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Atopic AsthmaPhase 2/3NCT01049178

Randomized Controlled Trial of Silymarin in Asthma

A Phase 2/3 study testing Oral Silymarin and Oral Silymarin, maintenance dose in people with Atopic Asthma, run by Vanderbilt University at 1 site in United States.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Atopic Asthma
What is being tested?
Oral Silymarin and Oral Silymarin, maintenance dose
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
0 participants
Where
1 siteUnited States
Study dates
Sep 2010to Sep 2010
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Inclusion Criteria Male or female subject with confirmed asthma, AND
  • 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

Who cannot join

  • 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)
Show all 10Show fewer
  • 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)

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Vanderbilt University Medical Center

    Nashville, Tennessee, 37232-2650

Other trials in United States

About this study

Official title: Antioxidant Enzyme Induction as a New Approach to Therapy in Patients With Asthma

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.

Read the detailed description

SPECIFIC AIMS

Dietary intake of exogenous antioxidants has been shown to have only a modest impact on asthma inception and control. Our work has demonstrated that endogenous antioxidant enzyme concentrations are a far stronger predictor of asthma inception compared with dietary antioxidant intake and/or serum antioxidant concentrations. This is likely because we regulate oxidative stress to a greater extent, not by exogenous intake, but by antioxidant enzymes. The milk thistle plant extract, silymarin, has been shown to be an inducer of the endogenous antioxidant enzymes, superoxide dismutase and catalase. As reactive oxygen species have been implicated in the pathogenesis of asthma and, in atopic asthmatics, endogenous superoxide dismutase (SOD) enzyme levels are known to decrease, this supports that increasing SOD levels, either by induction of endogenous SOD or replacing a failed endogenous SOD enzyme system with a mimetic of the endogenous enzyme, would be beneficial and protective. We hypothesize that administration of silymarin, an inducer of antioxidant enzymes, to subjects with atopic asthma will increase antioxidant enzyme concentrations, decrease markers of oxidative stress, decrease indirect measures of airway inflammation that have been correlated with clinical outcomes (exhaled nitric oxide, eNO), and thus improve lung function and symptom scores in participants with asthma. To test this hypothesis we will conduct a randomized, double-masked, placebo-controlled cross-over pilot investigation of an inducer of endogenous antioxidant enzymes, silymarin, in asthma. No clinical trial has tested either silymarin, or any inducer of antioxidant enzymes in patients with asthma. We therefore aim to determine whether this novel treatment is effective, and if both inflammatory and clinical endpoints are improved with treatment.

Specific questions related to modification of endogenous antioxidant enzymes in prevalent asthma that this investigation aims to address are whether induction of antioxidant enzymes can alter inflammatory markers in asthma that are known to be linked with clinical endpoints, lung function and oxidant stress. Measurements of antioxidant enzymes will be made in blood samples prior to and following administration of silymarin; measures of systemic oxidative stress will be made in urine samples using an assay for isoprostanes, considered the most accurate marker of oxidative stress currently available; measures of airway inflammation will be measured using exhaled NO, and lung function testing and symptom control will be assessed as clinical measures of disease control.

Aim #1: To confirm that oral administration of silymarin in subjects with atopic asthma increases endogenous antioxidant enzymes. We hypothesize that silymarin will increase levels of antioxidant enzymes, superoxide dismutase activity, catalase activity, and glutathione peroxidase activity in subjects with atopic asthma. To test this hypothesis, we will first conduct a dose escalation study to determine optimal dosing, dose effect, and washout on airway inflammation, followed by a randomized, double-masked, placebo-controlled cross-over pilot investigation of supplementation with silymarin in subjects with atopic asthma with measurements of antioxidant enzyme activity pre-, during and at the completion of both active supplementation and placebo arms of the study.

Aim #2: To determine whether oral administration of silymarin to subjects with atopic asthma alters indirect measures of airway inflammation and systemic oxidative stress. We hypothesize that silymarin will decrease airway inflammation and measures of systemic oxidative stress. To test this we will assess indirect measures of airway inflammation, including exhaled nitric oxide and nitric oxide related products, and measures of systemic oxidant stress, urinary isoprostanes pre-, during and at the end of supplementation in the study subjects enrolled in this clinical trial.

Aim #3: To determine whether oral administration of silymarin to subjects with atopic asthma improves asthma morbidity, daily symptoms, disease control, disease exacerbations, and spirometry. We hypothesize that silymarin will improve asthma control and decrease morbidity. Although not powered for these outcomes, to test this hypothesis we will assess and evaluate the trends and magnitude of the effect of silymarin on asthma control, spirometry and disease exacerbations in the above study subjects.

Aim #4: To determine feasibility, acceptance of randomization, adherence to therapy, acceptance of drug delivery and dosing, ability to maintain blinding, and clinical effect size. The intent of this aim is to optimize the overall protocol design and procedures for a future larger study.

Conditions
Atopic Asthma
Being tested
Oral Silymarin, Oral Silymarin, maintenance dose, Placebo
Keywords
antioxidant enzymes, asthma, silymarin, RCT
Medical subject headings
Asthma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Oral SilymarinDrug

    Also called Legalon, Milk Thistle

    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.

  • Oral Silymarin, maintenance doseDrug

    Also called Legalon, Milk Thistle

    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.

  • PlaceboDrug

Study groups in NCT01049178
Study groupRoleWhat they receive
Oral silymarin doseExperimentalDose escalation study
Receives: Drug: Oral Silymarin; Drug: Oral Silymarin, maintenance dose
placeboPlacebo comparatorA randomized, double-masked, placebo-controlled cross-over clinical pilot investigation of an inducer of endogenous antioxidant enzymes, silymarin, in humans with atopic asthma.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: 20-40 weeks

Secondary outcomes (1)
  1. Spirometry, disease control, urinary isoprostanes, antioxidant enzyme concentrations, silybin concentrations, acceptability, ability to maintain blinding, effect size for secondary clinical outcomes.

    Measured: 20-40 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jan 2010 (estimated)
  2. Study startSep 2010
  3. Primary completionSep 2010
  4. Study completionSep 2010

Why it stopped: Lack of funding

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Double blind
Who is masked
Participant, Care provider
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01049178
Sponsor's protocol ID
IRB 090053
Status last verified
Feb 2014
First submitted
4 May 2009
Last updated
24 Feb 2014
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 17729112
  • 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.

    PubMed 7735589
  • 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.

    PubMed 10792352
  • 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.

    PubMed 9659349
  • 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.

    PubMed 7879729
  • 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.

    PubMed 8333425
  • 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.

    PubMed 15743779
  • 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.

    PubMed 10696986
  • 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.

    PubMed 17305535
  • 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.

    PubMed 1572758
  • 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.

    PubMed 17913795
  • 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.

    PubMed 16413416
  • 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.

    PubMed 8479912
  • 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.

    PubMed 10719231

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Oral Silymarin and Oral Silymarin, maintenance dose in people with Atopic Asthma, run by Vanderbilt University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 24 Feb 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Exhaled nitric oxide (eNO), an indirect measure of airway inflammation that correlates with clinical asthma measures. (time frame: 20-40 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01049178, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Feb 2014.

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