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N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00915200
Recruitment Status : Completed
First Posted : June 5, 2009
Last Update Posted : June 27, 2016
Sponsor:
Collaborators:
National Center for Complementary and Integrative Health (NCCIH)
VA Office of Research and Development
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

Tracking Information
First Submitted Date  ICMJE June 2, 2009
First Posted Date  ICMJE June 5, 2009
Last Update Posted Date June 27, 2016
Study Start Date  ICMJE October 2009
Actual Primary Completion Date April 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 4, 2009)
Urinary Albumin excretion [ Time Frame: 3-month ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2009)
  • urinary alpha-1 microglobulin excretion [ Time Frame: 3-month ]
  • urinary C-C-chemokines excretion [ Time Frame: 3-month ]
  • peripheral blood monocyte glutathione content [ Time Frame: 3-month ]
  • tolerance and safety [ Time Frame: 3-month ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy
Official Title  ICMJE N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy.
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Diabetic Nephropathies
  • Proteinuria
  • Oxidative Stress
Intervention  ICMJE
  • 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: high-dose silibin
    960 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
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    N-acetylcysteine placebo + silibin placebo
    Interventions:
    • Dietary Supplement: N-acetylcysteine placebo
    • Dietary Supplement: silibin placebo
  • Experimental: N-acetylcysteine
    N-acetylcysteine active + silibin placebo
    Interventions:
    • Dietary Supplement: N-acetylcysteine
    • Dietary Supplement: silibin placebo
  • Experimental: silibin
    N-acetylcysteine placebo + silibin active
    Interventions:
    • Dietary Supplement: silibin
    • Dietary Supplement: N-acetylcysteine placebo
    • Dietary Supplement: silibin placebo
  • Experimental: N-acetycysteine + silibin
    N-acetylcysteine active + silibin active
    Interventions:
    • Dietary Supplement: N-acetylcysteine
    • Dietary Supplement: silibin
    • Dietary Supplement: silibin placebo
  • Experimental: N-acetylcysteine + high-dose silibin
    N-acetylcysteine active + high-dose silibin active
    Interventions:
    • Dietary Supplement: N-acetylcysteine
    • Dietary Supplement: high-dose silibin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 23, 2016)
114
Original Estimated Enrollment  ICMJE
 (submitted: June 4, 2009)
150
Actual Study Completion Date  ICMJE April 2016
Actual Primary Completion Date April 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00915200
Other Study ID Numbers  ICMJE NIH 1R21AT004490
1I01CX000264-01A2 ( U.S. NIH Grant/Contract )
R21AT004490 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party The University of Texas Health Science Center at San Antonio
Study Sponsor  ICMJE The University of Texas Health Science Center at San Antonio
Collaborators  ICMJE
  • National Center for Complementary and Integrative Health (NCCIH)
  • VA Office of Research and Development
Investigators  ICMJE
Principal Investigator: Paolo Fanti, M.D. University of Texas
PRS Account The University of Texas Health Science Center at San Antonio
Verification Date June 2016

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