R21AT004490
Study First Received:	June 2, 2009
Last Updated:	August 7, 2009
ClinicalTrials.gov Identifier:	NCT00915200 History of Changes
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

Study placed in the following topic categories:

Anti-Infective Agents
Renal Insufficiency
Antioxidants
Diabetic Nephropathies
Urination Disorders
Lecithin
Diabetes Mellitus
Stress
Endocrine System Diseases
Antiviral Agents
Silybin
Inflammation

Signs and Symptoms
Proteinuria
Urologic Diseases
Renal Insufficiency, Chronic
Expectorants
Silymarin
Acetylcysteine
Endocrinopathy
Kidney Diseases
Milk Thistle
N-monoacetylcystine
Diabetes Complications

Additional relevant MeSH terms:

Respiratory System Agents
Anti-Infective Agents
Diabetic Nephropathies
Antioxidants
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Silybin
Signs and Symptoms
Urologic Diseases
Therapeutic Uses
Free Radical Scavengers
Acetylcysteine
Kidney Diseases

Diabetes Complications
Antidotes
Urination Disorders
Diabetes Mellitus
Endocrine System Diseases
Antiviral Agents
Protective Agents
Pharmacologic Actions
Urological Manifestations
Proteinuria
Expectorants
N-monoacetylcystine

ClinicalTrials.gov processed this record on September 03, 2009