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

VA Office of Research and Development

Status and phase: Completed; Phase 2

Conditions: Diabetic Nephropathy; Proteinuria; Oxidative Stress

Treatments: Drug: N-acetylcysteine active and silibin placebo; Drug: N-acetylcysteine placebo and silibin active; Drug: N-acetylcysteine active + high-dose silibin active; Drug: N-acetylcysteine active and silibin active; Drug: N-acetylcysteine placebo and silibin placebo

Study type: Interventional

Funder types: Other U.S. Federal agency; NIH

Identifiers

NCT01265563

VA 1I01CX000264-01A2 (Registry Identifier)

CLIN-004-10S

1R21AT004490-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 108 patients

Sex: All

Ages: 18 to 76 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

---

108 participants in 5 patient groups, including a placebo group

NAC placebo and Silibin placebo

Placebo Comparator group

Description:

Drug: N-acetylcysteine placebo and Drug: Silibin placebo

Treatment:

Drug: N-acetylcysteine placebo and silibin placebo

NAC active and Silibin placebo

Experimental group

Description:

Drug: N-acetylcysteine and Drug: Silibin placebo

Treatment:

Drug: N-acetylcysteine active and silibin placebo

NAC placebo and Silibin active

Experimental group

Description:

Drug: N-acetylcysteine placebo and Drug: Silibin active

Treatment:

Drug: N-acetylcysteine placebo and silibin active

NAC active and Silibin active

Experimental group

Description:

Drug: N-acetylcysteine active and Drug: Silibin active

Treatment:

Drug: N-acetylcysteine active and silibin active

NAC active and High-dose Silibin active

Experimental group

Description:

Drug: N-acetylcysteine active and Drug: Silibin higher dose active

Treatment:

Drug: N-acetylcysteine active + high-dose silibin active