Randomized Controlled Trial of Silymarin in Asthma

NCT01049178 | Withdrawn Phase 2 DMC

• 1 other identifier: IRB 090053
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine if intake of the antioxidant enzyme inducer, silymarin, will improve lung function and symptom scores in participants with asthma.

Conditions

Atopic Asthma

Keywords

antioxidant enzymes; asthma; silymarin; RCT

Outcome Measures

Primary Outcomes (1)

• Exhaled nitric oxide (eNO), an indirect measure of airway inflammation that correlates with clinical asthma measures.

  20-40 weeks

Secondary Outcomes (1)

• Spirometry, disease control, urinary isoprostanes, antioxidant enzyme concentrations, silybin concentrations, acceptability, ability to maintain blinding, effect size for secondary clinical outcomes.

  20-40 weeks

Study Arms (2)

Oral silymarin dose

EXPERIMENTAL

Dose escalation study

Drug: Oral Silymarin; Drug: Oral Silymarin, maintenance dose

placebo

PLACEBO COMPARATOR

A randomized, double-masked, placebo-controlled cross-over clinical pilot investigation of an inducer of endogenous antioxidant enzymes, silymarin, in humans with atopic asthma.

Drug: Placebo

Interventions

Oral Silymarin DRUG

Dose Level 1: 1 capsules (1 cap at 140mg/cap) given three times per day for a total daily dose of 420 mg 28-days post Dose Level 1 Dose Level 2: 3 capsules (3 caps at 140mg/cap = 420 mg) given three times per day for a total daily dose of 1260 mg Day 56 (28-days post Dose Level 2) Dose Level 3: 5 capsules (5 caps at 140mg/cap = 700 mg) given three times per day for a total daily dose of 2100 mg Day 84 (28-days post Dose Level 3) We will evaluate change from baseline at each dose to determine the minimum effective dose.

Also known as: Legalon, Milk Thistle

Oral silymarin dose

Oral Silymarin, maintenance dose DRUG

The maintenance Silymarin dose will be selected based on the dose escalation study and will be dosed PO three times daily as recommended. Silymarin will be provided as a capsule S. marianum (70-80% silymarin), along with an identical appearance placebo capsule created by our investigational pharmacyAt each visit a questionnaire regarding daily symptoms and disease control, the asthma control test (ACT) will be completed, eNO measured, urine collected, spirometry (lung function) measured, venipuncture performed for blood collection (20 mL), as well as assessment of acceptability, toxicity, and masking.

Also known as: Legalon, Milk Thistle

Oral silymarin dose

Placebo DRUG

placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Asthma Control Test (ACT) Score of 15-20, AND
• Documented atopy by prick skin testing (most study participants will likely have participated in one of the investigators prior observational studies and will have had skin testing, if not, this will be performed at an in-person screening visit), AND
• For women: Not pregnant, as determined by a negative urinary pregnancy test at the initial visit(visit 1), AND at the start of the cross-over period (visit 4), AND using birth control

You may not qualify if:

• Known allergies to plants in the Asteraceae family (thistles, daisies, artichokes, kiwi)
• Non-asthmatic, or inadequate documentation which includes lack of signs and symptoms of asthma, or lack of prior confirmatory testing
• Pregnant
• Age \< 18 years
• Non-English speaking
• Current smoker (current, or within last year)
• Chronic Obstructive Pulmonary Disease(COPD)
• Unable to swallow capsules
• Unable to obtain informed consent
• Unable to comply with avoidance of honey and propolis containing foods (which interfere with the silybin assays for measurement of plasma concentrations)

Sponsors & Collaborators

• Vanderbilt University: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232-2650, United States

Location

Related Publications (14)

• Wu P, Roberts LJ 2nd, Shintani AK, Sheller JR, Minton PA, Higgins SB, Hartert TV. Changes in urinary dinor dihydro F(2)-isoprostane metabolite concentrations, a marker of oxidative stress, during and following asthma exacerbations. Free Radic Res. 2007 Sep;41(9):956-62. doi: 10.1080/10715760701444600.

  PMID: 17729112 BACKGROUND

• Britton JR, Pavord ID, Richards KA, Knox AJ, Wisniewski AF, Lewis SA, Tattersfield AE, Weiss ST. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med. 1995 May;151(5):1383-7. doi: 10.1164/ajrccm.151.5.7735589.

