N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

Oxidative Stress Clinical Trial

— CGDN  

Official title:

Correction of Glutathione Deficiency for Treatment of Diabetic Nephropathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01265563
• Other study ID #: CLIN-004-10S
• Secondary ID: 1R21AT004490-01A
• Status: Completed
• Phase: Phase 2
• Start date: January 2011
• Est. completion date: December 2016

Study information

• Verified date: September 2018
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 108
• Est. completion date: December 2016
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 76 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetic Nephropathies
• Diabetic Nephropathy
• Kidney Diseases
• Oxidative Stress
• Proteinuria

Intervention

Drug:
• N-acetylcysteine placebo and silibin placebo
Dietary Supplement: N-acetylcysteine placebo excipient and silibin placebo orally twice daily for three months
• N-acetylcysteine active and silibin placebo
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin placebo orally twice a day for three months
• N-acetylcysteine placebo and silibin active
Dietary Supplement: silibin 480 mg orally twice daily and N-acetylcysteine placebo orally twice a day for three months
• N-acetylcysteine active and silibin active
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 480 mg orally twice daily for three months
• N-acetylcysteine active + high-dose silibin active
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 960 mg orally twice daily for three months

Locations

Country	Name	City	State
United States	South Texas Health Care System, San Antonio, TX	San Antonio	Texas

Sponsors (2)

Lead Sponsor	Collaborator
VA Office of Research and Development	National Center for Complementary and Integrative Health (NCCIH)

Country where clinical trial is conducted

United States, 

References & Publications (7)

Cunningham SE, Verkaik D, Gross G, Khazim K, Hirachan P, Agarwal G, Lorenzo C, Matteucci E, Bansal S, Fanti P. Comparison of Nutrition Profile and Diet Record Between Veteran and Nonveteran End-Stage Renal Disease Patients Receiving Hemodialysis in Vetera — View Citation

Debnath S, Thameem F, Alves T, Nolen J, Al-Shahrouri H, Bansal S, Abboud HE, Fanti P. Diabetic nephropathy among Mexican Americans. Clin Nephrol. 2012 Apr;77(4):332-44. Review. — View Citation

Fanti P, Giustarini D, Rossi R, Cunningham SE, Folli F, Khazim K, Cornell J, Matteucci E, Bansal S. Dietary Intake of Proteins and Calories Is Inversely Associated With The Oxidation State of Plasma Thiols in End-Stage Renal Disease Patients. J Ren Nutr. — View Citation

Giustarini D, Dalle-Donne I, Milzani A, Fanti P, Rossi R. Analysis of GSH and GSSG after derivatization with N-ethylmaleimide. Nat Protoc. 2013 Sep;8(9):1660-9. doi: 10.1038/nprot.2013.095. Epub 2013 Aug 1. — View Citation

Giustarini D, Galvagni F, Orlandini M, Fanti P, Rossi R. Immediate stabilization of human blood for delayed quantification of endogenous thiols and disulfides. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Apr 15;1019:51-8. doi: 10.1016/j.jchromb.20 — View Citation

Khazim K, Giustarini D, Rossi R, Verkaik D, Cornell JE, Cunningham SE, Mohammad M, Trochta K, Lorenzo C, Folli F, Bansal S, Fanti P. Glutathione redox potential is low and glutathionylated and cysteinylated hemoglobin levels are elevated in maintenance he — View Citation

Khazim K, Gorin Y, Cavaglieri RC, Abboud HE, Fanti P. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo. Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F691-700. doi: 10.1152/ajprenal.00028.2013 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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