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

Primary Purpose

Diabetic Nephropathy, Proteinuria, Oxidative Stress

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
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
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetic Nephropathy focused on measuring silymarin, glutathione, diabetic nephropathies, oxidative stress, N-acetylcysteine, protein tholation

Eligibility Criteria

18 Years - 76 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • South Texas Health Care System, San Antonio, TX

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Placebo Comparator

Experimental

Experimental

Experimental

Experimental

Arm Label

NAC placebo and Silibin placebo

NAC active and Silibin placebo

NAC placebo and Silibin active

NAC active and Silibin active

NAC active and High-dose Silibin active

Arm Description

Drug: N-acetylcysteine placebo and Drug: Silibin placebo

Drug: N-acetylcysteine and Drug: Silibin placebo

Drug: N-acetylcysteine placebo and Drug: Silibin active

Drug: N-acetylcysteine active and Drug: Silibin active

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

Outcomes

Primary Outcome Measures

Change From Baseline in Urinary Albumin Excretion
Urine albumin to creatinine ratio was assessed at the end of run in period and after 3 months administration of study intervention.

Secondary Outcome Measures

Change From Baseline in Hemoglobin-A1c
Hemoglobin A1C was assessed at the end of the run in period and after 3 months of administration of study interventions. Here is delta HgA1C is reported between the two periods
Urinary Alpha-1 Microglobulin, Inflammatory Cytokines and C-C Chemokines
Urinary alpha-1 microglobulin, inflammatory cytokines and C-C chemokines were never measured and analyzed.

Full Information

First Posted
December 10, 2010
Last Updated
September 19, 2018
Sponsor
VA Office of Research and Development
Collaborators
National Center for Complementary and Integrative Health (NCCIH)
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1. Study Identification

Unique Protocol Identification Number
NCT01265563
Brief Title
N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy
Acronym
CGDN
Official Title
Correction of Glutathione Deficiency for Treatment of Diabetic Nephropathy
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
January 2011 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development
Collaborators
National Center for Complementary and Integrative Health (NCCIH)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetic Nephropathy, Proteinuria, Oxidative Stress
Keywords
silymarin, glutathione, diabetic nephropathies, oxidative stress, N-acetylcysteine, protein tholation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
108 (Actual)

8. Arms, Groups, and Interventions

Arm Title
NAC placebo and Silibin placebo
Arm Type
Placebo Comparator
Arm Description
Drug: N-acetylcysteine placebo and Drug: Silibin placebo
Arm Title
NAC active and Silibin placebo
Arm Type
Experimental
Arm Description
Drug: N-acetylcysteine and Drug: Silibin placebo
Arm Title
NAC placebo and Silibin active
Arm Type
Experimental
Arm Description
Drug: N-acetylcysteine placebo and Drug: Silibin active
Arm Title
NAC active and Silibin active
Arm Type
Experimental
Arm Description
Drug: N-acetylcysteine active and Drug: Silibin active
Arm Title
NAC active and High-dose Silibin active
Arm Type
Experimental
Arm Description
Drug: N-acetylcysteine active and Drug: Silibin higher dose active
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine placebo and silibin placebo
Other Intervention Name(s)
NAC placebo, Silibin-phosphatidylcholine placebo, Siliphos placebo
Intervention Description
Dietary Supplement: N-acetylcysteine placebo excipient and silibin placebo orally twice daily for three months
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine active and silibin placebo
Other Intervention Name(s)
NAC, Silibin-phosphatidylcholine placebo, Siliphos placebo
Intervention Description
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin placebo orally twice a day for three months
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine placebo and silibin active
Other Intervention Name(s)
NAC Placebo, Silibin-phosphatidylcholine, Siliphos
Intervention Description
Dietary Supplement: silibin 480 mg orally twice daily and N-acetylcysteine placebo orally twice a day for three months
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine active and silibin active
Other Intervention Name(s)
NAC, Silibin-phosphatidylcholine, Siliphos
Intervention Description
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 480 mg orally twice daily for three months
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine active + high-dose silibin active
Other Intervention Name(s)
NAC, Silibin-phosphatidylcholine, Siliphos
Intervention Description
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 960 mg orally twice daily for three months
Primary Outcome Measure Information:
Title
Change From Baseline in Urinary Albumin Excretion
Description
Urine albumin to creatinine ratio was assessed at the end of run in period and after 3 months administration of study intervention.
Time Frame
Baseline and 3 months
Secondary Outcome Measure Information:
Title
Change From Baseline in Hemoglobin-A1c
Description
Hemoglobin A1C was assessed at the end of the run in period and after 3 months of administration of study interventions. Here is delta HgA1C is reported between the two periods
Time Frame
Baseline and 3 months
Title
Urinary Alpha-1 Microglobulin, Inflammatory Cytokines and C-C Chemokines
Description
Urinary alpha-1 microglobulin, inflammatory cytokines and C-C chemokines were never measured and analyzed.
Time Frame
Baseline and 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
76 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paolo Fanti, MD
Organizational Affiliation
South Texas Health Care System, San Antonio, TX
Official's Role
Principal Investigator
Facility Information:
Facility Name
South Texas Health Care System, San Antonio, TX
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
22445478
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.
Results Reference
background
PubMed Identifier
23928499
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.
Results Reference
background
PubMed Identifier
23333585
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.
Results Reference
result
PubMed Identifier
25899538
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.
Results Reference
result
PubMed Identifier
26235932
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.
Results Reference
result
PubMed Identifier
26896310
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.
Results Reference
result
PubMed Identifier
23804455
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.
Results Reference
result

Learn more about this trial

N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

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