Overview

This trial is active, not recruiting.

Conditions diabetic nephropathy, proteinuria, oxidative stress
Treatments n-acetylcysteine placebo + silibin placebo, n-acetylcysteine active + silibin placebo, n-acetylcysteine placebo + silibin active, n-acetylcysteine active + silibin active, n-acetylcysteine active + high-dose silibin active
Phase phase 2
Sponsor VA Office of Research and Development
Collaborator National Center for Complementary and Integrative Health (NCCIH)
Start date January 2011
End date February 2015
Trial size 110 participants
Trial identifier NCT01265563, 1R21AT004490-01A1, CLIN-004-10S, VA 1I01CX000264-01A2

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose treatment
Arm
(Placebo Comparator)
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
n-acetylcysteine placebo + silibin placebo NAC placebo Dietary Supplement: silibin placebo excipient orally twice daily for three months Or silibin-phosphatidylcholine placebo, Siliphos placebo
Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months
(Experimental)
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
n-acetylcysteine active + silibin placebo NAC Dietary Supplement: silibin placebo excipient orally twice daily for three months Or Silibin-phosphatidylcholine placebo, Siliphos placebo
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months
(Experimental)
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
n-acetylcysteine placebo + silibin active Silibin-phosphatidylcholine, Siliphos Dietary Supplement: N-acetylcysteine placebo excipient orally twice daily for three months
Dietary Supplement: silibin 480 mg orally twice daily for three months (Other Name) Silibin-phosphatidylcholine placebo, Siliphos placebo (Other Name) NAC placebo Dietary Supplement: silibin placebo excipient orally twice daily for three months
(Experimental)
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
n-acetylcysteine active + silibin active Silibin-phosphatidylcholine placebo, Siliphos placebo
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 Silibin-phosphatidylcholine, Siliphos Dietary Supplement: silibin placebo excipient orally twice daily for three months (Other Name): Silibin-phosphatidylcholine, Siliphos Dietary Supplement: silibin placebo excipient orally twice daily for three months
(Experimental)
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
n-acetylcysteine active + high-dose silibin active NAC Dietary Supplement: high-dose silibin 960 mg orally twice daily for three months Or Other Name: Silibin-phosphatidylcholine, Siliphos
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily for three months

Primary Outcomes

Measure
Change from baseline in urinary albumin excretion
time frame: 3-month

Secondary Outcomes

Measure
Change from baseline in urinary alpha-1 microglobulin excretion
time frame: 3-month
Change from baseline in urinary C-C-chemokines excretion
time frame: 3-month
Change from baseline in peripheral blood monocyte glutathione content
time frame: 3-month
adverse events
time frame: 1-month
Change from baseline in hemoglobin level
time frame: 1-month
Change from baseline in serum electrolytes
time frame: 1-month
Change from baseline in estimated glomerular filtration rate
time frame: 1-month
Change from baseline in measured glomerular filtration rate
time frame: 3-month
Change from baseline in hemoglobin-A1c
time frame: 1-month

Eligibility Criteria

Male or female participants from 18 years up to 76 years old.

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

Additional Information

Official title Correction of Glutathione Deficiency for Treatment of Diabetic Nephropathy
Principal investigator Paolo Fanti, MD
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.
Trial information was received from ClinicalTrials.gov and was last updated in April 2016.
Information provided to ClinicalTrials.gov by VA Office of Research and Development.