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

September 19, 2018 updated by: VA Office of Research and Development

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

108

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • San Antonio, Texas, United States, 78229
        • South Texas Health Care System, San Antonio, TX

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: NAC placebo and Silibin placebo
Drug: N-acetylcysteine placebo and Drug: Silibin placebo
Drug: N-acetylcysteine placebo and silibin placebo
Dietary Supplement: N-acetylcysteine placebo excipient and silibin placebo orally twice daily for three months
Other Names:
  • NAC placebo, Silibin-phosphatidylcholine placebo, Siliphos placebo
Experimental: NAC active and Silibin placebo
Drug: N-acetylcysteine and Drug: Silibin 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 Names:
  • NAC, Silibin-phosphatidylcholine placebo, Siliphos placebo
Experimental: NAC placebo and Silibin active
Drug: N-acetylcysteine placebo and Drug: Silibin active
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 Names:
  • NAC Placebo, Silibin-phosphatidylcholine, Siliphos
Experimental: NAC active and Silibin active
Drug: N-acetylcysteine active and Drug: Silibin active
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 Names:
  • NAC, Silibin-phosphatidylcholine, Siliphos
Experimental: NAC active and High-dose Silibin active
Drug: N-acetylcysteine active and Drug: Silibin higher dose active
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 Names:
  • NAC, Silibin-phosphatidylcholine, Siliphos

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline and 3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline and 3 months
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 analyzed.
Baseline and 3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Collaborators

National Center for Complementary and Integrative Health (NCCIH)

Investigators

  • Principal Investigator: Paolo Fanti, MD, South Texas Health Care System, San Antonio, TX

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2011

Primary Completion (Actual)

February 1, 2015

Study Completion (Actual)

December 1, 2016

Study Registration Dates

First Submitted

December 10, 2010

First Submitted That Met QC Criteria

December 21, 2010

First Posted (Estimate)

December 23, 2010

Study Record Updates

Last Update Posted (Actual)

October 19, 2018

Last Update Submitted That Met QC Criteria

September 19, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CLIN-004-10S
  • 1R21AT004490-01A1 (U.S. NIH Grant/Contract)
  • VA 1I01CX000264-01A2 (Registry Identifier: VA)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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