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N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy (CGDN)

This study has been completed.
Sponsor:
Collaborator:
National Center for Complementary and Integrative Health (NCCIH)
Information provided by (Responsible Party):
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT01265563
First received: December 10, 2010
Last updated: March 31, 2017
Last verified: March 2017
December 10, 2010
March 31, 2017
January 2011
February 2015   (Final data collection date for primary outcome measure)
Change From Baseline in Urinary Albumin Excretion [ Time Frame: Baseline and 3 months ]
Urine albumin to creatinine ratio was assessed at the end of run in period and after 3 months administration of study intervention.
Change From Baseline in Urinary Albumin Excretion [ Time Frame: 3-month ]
Complete list of historical versions of study NCT01265563 on ClinicalTrials.gov Archive Site
  • Change From Baseline in Hemoglobin-A1c [ Time Frame: Baseline and 3 months ]
    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
  • Urinary Alpha-1 Microglobulin, Inflammatory Cytokines and C-C Chemokines [ Time Frame: Baseline and 3 months ]
    Urinary alpha-1 microglobulin, inflammatory cytokines and C-C chemokines were never measured and analysed.
  • 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 ]
Not Provided
Not Provided
 
N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy
Correction of Glutathione Deficiency for Treatment of Diabetic Nephropathy
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.

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.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Treatment
  • Diabetic Nephropathy
  • Proteinuria
  • Oxidative Stress
  • Drug: N-acetylcysteine placebo and silibin placebo
    Dietary Supplement: N-acetylcysteine placebo excipient and silibin placebo orally twice daily for three months
    Other Name: NAC placebo, Silibin-phosphatidylcholine placebo, Siliphos placebo
  • Drug: 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
    Other Name: NAC, Silibin-phosphatidylcholine placebo, Siliphos placebo
  • Drug: 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
    Other Name: NAC Placebo, Silibin-phosphatidylcholine, Siliphos
  • Drug: 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
    Other Name: NAC, Silibin-phosphatidylcholine, Siliphos
  • Drug: 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
    Other Name: NAC, Silibin-phosphatidylcholine, Siliphos
  • Placebo Comparator: NAC placebo and Silibin placebo
    Drug: N-acetylcysteine placebo and Drug: Silibin placebo
    Intervention: Drug: N-acetylcysteine placebo and silibin placebo
  • Experimental: NAC active and Silibin placebo
    Drug: N-acetylcysteine and Drug: Silibin placebo
    Intervention: Drug: N-acetylcysteine active and silibin placebo
  • Experimental: NAC placebo and Silibin active
    Drug: N-acetylcysteine placebo and Drug: Silibin active
    Intervention: Drug: N-acetylcysteine placebo and silibin active
  • Experimental: NAC active and Silibin active
    Drug: N-acetylcysteine active and Drug: Silibin active
    Intervention: Drug: N-acetylcysteine active and silibin active
  • Experimental: NAC active and High-dose Silibin active
    Drug: N-acetylcysteine active and Drug: Silibin higher dose active
    Intervention: Drug: N-acetylcysteine active + high-dose silibin active

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
108
December 2016
February 2015   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: All
18 Years to 76 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01265563
CLIN-004-10S
1R21AT004490-01A1 ( U.S. NIH Grant/Contract )
VA 1I01CX000264-01A2 ( Registry Identifier: VA )
Yes
Not Provided
Plan to Share IPD: Undecided
VA Office of Research and Development
VA Office of Research and Development
National Center for Complementary and Integrative Health (NCCIH)
Principal Investigator: Paolo Fanti, MD South Texas Health Care System, San Antonio, TX
VA Office of Research and Development
March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP