Study of Acid Reflux in Asthma

• Exacerbation Components: >=30% Drop in Peak Expiratory Flow on 2 Consecutive Days [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
• Exacerbation Components: Urgent Care Visit [ Time Frame: Measured at Month 6 ] [ Designated as safety issue: No ]
• Exacerbation Components: New Use of Oral Corticosteroids [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
• Asthma Episodes, According to Definition That Included Increased Use of Beta-agonists [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
• Use of Rescue Medications [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Increase in the use of rescue meds by 4 or more uses on a particular day above the average uses during the run-in period.
• Night Awakening [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Rate of awakening at night because of asthma symptoms
• Pulmonary Function: Change in Prebronchodilator FEV1 [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change in pre-bronchodilator FEV1 - forced expiratory volume in 1 second; a measure of pulmonary function. The treatment effect is the difference in the mean change in between the groups.
• Pulmonary Function: Change in Prebronchodilator Forced Vital Capacity [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Pulmonary function measured by mean change in Prebronchodilator forced vital capacity from baseline to 24 weeks
• Pulmonary Function: Change in Peak Flow Rate [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change from baseline to 24 weeks in the peak flow rate - how forceful patient can blow out air
• Pulmonary Function: Change in PC20 [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean Change in the dose of methacholine that results in a 20% drop in FEV1
• Change in Juniper Asthma Control Score(JACQ) [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change. Scores on the JACQ range from 0 to 6, with lower scores indicating better asthma control and 0.5 as the minimal clinically important difference.
• Change in Asthma Symptom Utility Index (ASUI) [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change. Scores on the ASUI range from 0 to 1, with higher scores indicating less severe asthma.
• Change in the Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ) [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change. Scores on the Mini-Asthma Quality of Life Questionnaire (mini-AQLQ)range from 1 to 7, with higher scores indicating better quality of life and 0.5 as the minimal clinically important difference.
• Change in Medical Outcomes Study Short-Form 36 Score Quality of Life Score: Physical Component [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change. Scores on the Medical Outcomes Study Short-Form 36 range from 1 to 100, with higher scores indicating better quality of life and 5 as the minimal clinically important difference.
• Change in Medical Outcomes Study Short-Form 36 Quality of Life Score: Mental Component [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change. Scores on the Medical Outcomes Study Short-Form 36 range from 1 to 100, with higher scores indicating better quality of life and 5 as the minimal clinically important difference.
• Change in Gastric Symptoms: Gastroesophageal Reflux Disease Symptom Assessment Scale Score [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change. The Gastroesophageal Reflux Disease Symptom Assessment Scale score ranges from 0 to 3, with lower numbers indicating less distress.
• Change in Number of Gastric Symptoms: No. of Symptoms [ Time Frame: Baseline to 24 Weeks ] [ Designated as safety issue: No ]
  Mean change

BACKGROUND:

Gastroesophageal reflux (GERD) is frequent in asthmatics with poor asthma control, often occurs without symptoms, and can induce bronchoconstriction. Poorly controlled asthmatics are often treated for GERD with drugs that suppress gastric acid, but this treatment is expensive and the benefit of such treatment is not established. Proton pump inhibitors are a relatively new class of medications that provide highly effective treatment for GERD and associated problems. This success has led many doctors to begin PPI treatment in their asthma patients in an attempt to achieve better asthma control.

DESIGN NARRATIVE:

The randomized, placebo-controlled trial will enroll 400 asthmatics, ages 18 or older, who have poor asthma control on inhaled steroids, defined on the basis of excessive bronchodilator use, nocturnal awakenings, or frequent exacerbations. Participants will be randomly assigned to treatment with either a proton pump inhibitor, esomeprazole (Nexium) 40 mg twice a day, or matching placebo. The presence, severity, and temporal relationship of GERD to asthma symptoms will be documented with 24 hour ambulatory esophageal potential Hydrogen (pH) probe monitoring, but participants will be enrolled irrespective of the severity of GERD. The primary outcome measure is the proportion of participants who have exacerbations of asthma within a 6-month period defined by asthma diaries and interviews. Secondary outcome measures include asthma symptom and control scores, asthma-specific and generic health-related quality of life, GERD symptoms, health care use, pulmonary function, and airways reactivity. Pre-specified subgroup analyses will be conducted to determine if there are clinical or demographic characteristics that predict benefit from treatment of GERD in asthma.

