Study of Acid Reflux in Asthma

• ClinicalTrials.gov Identifier: NCT00069823
• Recruitment Status: Completed
• First Posted: October 3, 2003
• Results First Posted: October 19, 2012
• Last Update Posted: December 19, 2012
• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: American Lung Association Asthma Clinical Research Centers; National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Robert Wise, Johns Hopkins Bloomberg School of Public Health

Tracking Information

• First Submitted Date: October 1, 2003
• First Posted Date: October 3, 2003
• Results First Submitted Date: May 14, 2010
• Results First Posted Date: October 19, 2012
• Last Update Posted Date: December 19, 2012
• Study Start Date: September 2003
• Actual Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 17, 2012)

Episodes of Poor Asthma Control (EPAC) From Diary Cards, According to Definition That Did Not Include Use of Beta-agonists as a Criterion [ Time Frame: Baseline to 24 Weeks ]

Episodes of poor asthma control was defined as any one of the following: 2 consecutive days with a drop in peak flow >=30% of baseline; urgent care for asthma; or new use of oral corticosteroids for asthma

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: December 17, 2012)

• Exacerbation Components: >=30% Drop in Peak Expiratory Flow on 2 Consecutive Days [ Time Frame: Baseline to 24 Weeks ]
• Exacerbation Components: Urgent Care Visit [ Time Frame: Measured at Month 6 ]
• Exacerbation Components: New Use of Oral Corticosteroids [ Time Frame: Baseline to 24 Weeks ]
• Asthma Episodes, According to Definition That Included Increased Use of Beta-agonists [ Time Frame: Baseline to 24 Weeks ]
• Use of Rescue Medications [ Time Frame: Baseline to 24 Weeks ]
  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 ]
  Rate of awakening at night because of asthma symptoms
• Pulmonary Function: Change in Prebronchodilator FEV1 [ Time Frame: Baseline to 24 Weeks ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  Mean change

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Acid Reflux in Asthma
• Official Title: The Study of Acid Reflux in Asthma
• Brief Summary: The purpose of this study is to determine if subjects with symptomatic asthma who are assigned to treatment with a proton pump inhibitor (PPI) drug such as Nexium have fewer asthma attacks than similar subjects assigned to placebo treatment.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Asthma
• Lung Diseases
• Lung Diseases, Obstructive

Intervention

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

Study Arms

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

Publications *

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 18, 2012): 403
• Original Enrollment: Not Provided
• Actual Study Completion Date: May 2008
• Actual Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00069823
• Other Study ID Numbers: 157; U01HL072968 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Robert Wise, Johns Hopkins Bloomberg School of Public Health
• Original Responsible Party: Not Provided
• Current Study Sponsor: Johns Hopkins Bloomberg School of Public Health
• Original Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Collaborators

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

Investigators

• Principal Investigator: Robert Wise; Johns Hopkins University School of Public Health

• PRS Account: Johns Hopkins Bloomberg School of Public Health
• Verification Date: December 2012