Clinical trial NCT01265563
Conditions: Diabetic Nephropathy Proteinuria Oxidative Stress
Keywords: silymarin glutathione diabetic nephropathies oxidative stress N-acetylcysteine protein tholation
Sponsor: VA Office of Research and Development
Start date: 2011-01-01; Completion date: 2016-12-01
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: Drug: N-acetylcysteine placebo and Drug: Silibin placebo arm 2: Drug: N-acetylcysteine and Drug: Silibin placebo arm 3: Drug: N-acetylcysteine placebo and Drug: Silibin active arm 4: Drug: N-acetylcysteine active and Drug: Silibin active arm 5: Drug: N-acetylcysteine active and Drug: Silibin higher dose active
Interventions: intervention 1: N-acetylcysteine placebo and silibin placebo intervention 2: N-acetylcysteine active and silibin placebo intervention 3: N-acetylcysteine placebo and silibin active intervention 4: N-acetylcysteine active and silibin active intervention 5: N-acetylcysteine active + high-dose silibin active
Intervention descriptions: intervention 1: Dietary Supplement: N-acetylcysteine placebo excipient and silibin placebo orally twice daily for three months intervention 2: Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin placebo orally twice a day for three months intervention 3: Dietary Supplement: silibin 480 mg orally twice daily and N-acetylcysteine placebo orally twice a day for three months intervention 4: Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 480 mg orally twice daily for three months intervention 5: Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 960 mg orally twice daily for three months

Protocol documents: