Official Title: “Elucidation of Acid-Induced Pulmonary Inflammation”

We propose to study how heartburn may lead to different types of inflammation in one's airways. Additionally, we hope to determine whether aggressive treatment of heartburn results in improvement in both symptoms of heartburn and asthma but also in documented improvement in airway inflammation as determined by biopsy. The results of this study will be important in directing future research into the relationship between heartburn and asthma and may provide a clue whether certain subtypes of asthma may be caused primarily by GER.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: December 2008

Currently, many Americans suffer from asthma. The exact mechanism by which airway inflammation leads to asthma symptoms has yet to be clearly explained. In previous studies, persons with asthma appear to have different types of inflammation in their lungs. The reasons for this difference remain a mystery. Allergy is known to play a role in bronchospasm. Other mechanisms have not been discovered.

It is known that asthma and heartburn are correlated. Studies have confirmed a direct relationship between cough and heartburn (Gastroesophageal reflux). Other researchers have determined that asthma is often worsened by gastroesophageal reflux (GER). Determination of the exact relationship between these two entities remains unclear.

We propose that heartburn may contribute to airway inflammation in asthmatics, resulting in different patterns of inflammation between those people with and without GER. In fact, adult-onset asthma may result primarily from longstanding heartburn. This has yet to be proven.

We propose to study how heartburn may lead to different types of inflammation in one's airways. Additionally, we hope to determine whether aggressive treatment of heartburn results in improvement in both symptoms of heartburn and asthma but also in documented improvement in airway inflammation as determined by biopsy. The results of this study will be important in directing future research into the relationship between heartburn and asthma and may provide a clue whether certain subtypes of asthma may be caused primarily by GER.

A total of 30 subjects will be studied, randomized to twice daily esomeprazole versus placebo. Study procedures are as follows:

A. Esophageal studies and validated questionnaires:

Patients will be evaluated with validated SF-36 Quality of Life Questionnaire, Mini-asthma Quality of Life Questionnaire, and GER Questionnaire 35-7. Patients will undergo esophageal manometry and pH detection with a 24- hour pH probe to confirm the presence of pathologic GER.

B. Bronchoscopy:

After an overnight fast, subjects will report to the bronchoscopy suite as directed.

Bronchoscopy with bronchoalveolar lavage and bronchial biopsy will be performed by Dr. Wayne Samuelson following the University of Utah's standardized protocol. Bronchoscopy and endobronchial biopsies present minimal risk to asthmatic airways when performed by appropriate, trained personnel.40-42 Conscious sedation with intravenous remifentanyl and propofol will be administered by a trained nurse experienced in conscious sedation. The nose and pharynx will be anesthetized with 1% lidocaine administered by nebulization and by lidocaine jelly administered topically to the nasal mucosa. Additional lidocaine will be administered via the bronchoscope to the vocal cords, trachea, main carina and mainstem bronchi. The total dose of lidocaine will not exceed 400 mg 43. All subjects will have continuous cardiac and oxygen saturation monitoring and will receive supplemental oxygen during the procedure sufficient to maintain SpO2 > 90%.

The subject will be placed in a recumbent position and the bronchoscope will be introduced via the nose. After passing the vocal cords, the bronchoscope will be introduced via the right mainstem bronchus into the right middle lobe where it will be wedged into a segmental bronchus. (Should, for any reason, the right middle lobe be inaccessible, the same procedure will be used to wedge the bronchoscope into a lingular segment in the left lung.) A 60 cc aliquot of room temperature normal saline will be instilled through the bronchoscope and recovered using the same syringe. This procedure will be repeated three more times (total lavage volume of 240 cc) and the recovered volumes will be pooled and measured. Forceps biopsies of respiratory mucosa will then be taken from the trachea, main carina, bronchus intermedius and right middle lobe areas. Two to six biopsies will be taken from each site.

Specific tissue from each site will be frozen and stored for future use.

