CompletedNCT01265563CGDNUpdated Oct 19, 2018Results posted

N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

A Phase 2 interventional study of N-acetylcysteine placebo and silibin placebo and N-acetylcysteine active and silibin placebo in Diabetic Nephropathy, Proteinuria and Oxidative Stress, sponsored by VA Office of Research and Development. Completed at 1 site in United States. Open to participants aged 18 Years to 76 Years. Per ClinicalTrials.gov, last updated 2018-10-19.

Sponsored by VA Office of Research and Development · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 108
Allocation: Randomized
Ages: 18 Years to 76 Years
Sex: All

Study 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.

Read the 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.

Conditions studied

Diabetic Nephropathy
Proteinuria
Oxidative Stress

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Keywords

silymarin
glutathione
diabetic nephropathies
oxidative stress
N-acetylcysteine
protein tholation

In context

Kidney Diseases

3,840 studies on the registry are indexed under Kidney Diseases; 500 are open to participants now.

This study's enrollment of 108 is above the median of 70 across 2,640 interventional studies indexed under Kidney Diseases.

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Lead sponsor

VA Office of Research and Development is the lead sponsor of 1,733 studies on the registry; 396 are open to participants now.

Of its 206 completed or terminated interventional studies of FDA-regulated products, 180 (87%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 76 Years
Sexes eligible: All
Accepts healthy volunteers: No

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

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

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Triple (Participant, Care provider, Investigator)
Enrollment: 108 participants (actual)

Study arms

Placebo comparator
NAC placebo and Silibin placebo
Drug: N-acetylcysteine placebo and Drug: Silibin placebo
Drug: N-acetylcysteine placebo and silibin placebo
Experimental
NAC active and Silibin placebo
Drug: N-acetylcysteine and Drug: Silibin placebo
Drug: N-acetylcysteine active and silibin placebo
Experimental
NAC placebo and Silibin active
Drug: N-acetylcysteine placebo and Drug: Silibin active
Drug: N-acetylcysteine placebo and silibin active
Experimental
NAC active and Silibin active
Drug: N-acetylcysteine active and Drug: Silibin active
Drug: N-acetylcysteine active and silibin active
Experimental
NAC active and High-dose Silibin active
Drug: N-acetylcysteine active and Drug: Silibin higher dose active
Drug: N-acetylcysteine active + high-dose silibin active

Interventions

DrugN-acetylcysteine placebo and silibin placebo
Dietary Supplement: N-acetylcysteine placebo excipient and silibin placebo orally twice daily for three months
Also known as: NAC placebo, Silibin-phosphatidylcholine placebo, Siliphos placebo
DrugN-acetylcysteine active and silibin placebo
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin placebo orally twice a day for three months
Also known as: NAC, Silibin-phosphatidylcholine placebo, Siliphos placebo
DrugN-acetylcysteine placebo and silibin active
Dietary Supplement: silibin 480 mg orally twice daily and N-acetylcysteine placebo orally twice a day for three months
Also known as: NAC Placebo, Silibin-phosphatidylcholine, Siliphos
DrugN-acetylcysteine active and silibin active
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 480 mg orally twice daily for three months
Also known as: NAC, Silibin-phosphatidylcholine, Siliphos
DrugN-acetylcysteine active + high-dose silibin active
Dietary Supplement: N-acetylcysteine 600 mg orally twice daily and silibin 960 mg orally twice daily for three months
Also known as: NAC, Silibin-phosphatidylcholine, Siliphos

What researchers measure

Primary outcomes

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.
Time frame: Baseline and 3 months

Secondary outcomes

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
Time frame: Baseline and 3 months
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.
Time frame: Baseline and 3 months

Results

Posted Mar 31, 2017

Participant flow

213 subjects met the inclusion criteria on screening from 2 clinic locations: VA and University Hospital Renal clinics.Many had exclusion criteria and few refused to participate. 108 subjects finally enrolled in the study.

Participant flow — Overall Study
Milestone	NAC Placebo + Silibin Placebo	NAC Active + Silibin Placebo	NAC Placebo + Silibin Active	NAC Active + Silibin Active	NAC Active + High Dose Silibin Active
Started	16	13	17	16	16
Completed	16	12	16	16	14
Not completed	0	1	1	0	2
Withdrew: Withdrawal by subject	0	1	1	0	2

Outcome measures

PrimaryChange 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.

Time frame:: Baseline and 3 months
Reported as:: Mean · mg/g

Change From Baseline in Urinary Albumin Excretion
mg/g	NAC Placebo + Silibin Placebo	NAC Active + Silibin Placebo	NAC Placebo + Silibin Active	NAC Active + Silibin Active	NAC Active + High-dose Silibin Active
Change From Baseline in Urinary Albumin Excretion	50.5 ± 291.2	-28.13 ± 578.32	-4.5 ± 541	96.6 ± 422.4	353.71 ± 732.67

SecondaryChange 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

Time frame:: Baseline and 3 months
Reported as:: Mean · percentage

Change From Baseline in Hemoglobin-A1c
percentage	NAC Placebo + Silibin Placebo	NAC Active + Silibin Placebo	NAC Placebo + Silibin Active	NAC Active + Silibin Active	NAC Active + High-dose Silibin Active
Change From Baseline in Hemoglobin-A1c	0.35 ± 0.58	-0.18 ± 0.68	0.72 ± 2.91	0.4 ± 2.19	0.2 ± 1.14

SecondaryUrinary Alpha-1 Microglobulin, Inflammatory Cytokines and C-C Chemokines

Urinary alpha-1 microglobulin, inflammatory cytokines and C-C chemokines were never measured and analyzed.

Time frame:: Baseline and 3 months

No measurements were reported for this outcome.

Adverse events

Collected over 3 months. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
NAC Placebo + Silibin Placebo	0/16 (0%)	1/16 (6.3%)	7/16 (43.8%)
NAC Active + Silibin Placebo	0/12 (0%)	1/12 (8.3%)	7/12 (58.3%)
NAC Placebo + Silibin Active	0/16 (0%)	1/16 (6.3%)	6/16 (37.5%)
NAC Active + Silibin Active	0/16 (0%)	1/16 (6.3%)	8/16 (50%)
NAC Active + High-dose Silibin Active	0/14 (0%)	1/14 (7.1%)	9/14 (64.3%)

Most frequent serious events

Most frequent serious events
Event	NAC Placebo + Silibin Placebo	NAC Active + Silibin Placebo	NAC Placebo + Silibin Active	NAC Active + Silibin Active	NAC Active + High-dose Silibin Active
Chest PainCardiac disorders	0/16	1/12	0/16	0/16	0/14
BradycardiaCardiac disorders	0/16	0/12	0/16	0/16	1/14
WheezingRespiratory, thoracic and mediastinal disorders	0/16	0/12	1/16	0/16	0/14
Motor Vehicle AccidentMusculoskeletal and connective tissue disorders	1/16	0/12	0/16	0/16	0/14
OsteomyelitisMusculoskeletal and connective tissue disorders	0/16	0/12	0/16	1/16	0/14

Most frequent other events

Most frequent other events
Event	NAC Placebo + Silibin Placebo	NAC Active + Silibin Placebo	NAC Placebo + Silibin Active	NAC Active + Silibin Active	NAC Active + High-dose Silibin Active
Heart burn, nausea, diarrhea, abd pain, anorexiaGastrointestinal disorders	2/16	4/12	2/16	5/16	4/14
Congestion, Sore throat, MyalgiasGeneral disorders	1/16	0/12	3/16	1/16	1/14
AKI, hyperkalemia, EdemaRenal and urinary disorders	0/16	2/12	0/16	1/16	2/14
Infection - soft tissue, UTIGeneral disorders	2/16	0/12	0/16	0/16	1/14
FlushingImmune system disorders	0/16	1/12	0/16	0/16	0/14
HypoglycemiaEndocrine disorders	1/16	0/12	0/16	0/16	1/14
VertigoNervous system disorders	1/16	0/12	0/16	0/16	0/14
Fracture, sprain, stiffnessMusculoskeletal and connective tissue disorders	0/16	0/12	0/16	1/16	0/14
HypotensionCardiac disorders	0/16	0/12	1/16	0/16	0/14

Baseline characteristics

Age, Customized
Age, Customized(years)	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	Total
Age	65.3 ± 5.74	64 ± 6.4	61.9 ± 8.39	64.81 ± 8.113	59.56 ± 7.78	63.09 ± 7.5

Sex: Female, Male
Sex: Female, Male(Participants)	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	Total
Female	1	2	0	2	2	7
Male	15	11	17	14	14	71

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	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	Total
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	1	0	0	1
Black or African American	1	1	1	1	1	5
White	15	12	15	14	15	71
More than one race	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	1	0	1

BMI
BMI(kg/M^2)	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	Total
Mean	30.21 ± 9.28	39.9 ± 9.17	35.86 ± 8.63	35.65 ± 5.16	35.72 ± 7.5	35.31 ± 7.67

Systolic BP
Systolic BP(mmHg)	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	Total
Mean	138.5 ± 21.76	125.54 ± 22.77	147.41 ± 16.8	137.13 ± 17.10	142.8 ± 12	139.15 ± 19.02

Diastolic BP
Diastolic BP(mmHg)	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	Total
Mean	70.44 ± 15.83	62.71 ± 12.63	77.47 ± 9.53	70.88 ± 8.37	74.25 ± 9.61	71.93 ± 12.08

Study locations

1 site

South Texas Health Care System, San Antonio, TX
San Antonio, Texas 78229, United States

References and documents

Publications

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. PubMed 22445478 ↗
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. PubMed 23928499 ↗
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. PubMed 23333585 ↗
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. PubMed 25899538 ↗
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. PubMed 26235932 ↗
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. PubMed 26896310 ↗
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. PubMed 23804455 ↗

Individual participant data

Plan to share: Undecided

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Oct 19, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01265563
Lead sponsor: VA Office of Research and Development
Collaborators: National Center for Complementary and Integrative Health (NCCIH)
Responsible party: Sponsor
First posted: Dec 23, 2010
Start date: Jan 2011
Primary completion: Feb 2015
Completion: Dec 2016
Results posted: Mar 31, 2017
Last update: Oct 19, 2018

Study contacts

Paolo Fanti, MD

principal investigator · South Texas Health Care System, San Antonio, TX

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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