Clinical trial NCT01265563: N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy
Official title: Correction of Glutathione Deficiency for Treatment of Diabetic Nephropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetic Nephropathy
Proteinuria
Oxidative Stress
Keywords: silymarin
glutathione
diabetic nephropathies
oxidative stress
N-acetylcysteine
protein tholation
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: National Center for Complementary and Integrative Health (NCCIH)
First posted: 2010-12-23
Enrollment: 108
Sex: ALL
Minimum age (years): 18
Maximum age (years): 76
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Urinary Albumin Excretion
timeFrame: Baseline and 3 months
Secondary outcomes:
measure: Change From Baseline in Hemoglobin-A1c
timeFrame: Baseline and 3 months
measure: Urinary Alpha-1 Microglobulin, Inflammatory Cytokines and C-C Chemokines
timeFrame: Baseline and 3 months
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: South Texas Health Care System, San Antonio, TX
state: Texas
Study officials:
affiliation: South Texas Health Care System, San Antonio, TX
name: Paolo Fanti, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Debnath S, Thameem F, Alves T, Nolen J, Al-Shahrouri H, Bansal S, Abboud HE, Fanti P. Diabetic nephropathy among Mexican Americans. Clin Nephrol. 2012 Apr;77(4):332-44. doi: 10.5414/cn107487.
citation: Giustarini D, Dalle-Donne I, Milzani A, Fanti P, Rossi R. Analysis of GSH and GSSG after derivatization with N-ethylmaleimide. Nat Protoc. 2013 Sep;8(9):1660-9. doi: 10.1038/nprot.2013.095. Epub 2013 Aug 1.
citation: Khazim K, Giustarini D, Rossi R, Verkaik D, Cornell JE, Cunningham SE, Mohammad M, Trochta K, Lorenzo C, Folli F, Bansal S, Fanti P. Glutathione redox potential is low and glutathionylated and cysteinylated hemoglobin levels are elevated in maintenance hemodialysis patients. Transl Res. 2013 Jul;162(1):16-25. doi: 10.1016/j.trsl.2012.12.014. Epub 2013 Jan 17.
citation: Cunningham SE, Verkaik D, Gross G, Khazim K, Hirachan P, Agarwal G, Lorenzo C, Matteucci E, Bansal S, Fanti P. Comparison of Nutrition Profile and Diet Record Between Veteran and Nonveteran End-Stage Renal Disease Patients Receiving Hemodialysis in Veterans Affairs and Community Clinics in Metropolitan South-Central Texas. Nutr Clin Pract. 2015 Oct;30(5):698-708. doi: 10.1177/0884533615575046. Epub 2015 Apr 21.
citation: Fanti P, Giustarini D, Rossi R, Cunningham SE, Folli F, Khazim K, Cornell J, Matteucci E, Bansal S. Dietary Intake of Proteins and Calories Is Inversely Associated With The Oxidation State of Plasma Thiols in End-Stage Renal Disease Patients. J Ren Nutr. 2015 Nov;25(6):494-503. doi: 10.1053/j.jrn.2015.06.003. Epub 2015 Jul 31.
citation: Giustarini D, Galvagni F, Orlandini M, Fanti P, Rossi R. Immediate stabilization of human blood for delayed quantification of endogenous thiols and disulfides. J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Apr 15;1019:51-8. doi: 10.1016/j.jchromb.2016.02.009. Epub 2016 Feb 8.
citation: Khazim K, Gorin Y, Cavaglieri RC, Abboud HE, Fanti P. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo. Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F691-700. doi: 10.1152/ajprenal.00028.2013. Epub 2013 Jun 26.