Individuals will be randomized to esomeprazole 40 mg twice daily or placebo (all patients will undergo lifestyle modification for reflux). It has been determined in previous studies that higher levels of acid suppression are needed to result in clinical improvement in asthma.52 The drug will be taken for 3-5 months. The variable duration of drug consumption allows for stabilization of medical therapy prior to repeat biopsies (if needed).

Patients will be monitored by telephone at monthly intervals. Rescue inhaler use, hospitalizations, exercise tolerance, and study compliance will be assessed and recorded to document clinical progress. Patients will be asked to maintain their standard inhaler therapy (especially that of inhaled steroids). Any changes to the therapy will be immediately reported to the investigators. If subjects experience an acute flare, appropriate medications will be given until the patient is stable to return to their initial inhaler regimen. The variable time frame for repeat bronchoscopy (3-5 months) was chosen to allow for stabilization of inhaler regimen (if this was disrupted) prior to repeat biopsies. If patients remain on stable medication throughout the trial, repeat bronchoscopy will be performed at 3 months.

After 2 months of therapy, the mini-asthma quality of life instrument and SF-36 will be administered again. This will also administered at the end of the trial.

After 3-5 months, patients will once again undergo bronchoscopy with BAL/biopsies. Cytokine protein arrays will be repeated. Comparisons will then be made intra-group before and after therapy. Additional comparisons of inflammation and bronchial hyper-responsiveness will be made between groups. Randomization will allow the investigators to control for any changes in cytokine patterns due to seasonal affect (if both groups reduce the concentration of IL-5 in a similar pattern, this is more likely seasonal than due to acid suppression).

Intervention(s) in this Clinical Trial

• Drug: lansoprazole
  • 30 mg of placebo or lansoprazole twice daily for 2-4 months
• Drug: placebo
  • placebo comparator to lansoprazole, 30 mg, twice a day

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
• Placebo Comparator: 2
  • placebo

Primary Measures

• To determine whether treatment of asthmatics with gastric acid suppressing medication will decrease bronchial inflammation and bronchoreactivity in asthmatics. We will demonstrate a decrease in specific cytokine expression and inflammatory infiltrate in
  • Time Frame: 6 months
    Safety Issue?: No

Secondary Measures

• To determine whether reduction in inflammation in pulmonary biopsies (as defined by reduction in specific cytokines or cellular infiltrate) correlates with improvement in pulmonary symptoms as defined by use of rescue inhalers or validated asthma quality
  • Time Frame: 6 months
    Safety Issue?: No

Inclusion Criteria:

• 1. asthmatic
• 2. Gastroesophageal reflux

Exclusion Criteria:

• 1. Severe asthmatics who have been hospitalized within the last 6 months or who have required oral steroid use within the last 4 weeks
• 2. Severe coronary artery disease
• 3. Cigarette/cigar smoking within the last 6 months
• 4. Documented allergies affecting the respiratory system
• 5. Subjects with contraindications to pH/impedance probe
• 1. Hemophilia
• 2. Septal deviation
• 6. Subjects with contraindications to bronchoscopy as outlined by the American Thoracic
• Society Guidelines
• 7. Anticoagulation
• 8. Pregnancy
• 9. Incarcerated patients
• 10. Current oral steroid use (may suppress levels of inflammation)
• 11. Upper respiratory infection within the last 2 weeks
• 12. Ongoing acid suppression with a proton pump inhibitor, however, patients may be included if they have discontinued their proton pump inhibitor within the last 1 month with stable asthma symptoms as defined by stable utilization of inhaled steroids

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Utah

Overall Clinical Trial Officials and Contacts

Kathryn Peterson, MD Principal Investigator University of Utah  

Overall Contact: Kristen L Thomas, BS 801-587-9854 kristen.thomas@hsc.utah.edu

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00361972

Study ID Number: 15444

ClinicalTrials.gov Identifier: NCT00361972

Health Authority: United States: Institutional Review Board