  PMID: 7735589 BACKGROUND

• Fogarty A, Britton J. The role of diet in the aetiology of asthma. Clin Exp Allergy. 2000 May;30(5):615-27. doi: 10.1046/j.1365-2222.2000.00766.x. No abstract available.

  PMID: 10792352 BACKGROUND

• Grievink L, Smit HA, Ocke MC, van 't Veer P, Kromhout D. Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms and pulmonary function: the MORGEN study. Thorax. 1998 Mar;53(3):166-71. doi: 10.1136/thx.53.3.166.

  PMID: 9659349 BACKGROUND

• Hatch GE. Asthma, inhaled oxidants, and dietary antioxidants. Am J Clin Nutr. 1995 Mar;61(3 Suppl):625S-630S. doi: 10.1093/ajcn/61.3.625S.

  PMID: 7879729 BACKGROUND

• Miedema I, Feskens EJ, Heederik D, Kromhout D. Dietary determinants of long-term incidence of chronic nonspecific lung diseases. The Zutphen Study. Am J Epidemiol. 1993 Jul 1;138(1):37-45. doi: 10.1093/oxfordjournals.aje.a116775.

  PMID: 8333425 BACKGROUND

• Comhair SA, Xu W, Ghosh S, Thunnissen FB, Almasan A, Calhoun WJ, Janocha AJ, Zheng L, Hazen SL, Erzurum SC. Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity. Am J Pathol. 2005 Mar;166(3):663-74. doi: 10.1016/S0002-9440(10)62288-2.

  PMID: 15743779 BACKGROUND

• Comhair SA, Bhathena PR, Dweik RA, Kavuru M, Erzurum SC. Rapid loss of superoxide dismutase activity during antigen-induced asthmatic response. Lancet. 2000 Feb 19;355(9204):624. doi: 10.1016/S0140-6736(99)04736-4.

  PMID: 10696986 BACKGROUND

• Gazak R, Walterova D, Kren V. Silybin and silymarin--new and emerging applications in medicine. Curr Med Chem. 2007;14(3):315-38. doi: 10.2174/092986707779941159.

  PMID: 17305535 BACKGROUND

• Weyhenmeyer R, Mascher H, Birkmayer J. Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther Toxicol. 1992 Apr;30(4):134-8.

  PMID: 1572758 BACKGROUND

• Wen Z, Dumas TE, Schrieber SJ, Hawke RL, Fried MW, Smith PC. Pharmacokinetics and metabolic profile of free, conjugated, and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract. Drug Metab Dispos. 2008 Jan;36(1):65-72. doi: 10.1124/dmd.107.017566. Epub 2007 Oct 3.

  PMID: 17913795 BACKGROUND

• Nelson SK, Bose SK, Grunwald GK, Myhill P, McCord JM. The induction of human superoxide dismutase and catalase in vivo: a fundamentally new approach to antioxidant therapy. Free Radic Biol Med. 2006 Jan 15;40(2):341-7. doi: 10.1016/j.freeradbiomed.2005.08.043.

  PMID: 16413416 BACKGROUND

• Erzurum SC, Lemarchand P, Rosenfeld MA, Yoo JH, Crystal RG. Protection of human endothelial cells from oxidant injury by adenovirus-mediated transfer of the human catalase cDNA. Nucleic Acids Res. 1993 Apr 11;21(7):1607-12. doi: 10.1093/nar/21.7.1607.

  PMID: 8479912 BACKGROUND

• Roberts LJ, Morrow JD. Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. Free Radic Biol Med. 2000 Feb 15;28(4):505-13. doi: 10.1016/s0891-5849(99)00264-6.

  PMID: 10719231 BACKGROUND

MeSH Terms

Conditions

Asthma

Interventions

Silymarin; milk-thistle extract

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Flavonolignans; Flavonoids; Chromones; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Tina V. Hartert, MD, MPH

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: May 4, 2009
• First Posted: January 14, 2010
• Study Start: September 1, 2010
• Primary Completion: September 1, 2010
• Study Completion: September 1, 2010
• Last Updated: February 24, 2014

Record last verified: 2014-02

Locations

US (1)