• Asthma
• Lung Diseases
• Lung Diseases, Obstructive

• Drug: Esomeprazole
  Proton pump inhibitor 40 mg orally twice daily
  Other Name: Nexium
• Drug: Placebo proton pump inhibitor
  Placebo proton pump inhibitor

• Experimental: Esomeprazole
  Proton pump inhibitor of gastric acid
  Intervention: Drug: Esomeprazole
• Placebo Comparator: Placebo for esomeprazoe
  Placebo
  Intervention: Drug: Placebo proton pump inhibitor

• Bime C, Wei CY, Holbrook JT, Sockrider MM, Revicki DA, Wise RA. Asthma symptom utility index: reliability, validity, responsiveness, and the minimal important difference in adult asthmatic patients. J Allergy Clin Immunol. 2012 Nov;130(5):1078-84. doi: 10.1016/j.jaci.2012.07.058. Epub 2012 Sep 29.
• Bime C, Wei CY, Holbrook J, Smith LJ, Wise RA. Association of dietary soy genistein intake with lung function and asthma control: a post-hoc analysis of patients enrolled in a prospective multicentre clinical trial. Prim Care Respir J. 2012 Dec;21(4):398-404. doi: 10.4104/pcrj.2012.00073.
• DiMango E, Holbrook JT, Simpson E, Reibman J, Richter J, Narula S, Prusakowski N, Mastronarde JG, Wise RA; American Lung Association Asthma Clinical Research Centers. Effects of asymptomatic proximal and distal gastroesophageal reflux on asthma severity. Am J Respir Crit Care Med. 2009 Nov 1;180(9):809-16. doi: 10.1164/rccm.200904-0625OC. Epub 2009 Aug 6.
• American Lung Association Asthma Clinical Research Centers, Mastronarde JG, Anthonisen NR, Castro M, Holbrook JT, Leone FT, Teague WG, Wise RA. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009 Apr 9;360(15):1487-99. doi: 10.1056/NEJMoa0806290.

Inclusion Criteria:

• The general goal of patient selection is to enroll patients for whom asthma physicians might prescribe GERD treatment, but where there is uncertainty whether it might be effective.
• Age 18 or older
• Physician diagnosed asthma
• If amount of air expired in the first second during a forced expiratory maneuver (FEV1) is greater than or equal to 70% predicted normal pre-bronchodilator: demonstrate methacholine 20% from post-diluent baseline (PC20). PC20 less than 16 mg/ml during Visit 1
• If FEV1 less than 70% and greater than or equal to 50% predicted normal pre-bronchodilator: demonstrate 12% reversibility during Visit 1 or within past 12 months
• Currently on stable dose of daily inhaled steroids for asthma control, i.e., inhaled corticosteroid equivalent to 400 ug/day of fluticasone44 or greater for 8 weeks or longer
• Poor asthma control: Either of the following; a score of 1.5 or greater on the Juniper Asthma Control Questionnaire; two or more episodes of asthma symptoms in the past 12 months with each episode requiring at least one of the following: an emergency department visit, unscheduled physician visit, prednisone course, hospitalization
• Non-smoker for 6 months or longer
• Less than 10 pack/year smoking history

Exclusion Criteria:

• Surgery: Previous anti-reflux or peptic ulcer surgery
• Pulmonary function: FEV1 less than 50% predicted normal pre-bronchodilator
• GERD Symptoms: Severe reflux constituting a clinical indication for treatment with a PPI or H2 blocker, typically two or more episodes per week of heartburn requiring antacids
• Other major chronic illnesses; conditions which in the judgment of the Study Physician would interfere with participation in the study, e.g., non-skin cancer, endocrine disease, coronary artery disease, congestive heart failure, stroke, severe hypertension, Type 1 insulin dependent diabetes mellitus, renal failure, liver disorders, immunodeficiency states, major neuropsychiatric disorder
• Medication use: Anti-reflux medication (proton pump inhibitors or H2 blockers) within 1 month Theophylline, azoles, iron, anti-coagulants, insulin (for Type I diabetes), digitalis, any investigative drugs within 1 month
• Drug allergy: Previous adverse effects from proton pump inhibitors or methacholine challenge
• Females of childbearing potential: Pregnant or lactating, unwilling to practice an adequate birth control method (abstinence, combination barrier and spermicide, or hormonal)
• Inability or unwillingness to provide consent
• Inability to perform baseline measurements
• Completion of less than 10 of the last 14 days of screening period diary entry
• Inability to be contacted by telephone
• Intention to move out of the area within 6 months

• American Lung Association Asthma Clinical Research Centers
• National Heart, Lung, and Blood Institute (NHLBI)