Asthma Clinical Research Network (ACRN) Trial - Macrolides in Asthma (MIA) (MIA)

• ClinicalTrials.gov Identifier: NCT00318708
• Recruitment Status: Completed
• First Posted: April 27, 2006
• Results First Posted: February 4, 2013
• Last Update Posted: March 23, 2018
• Sponsor: Milton S. Hershey Medical Center
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Vernon M. Chinchilli, PhD, Milton S. Hershey Medical Center

Study Description

Brief Summary:

Asthma can be caused by a variety of factors, including tobacco smoke, allergens, and respiratory airway infections. Many people use inhaled corticosteroid medications to treat their symptoms. These medications, however, are not effective for everyone. Clarithromycin is an antibiotic that may effectively treat asthma in these individuals. This study will evaluate the effectiveness of clarithromycin at controlling asthma symptoms.

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: clarithromycin; Drug: fluticasone propionate; Drug: placebo clarithromycin	Phase 3

Detailed Description:

Asthma prevalence has steadily increased in the United States since the early 1980s; currently, more than 20 million people are diagnosed with asthma. Individuals with this disease may experience periodic attacks of wheezing, shortness of breath, chest tightness, and coughing. While there are many known causes of asthma, including tobacco smoke and other allergens, the exact cause of some asthma cases remains unknown. Research has shown that in some individuals, respiratory airway infections may play a role in the onset and severity of the disease. Inhaled corticosteroids are commonly used to treat asthma; however, they do not effectively control symptoms for everyone. Clarithromycin, an antibiotic medication used to treat bacterial infections, may be an effective asthma treatment for individuals who do not respond well to inhaled corticosteroids. The purpose of this study is to evaluate the effectiveness of clarithromycin at reducing asthma symptoms.

This study will begin with a 4-week run-in period to standardize participants' asthma medication usage. During this time, all participants will stop their current asthma medications and instead will receive inhaled fluticasone twice a day. Albuterol will be available as a rescue medication if necessary. Study visits will take place every 2 weeks. Blood and saliva samples will be obtained for laboratory tests and participants will complete standardized questionnaires to assess asthma symptoms and quality of life. Spirometry will be performed to measure lung function. Medication adherence will be monitored with a daily diary and an electronic pill counting device. At the end of Week 4, participants will be evaluated for study eligibility. If eligible, participants will undergo a bronchoscopy and a lung biopsy to test for Mycoplasma pneumoniae and Chlamydia pneumoniae, two bacteria that have been identified as possible factors in the development of asthma.

The treatment phase of the study will last 16 weeks. Participants will be randomly assigned to receive either 500 mg of clarithromycin or placebo twice a day, plus inhaled fluticasone. At monthly study visits, spirometry and blood collection will be performed. Standardized questionnaires to assess asthma symptoms will be completed every 2 weeks. Medical adherence will continue to be monitored. At the end of Week 16, participants will stop receiving clarithromycin or placebo, but will continue to receive fluticasone. Asthma symptoms, rescue medication usage, quality of life, and lung capacity will be assessed; tissue samples will be examined for the presence of Mycoplasma pneumoniae and Chlamydia pneumoniae. An 8-week washout period will follow to observe any lingering medication effects and to monitor for safety. Monthly study visits during this period will include spirometry and blood collection.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Asthma Clinical Research Network (ACRN) Trial - Macrolides in Asthma (MIA)
• Study Start Date: June 2006
• Actual Primary Completion Date: April 2009
• Actual Study Completion Date: April 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: clarithromycin + fluticasone; clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	Drug: clarithromycin; clarithromycin 500 mg twice daily (Biaxin); Other Name: Biaxin; Drug: fluticasone propionate; fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily); Other Name: Flovent®
Active Comparator: placebo + fluticasone; placebo clarithromycin twice daily + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	Drug: fluticasone propionate; fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily); Other Name: Flovent®; Drug: placebo clarithromycin; placebo clarithromycin twice daily; Other Name: placebo Biaxin

Outcome Measures

Primary Outcome Measures :

1. Juniper Asthma Control Questionnaire (ACQ) Results [ Time Frame: Measured every four weeks during the 16-week treatment period, with the change (week 16 minus baseline) as the primary outcome ]
   The Juniper asthma control questionnaire (ACQ) consists of six questions answered by the asthma patient with respect to symptoms, rescue medication use, and night-time awakenings due to asthma. A seventh item in the ACQ is the percent predicted FEV1. Each of the seven items is scored from from 0 (best) to 6 (worst), and then the seven items are averaged to yield a number from 0 (best) to 6 (worst). Asthma patients needed to display an ACQ greater than or equal to 1.25 in order to be eligible for randomization. A reduction of 0.5 units or more in the ACQ over the 16 weeks of treatment is considered to be clinically significant.

