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N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

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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

Study Description
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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.

Condition or disease Intervention/treatment 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 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 114 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy.
Study Start Date : October 2009
Actual Primary Completion Date : April 2016
Actual Study Completion Date : April 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo
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
Experimental: N-acetylcysteine
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
Experimental: silibin
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
Experimental: N-acetycysteine + silibin
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
Experimental: N-acetylcysteine + high-dose silibin
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


Outcome Measures
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Primary Outcome Measures :
  1. Urinary Albumin excretion [ Time Frame: 3-month ]

Secondary Outcome Measures :
  1. urinary alpha-1 microglobulin excretion [ Time Frame: 3-month ]
  2. urinary C-C-chemokines excretion [ Time Frame: 3-month ]
  3. peripheral blood monocyte glutathione content [ Time Frame: 3-month ]
  4. tolerance and safety [ Time Frame: 3-month ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00915200


Locations
United States, Texas
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
National Center for Complementary and Integrative Health (NCCIH)
VA Office of Research and Development
Investigators
Principal Investigator: Paolo Fanti, M.D. University of Texas
More Information
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Responsible Party: The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT00915200     History of Changes
Other Study ID Numbers: NIH 1R21AT004490
1I01CX000264-01A2 ( U.S. NIH Grant/Contract )
R21AT004490 ( U.S. NIH Grant/Contract )
First Posted: June 5, 2009    Key Record Dates
Last Update Posted: June 27, 2016
Last Verified: June 2016

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

Additional relevant MeSH terms:
Kidney Diseases
Diabetic Nephropathies
Proteinuria
Urologic Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Urination Disorders
Urological Manifestations
Signs and Symptoms
Acetylcysteine
N-monoacetylcystine
 Silybin
Silymarin
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes