N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2012 by The University of Texas Health Science Center at San Antonio
Sponsor:
Collaborators:
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier:
NCT00915200
First received: June 2, 2009
Last updated: July 10, 2012
Last verified: July 2012
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy.

Resource links provided by NLM:


Further study details as provided by The University of Texas Health Science Center at San Antonio:

Primary Outcome Measures:
  • Urinary Albumin excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • urinary alpha-1 microglobulin excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]
  • urinary C-C-chemokines excretion [ Time Frame: 3-month ] [ Designated as safety issue: No ]
  • peripheral blood monocyte glutathione content [ Time Frame: 3-month ] [ Designated as safety issue: No ]
  • tolerance and safety [ Time Frame: 3-month ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 225
Study Start Date: October 2009
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00915200

Contacts
Contact: Sriramanan Anandbabu, MBBS/MS 210-204-8580 anandbabu@uthscsa.edu
Contact: Paolo Fanti, M.D. 210-567-0880 fanti@uthscsa.edu

Locations
United States, Texas
University of Texas Hlth Sci Ctr San Ant Recruiting
San Antonio, Texas, United States, 78229
Contact: Sriramanan Anandbabu, MBBS/MS    210-204-8580    anandbabu@uthscsa.edu   
Contact: Paolo Fanti, M.D.    210-567-0880    fanti@uthscsa.edu   
Principal Investigator: Paolo Fanti, M.D.         
Sponsors and Collaborators
The University of Texas Health Science Center at San Antonio
Investigators
Principal Investigator: Paolo Fanti, M.D. University of Texas
  More Information

No publications provided

Responsible Party: The University of Texas Health Science Center at San Antonio
ClinicalTrials.gov Identifier: NCT00915200     History of Changes
Other Study ID Numbers: NIH 1R21AT004490-01A1, 1I01CX000264-01A2
Study First Received: June 2, 2009
Last Updated: July 10, 2012
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on October 19, 2014