Secondary Outcome Measures :

1. Asthma Rescue Medication Use [ Time Frame: the week-16 average minus the baseline-week average ]
   number of rescue puffs per day
2. AM Peak Expiratory Flow (PEF) [ Time Frame: the week-16 average minus the baseline-week average ]
   daily AM peak expiratory flow (PEF) measured in liters per minute
3. Forced Expiratory Volume in One Second (FEV1) [ Time Frame: the week-16 value minus the baseline-value ]
   Forced expiratory volume in one second (FEV1) from spirometry
4. Methacholine Provocative Concentration (PC20) [ Time Frame: the week-16 value minus the baseline-value ]
   Logarithm-base 2 transformed Methacholine provocative concentration (PC20) based on FEV1
5. Exhaled Nitric Oxide (eNO) [ Time Frame: the week-16 value minus the baseline-value ]
   Exhaled nitric oxide (eNO) measured in parts per billion
6. Asthma Quality of Life Questionnaire (AQLQ) [ Time Frame: the week-16 value minus the baseline-value ]
   The Asthma Quality of Life Questionnaire (AQLQ) consists of 32 questions, with each question ranging from 1 (worst) to 7 (best). The 32 questions are averaged to yield an overall score, which is reported here. Therefore, a positive change between the 16-week score and the baseline score represents improvement.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• History of physician-diagnosed asthma
• Methacholine PC20 less than or equal to 16 mg/ml and/or FEV1 improvement greater than or equal to 12% in response to 180 mcg albuterol
• Stable asthma for at least 6 weeks prior to study entry
• FEV1 greater than or equal to 60% of predicted result following 180 mcg albuterol
• Juniper ACQ score greater than or equal to 1.5 (optimal ACQ score cut-off point for asthma that is "not well-controlled" by NIH/Global Initiative for Asthma [GINA] guidelines)
• Nonsmoker (less than 10 pack-per-year lifetime smoking history and no smoking in the year prior to study entry)
• Able to perform spirometry, as per American Thoracic Society criteria
• 75% adherence with diary cards, fluticasone (monitored with Doser), and placebo pill trial (monitored electronically with Electronic Drug Exposure Monitor [eDEM] pill dose counter) for the final 2 weeks of the four-week run-in period
• At Visit 1, in steroid-naïve participants, no significant adrenal suppression, defined as a plasma cortisol concentration less than 5 mcg/dL. If adrenal suppression occurs, a 250 mcg corticotropin (ACTH) stimulation test will be performed. Plasma cortisol levels will be collected at baseline, and 30 and 60 minutes after the ACTH stimulation test. Participants must have a cortisol concentration greater than 20 mcg/dL on at least one of the post-ACTH time points
• Absence of bronchoscopy-induced exacerbation; if bronchoscopy-induced exacerbation has occurred, prednisone therapy must have stopped at least 6 weeks prior to study entry
• Absence of respiratory tract infection; if infection has occurred, infection-related symptoms must have stopped at least 6 weeks prior to study entry
• Has experienced no more than two exacerbations or respiratory tract infections prior to study entry
• If female and able to conceive, willing to utilize two medically acceptable forms of contraception (one non-barrier method with single barrier method OR double barrier method)

Exclusion Criteria:

• Presence of lung disease other than asthma
• Presence of vocal cord dysfunction, due to potential confounding of ACQ score
• Significant medical illness other than asthma
• History of atrial or ventricular tachyarrhythmia
• Use of any medication that has a significant interaction with clarithromycin, including herbal or alternative therapies
• Asthma exacerbation within 6 weeks of the screening visit or during the run-in period prior to bronchoscopy
• Use of systemic steroids or change in dose of controller therapy within 6 weeks of the screening visit
• Inability, in the opinion of the study investigator, to coordinate use of dry powder or metered-dose inhaler or to comply with medication regimens
• Inability or unwillingness to perform required study procedures
• Prolonged heart rate corrected QT-interval (greater than 450 msec in women and greater than 430 msec in men) on echocardiogram (ECG) at study entry
• Low potassium or magnesium levels (based on local Asthma Clinical Research Network laboratory definitions)
• Abnormal elevation of liver function tests (AST, ALT, total bilirubin, or alkaline phosphatase)
• Abnormal prothrombin time (PT) or partial thromboplastin time (PTT) results
• Reduced creatinine clearance
• Contraindication to bronchoscopy, as determined by medical history or physical examination
• Regular consumption of grapefruit or grapefruit juice
• Pregnant or breastfeeding

