IRB protocol violations

Asthma is a chronic lung disease that affects millions of people worldwide, including both children and adults. The cause of asthma is not known, but asthma is strongly associated with inflammation of the airways, often caused by allergies. In order to control this inflammation, most people with asthma are treated with inhaled medications that contain steroids. These medications do a good job of helping most people with asthma feel better. However, these medications are expensive, have side effects, and do not control symptoms in all people with asthma. Recently basic science research colleagues have shown that inflammation due to allergies can be reduced in experimental animals by a naturally occurring bile acid. Bile acids are chemicals made in the liver that are involved in maintaining healthy digestion of fat. Since bile acids are made by our bodies, they have become popular as over the counter supplements that are thought to be important in promoting a healthy liver and metabolism. Interestingly, other research has shown that bile acids may help patients with neurological disease and diabetes.

Given all of this information, the investigators propose that a specific bile acid called tauroursodeoxycholic acid (TUDCA) may be helpful in patients with asthma. Before studying this in a clinical trial, the current study is designed to demonstrate that people with asthma can take TUDCA safely and that it doesn't hurt their asthma. The study will involve inviting 12 patients with mild asthma to take TUDCA daily for 12 weeks. During this time the investigators will closely monitor them for any side effects and check their blood and breathing capacity for any signs of detrimental effects. In addition, the investigators will collect cells that line the nose, which are thought to be similar to cells in the airways of the lungs, to see if TUDCA is having any beneficial effects on inflammation. In order to ensure the use of high quality TUDCA, which may or may not be true of over the counter supplements, the investigators have asked the company that is supplying TUDCA for the studies mentioned previously involving neurological disease and diabetes to supply the drug; the brand name is Taurolite. In addition, even though TUDCA is available over the counter, in order to use it for research, the FDA has to approve this use. Accordingly, the investigators have applied for and received permission (IND) from the FDA to use Taurolite for this study.

Study Design: This study will be a Phase 1, pre-post intervention trial in patients with asthma who will be treated with TUDCA 1750 mg per day for 12 weeks. The investigators have obtained TUDCA from Bruschettini (http://www.bruschettini.com), which is an authorized Italian pharmaceutical company that can provide validation of the drug's manufacture and purity. Bruschettini markets TUDCA under the brand name Taurolite. The investigators have received an IND from the FDA for use of Taurolite in this study (see document).

Protocol: All participants will undergo an initial screening visit by telephone to determine. Participants will then present to the Vermont Lung Center in Colchester for 2 study visits, during which the following testing and information will be obtained:

Visit 1 (Baseline)

• Demographics: age, sex, height, weight
• Concomitant medical problems and medications
• Asthma control by ACT
• Lung function testing: spirometry (FEV1, FVC, FEV1/FVC) (43), forced oscillation technique (FOT) (R5, R20, X5, AX, Fres) (44)
• Fraction of exhaled nitric oxide (FeNO) as a general measure of eosinophilic inflammation(45)
• Blood sample collection for routine chemistries (10 cc), and for analysis of serum markers of inflammation (10 cc).
• Nasal brushing for collection of epithelial cells for analysis of serum markers of ER stress and UPR The participant will then receive a supply of medication, TUDCA 250 mg, to be taken 500 mg with breakfast, 500 mg with lunch, 750 mg with dinner, daily, for 12 weeks.

The participant will also receive a daily diary to use to record daily symptoms of asthma and any side effects, as well as compliance with taking the medication.

Visit 2 (Week 4) and Visit 3 (Week 8)

• Review of diary for side effects, adverse events
• Asthma control by ACT, spirometry, FeNO
• Blood for routine chemistries as part of ongoing safety monitoring Visit 4 (Week 12) All testing as listed for Visit 1 will be repeated, with collection of any remaining drug and all diary data.

Telephone Calls (Weeks 2,6,10) The investigators will call participants every 2 weeks in between study visits to assess tolerability and remind participants to complete their daily diaries. The investigators will use a standardized questionnaire for study coordinators to use during each assessment by telephone to determine whether there have been any adverse events.

Inclusion Criteria:

• Men and women, aged 18 and older, with a physician diagnosis of asthma
• Current non-smoker with < 10 pack-years smoking history and no smoking within the last year
• Stable asthma control over the last 3 months as defined by Asthma Control Test (ACT) ≥ 20 (40)
• Stable asthma medication regimen over the last 3 months
• FEV1 ≥ 70% predicted

Exclusion Criteria:

• Current smoking or ≥10 pack-years of smoking or any smoking within the last year
• Poor asthma control as defined by ACT< 20
• Exacerbation of disease within previous 4 weeks
• Recent upper respiratory infection within last 4 weeks
• Acute or chronic rhinosinusitis
• Use of chronic nasal corticosteroids, or any use of nasal corticosteroids during the study
• Concomitant heart, lung or GI disease (liver, peptic ulcer) that would potentially jeopardize the safety of the participant or interfere with interpretation of the results