N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy
Condition: Diabetic Nephropathy; Proteinuria; Oxidative Stress
MeSH terms: Kidney Diseases; Diabetic Nephropathies; Proteinuria
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

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.
    

Intervention name(s): N-acetylcysteine placebo and silibin placebo; N-acetylcysteine active and silibin placebo; N-acetylcysteine placebo and silibin active; N-acetylcysteine active and silibin active; N-acetylcysteine active + high-dose silibin active
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Dietary Supplement: N-acetylcysteine placebo excipient and silibin placebo orally twice daily for three months; Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin placebo orally twice a day for three months; Dietary Supplement: silibin 480 mg orally twice daily and N-acetylcysteine placebo orally twice a day for three months; Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 480 mg orally twice daily for three months; Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 960 mg orally twice daily for three months
Other intervention name(s): NAC placebo, Silibin-phosphatidylcholine placebo, Siliphos placebo; NAC, Silibin-phosphatidylcholine placebo, Siliphos placebo; NAC Placebo, Silibin-phosphatidylcholine, Siliphos; NAC, Silibin-phosphatidylcholine, Siliphos; NAC, Silibin-phosphatidylcholine, Siliphos
Intervention MeSH terms: Acetylcysteine; Silybin; N-monoacetylcystine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: silymarin; glutathione; diabetic nephropathies; oxidative stress; N-acetylcysteine; protein tholation