Contacts and Locations

Locations

United States, California

University of California, San Diego

San Diego, California, United States, 92093

University of California, San Francisco

San Francisco, California, United States, 94143

United States, Colorado

National Jewish Medical and Research Center

Denver, Colorado, United States, 80206

United States, Massachusetts

Brigham & Women's Hospital

Boston, Massachusetts, United States, 02115

United States, Missouri

Washington University, St. Louis

Saint Louis, Missouri, United States, 63130

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States, 27157

United States, Texas

University of Texas Medical Branch

Galveston, Texas, United States, 77555

United States, Wisconsin

University of Wisconsin, Madison

Madison, Wisconsin, United States, 53706

Sponsors and Collaborators

Milton S. Hershey Medical Center

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: William J. Calhoun, MD; University of Texas, Galveston
• Principal Investigator: Mario Castro, MD; Washington University School of Medicine
• Principal Investigator: Robert F. Lemanske, MD; University of Wisconsin, Madison
• Principal Investigator: Richard J. Martin, MD; National Jewish Health
• Principal Investigator: Elliot Israel, MD; Brigham and Women's Hospital
• Principal Investigator: Stephen P. Peters, MD, PhD; Wake Forest University Health Sciences
• Principal Investigator: Homer A. Boushey, MD; University of California, San Francsico
• Principal Investigator: Stephen I. Wasserman, MD; University of California, San Diego
• Principal Investigator: Emily DiMango, MD; Columbia University
• Principal Investigator: Monica Kraft, MD; Duke University
• Study Chair: Reuben M Cherniack, MD; National Jewish Health

More Information

Additional Information:

Click here for the Asthma Clinical Research Network (ACRN) web site 

Publications of Results:

Sutherland ER, King TS, Icitovic N, Ameredes BT, Bleecker E, Boushey HA, Calhoun WJ, Castro M, Cherniack RM, Chinchilli VM, Craig TJ, Denlinger L, DiMango EA, Fahy JV, Israel E, Jarjour N, Kraft M, Lazarus SC, Lemanske RF Jr, Peters SP, Ramsdell J, Sorkness CA, Szefler SJ, Walter MJ, Wasserman SI, Wechsler ME, Chu HW, Martin RJ; National Heart, Lung and Blood Institute's Asthma Clinical Research Network. A trial of clarithromycin for the treatment of suboptimally controlled asthma. J Allergy Clin Immunol. 2010 Oct;126(4):747-53. doi: 10.1016/j.jaci.2010.07.024.

• Responsible Party: Vernon M. Chinchilli, PhD, Distinguished Professor and Chair, Department of Public Health Sciences, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00318708
• Other Study ID Numbers: 377; U10HL074231 ( U.S. NIH Grant/Contract ); 5U10HL074231 ( U.S. NIH Grant/Contract ); 7U10HL074206 ( U.S. NIH Grant/Contract ); 5U10HL074208 ( U.S. NIH Grant/Contract ); 5U10HL074073 ( U.S. NIH Grant/Contract ); 5U10HL074227 ( U.S. NIH Grant/Contract ); 5U10HL074225 ( U.S. NIH Grant/Contract ); 5U10HL074204 ( U.S. NIH Grant/Contract ); 5U10HL074218 ( U.S. NIH Grant/Contract ); 5U10HL074212 ( U.S. NIH Grant/Contract )
• First Posted: April 27, 2006
• Results First Posted: February 4, 2013
• Last Update Posted: March 23, 2018
• Last Verified: March 2018

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Fluticasone; Xhance; Clarithromycin; Anti-Inflammatory Agents; Bronchodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Asthmatic Agents; Respiratory System Agents; Dermatologic Agents; Anti-Allergic Agents; Anti-Bacterial Agents; Anti-Infective Agents; Protein Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors