N-Acetylcysteine and Milk Thistle for Treatment of Diabetic Nephropathy

NCT ID: NCT00915200

Last Updated: 2016-06-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

114 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-10-31

Study Completion Date

2016-04-30

Brief Summary

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The study is designed to test if the combination of two potent antioxidant nutritional supplements, N-acetylcysteine and the milk thistle extract silibin, is capable of correcting the shedding of urine protein, the oxidative stress, and the inflammation in patients with type 2 diabetes mellitus and diabetic kidney disease.

Detailed Description

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Oxidative stress and 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 type 2 diabetes mellitus and related nephropathy. We 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 glutathione (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

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Diabetic Nephropathies Proteinuria Oxidative Stress

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Placebo

N-acetylcysteine placebo + silibin placebo

Group Type PLACEBO_COMPARATOR

N-acetylcysteine placebo

Intervention Type DIETARY_SUPPLEMENT

excipient orally twice daily for three months

silibin placebo

Intervention Type DIETARY_SUPPLEMENT

excipient orally twice daily for three months

N-acetylcysteine

N-acetylcysteine active + silibin placebo

Group Type EXPERIMENTAL

N-acetylcysteine

Intervention Type DIETARY_SUPPLEMENT

600 mg orally twice daily for three months

silibin placebo

Intervention Type DIETARY_SUPPLEMENT

excipient orally twice daily for three months

silibin

N-acetylcysteine placebo + silibin active

Group Type EXPERIMENTAL

silibin

Intervention Type DIETARY_SUPPLEMENT

480 mg orally twice daily for three months

N-acetylcysteine placebo

Intervention Type DIETARY_SUPPLEMENT

excipient orally twice daily for three months

silibin placebo

Intervention Type DIETARY_SUPPLEMENT

excipient orally twice daily for three months

N-acetycysteine + silibin

N-acetylcysteine active + silibin active

Group Type EXPERIMENTAL

N-acetylcysteine

Intervention Type DIETARY_SUPPLEMENT

600 mg orally twice daily for three months

silibin

Intervention Type DIETARY_SUPPLEMENT

480 mg orally twice daily for three months

silibin placebo

Intervention Type DIETARY_SUPPLEMENT

excipient orally twice daily for three months

N-acetylcysteine + high-dose silibin

N-acetylcysteine active + high-dose silibin active

Group Type EXPERIMENTAL

N-acetylcysteine

Intervention Type DIETARY_SUPPLEMENT

600 mg orally twice daily for three months

high-dose silibin

Intervention Type DIETARY_SUPPLEMENT

960 mg orally twice daily for three months

Interventions

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N-acetylcysteine

600 mg orally twice daily for three months

Intervention Type DIETARY_SUPPLEMENT

silibin

480 mg orally twice daily for three months

Intervention Type DIETARY_SUPPLEMENT

high-dose silibin

960 mg orally twice daily for three months

Intervention Type DIETARY_SUPPLEMENT

N-acetylcysteine placebo

excipient orally twice daily for three months

Intervention Type DIETARY_SUPPLEMENT

silibin placebo

excipient orally twice daily for three months

Intervention Type DIETARY_SUPPLEMENT

Other Intervention Names

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NAC silibin-phosphatidylcholine, Siliphos silibin-phosphatidylcholine, Siliphos NAC placebo silibin-phosphatidylcholine placebo, Siliphos placebo

Eligibility Criteria

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Inclusion Criteria

* Males or females, age 18-70 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 ARBs or ACE inhibitors.
* 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
* SBP \>170 mmHg or DBP \>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);
* 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, and 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
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Center for Complementary and Integrative Health (NCCIH)

NIH

Sponsor Role collaborator

VA Office of Research and Development

FED

Sponsor Role collaborator

The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Paolo Fanti, M.D.

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Locations

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University of Texas Hlth Sci Ctr San Ant

San Antonio, Texas, United States

Site Status

Countries

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United States

References

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Colombijn JM, Hooft L, Jun M, Webster AC, Bots ML, Verhaar MC, Vernooij RW. Antioxidants for adults with chronic kidney disease. Cochrane Database Syst Rev. 2023 Nov 2;11(11):CD008176. doi: 10.1002/14651858.CD008176.pub3.

Reference Type DERIVED
PMID: 37916745 (View on PubMed)

Other Identifiers

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1I01CX000264-01A2

Identifier Type: NIH

Identifier Source: secondary_id

View Link

R21AT004490

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NIH 1R21AT004490

Identifier Type: -

Identifier Source: org_study_id

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