Randomized Controlled Trial of Silymarin in Asthma

Sponsor

Vanderbilt University (Other)

Overall Status

Withdrawn

CT.gov ID

NCT01049178

Collaborator

(none)

Enrollment

Location

Arms

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Atopic Asthma	Drug: Oral Silymarin Drug: Oral Silymarin, maintenance dose Drug: Placebo	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Care Provider)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Sep 1, 2010

Actual Primary Completion Date :

Sep 1, 2010

Actual Study Completion Date :

Sep 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral silymarin dose Dose escalation study	Drug: Oral Silymarin 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. Other Names: Legalon Milk Thistle Drug: Oral Silymarin, maintenance dose 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. Other Names: Legalon Milk Thistle
Placebo Comparator: placebo 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

Arm

Intervention/Treatment

Experimental: Oral silymarin dose

Dose escalation study

Drug: Oral Silymarin

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.

Other Names:

Legalon

Milk Thistle

Drug: Oral Silymarin, maintenance dose

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.

Other Names:

Legalon

Milk Thistle

Placebo Comparator: placebo

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

Outcome Measures

Primary Outcome Measures

Exhaled nitric oxide (eNO), an indirect measure of airway inflammation that correlates with clinical asthma measures. [20-40 weeks]

Secondary Outcome Measures

Spirometry, disease control, urinary isoprostanes, antioxidant enzyme concentrations, silybin concentrations, acceptability, ability to maintain blinding, effect size for secondary clinical outcomes. [20-40 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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)