AZMATICS: AZithroMycin/Asthma Trial In Community Settings

AZMATICS: Azithromycin Asthma Trial In Community Settings

The purpose of this study is to assess the effectiveness of the azalide macrolide azithromycin in adults with persistent asthma.

Research Question: Will a 12-week treatment with the antibiotic, azithromycin, result in a statistically significant and clinically meaningful improvement in overall asthma symptoms and other patient-oriented asthma outcomes one year after initiation of treatment of adult primary care patients with asthma?

Experimental Design: The investigators propose a one-year randomized, placebo-controlled, blinded (investigator, patient, data collector, data analyst) trial of 12 weekly doses of azithromycin/placebo as adjunctive therapy (in addition to usual care) along with a parallel observational cohort who will participate 'open label' in 100 adult asthma patients recruited from practice-based research networks (e.g., Wisconsin Research and Education Network (WREN) and others). This "practical clinical trial" will (1) enroll a representative sample of asthma patients encountered in the practices of primary care physicians, (2) employ standard clinical trial methodology to ensure internally valid results and (3) measure outcomes important to patients, so that the results will be valid and applicable to the kinds of asthma patients encountered by family physicians and other primary care providers.

Active study sites -

• Wisconsin: Augusta, Cross Plains, La Crosse, Marshfield, Milwaukee, Madison,
• Mauston, Rice Lake, Tomah, Wausau
• Colorado: Monument
• Illinois: Peoria
• Nevada: Reno
• North Carolina: Granite Falls
• North Dakota: Minot
• Ohio: Cleveland, Berea
• Oklahoma: Ardmore, Claremore, Edmond, Lawton, Oklahoma City, Stroud, Tulsa, Weatherford
• Rhode Island: East Providence

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: Placebo; Drug: Azithromycin

Detailed Description

1.0 PROTOCOL SYNOPSIS

Approximately 100 eligible adult patients with physician-diagnosed asthma will either be randomized to 12-week treatment with azithromycin or an identical placebo, or join an observational open-label azithromycin cohort. Azithromycin is a widely marketed azalide antibiotic with an excellent safety profile. Azithromycin or placebo will be adjunctive therapy for usual asthma care. The following patient-reported data will be collected via Zoomerang™ (a commercially-available data collection tool) periodically until one year after randomization: (1) study medication adherence and side effects weekly until 12 weeks, (2) asthma control and exacerbations every 6 weeks until 12 months, and (3) asthma quality of life and asthma controller medication changes every 3 months until 12 months. The primary hypothesis is that azithromycin will significantly improve asthma control (decrease symptoms and medication use) by 3 months (end treatment) and the improvement will continue to 12 months (end study). The primary outcome variable is overall asthma symptoms. Secondary outcomes are asthma medication use, quality of life and exacerbations. We will examine the predictive value of baseline patient characteristics including age, sex, smoking, co-morbid respiratory diagnoses and degree of airflow limitation. We will also examine for any imbalances between study groups in controller medication use, other antibiotic prescriptions and acute respiratory illnesses during the one-year study period.

We will enroll subjects from the practices of Wisconsin Research and Education Network (WREN) members, UW Department of Family Medicine physicians, Dean Medical Center primary care physicians, and from other practice-based research networks (PBRNs), medical group practices and individual primary care practices throughout North America.

Patients with physician-diagnosed asthma aged 18 and older will be identified at point-of-service (office, urgent care, emergency room or hospital), by administrative data base review, or by physician recall. Most subjects will be the patients of study physicians. Other physicians in the group practice may refer subjects. Subjects also may be self-referred after responding to posters placed in the clinics. Some sites may elect to identify cases by medical record or database review, in which case only the personal physician may initiate patient contacts.

Treatment is azithromycin tablets, 600 milligrams orally once daily for 3 days, then 600 milligrams once weekly for an additional 11 weeks (total dose 8400 milligrams) or identical placebo, in addition to usual care for asthma.

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Peoria, Illinois, United States, 61602
      • ANSR
  • Kansas
    • Kansas City, Kansas, United States, 66211
      • AAFP National Research Network
  • Ohio
    • Cleveland, Ohio, United States, 44130
      • RAP - Cleveland Clinic
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center (OUHSC) and Oklahoma Physicians Resource/Research Network (OKPRN)
  • Wisconsin
    • Madison, Wisconsin, United States, 53713
      • Wisconsin Research and Education Network (WREN)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 and older (and at least 50 kg/110 pounds)

  • The lower weight limit was chosen to avoid exposure to greater than 12 mg/kg/day of azithromycin (a currently recommended dose for children)
  • We specify no upper age limit because asthma occurs throughout the age range and because asthma in the elderly is particularly severe and warrants inclusion.
• Physician-diagnosed asthma

• At the time of randomization, eligible subjects must either:

  • be having a documented asthma exacerbation OR
  • be reporting at least mild persistent asthma symptoms, as defined by GINA (Global Initiative for Asthma)
• Subjects must also have asthma symptoms for at least six months prior to randomization

• Documentation of objective evidence of reversible airway obstruction, either spontaneously or after treatment, is required prior to randomization. This requirement can be met by documentary evidence, within 2 years of randomization, of either:

  • a 12% or greater (and ≥200 mL) change in FEV1 OR
  • a 25% or greater (and >60 L/min) change in PEFR either spontaneously or as a result of treatment

Exclusion Criteria:

• Not English literate or without email and internet access
• Macrolide allergy
• Pregnancy or lactation
• Females of childbearing potential must agree to use an acceptable form of contraception during the treatment period
• Chronic use of macrolides, tetracyclines or quinolones Chronic use is defined as 4 or more weeks of continuous use within 6 months of randomization
• Asthma symptoms for less than 6 months prior to randomization Asthma symptoms must be present for at least 6 months to exclude patients without true chronic asthma
• Unstable asthma requiring immediate emergency care All patients with asthma exacerbations will receive usual urgent or emergency care for asthma and must be improving or stable in the judgment of the treating physician prior to being enrolled

• Specified co-morbidities likely to interfere with study assessments or follow up. Excluded comorbidities include:

  • cystic fibrosis
  • obstructive sleep apnea requiring CPAP
  • cardiomyopathy
  • congestive heart failure
  • terminal cancer
  • alcohol or other drug abuse
  • or any other serious medical condition that, in the opinion of the study physician, would seriously interfere with or preclude assessment of study outcomes or completion of study assessments
• Specified medical conditions for which macrolide administration may possibly be hazardous
• Patients with acute or chronic hepatitis, cirrhosis or other liver disease, chronic kidney disease, or history of prolonged cardiac repolarization and QT interval or torsades de pointes, are excluded

• Specified medications for which close monitoring has been recommended in the setting of macrolide administration Patients taking digoxin, theophylline, warfarin, ergotamine or dihydroergotamine, triazolam, carbamazepine, cyclosporine, hexobarbital or phenytoin are excluded.

  • If any of these medications are started after randomization and before completion of the 12-week treatment phase, study medication will be discontinued and the patient may remain in the study.

The intent of this protocol is to enroll a broadly generalizable sample of adult patients with physician-diagnosed asthma, either stable persistent or in exacerbation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azithromycin; Active adjunctive treatment	Drug: Azithromycin; 600 mg x 3 days, then 600 mg weekly x 11 weeks; Other Names: Zithromax
Placebo Comparator: Placebo; Adjunctive placebo	Drug: Placebo; Matching placebo
Other: Observational Cohort; Eligible participants who declined randomization, offered enrollment in parallel, open-label azithromycin treatment arm	Drug: Azithromycin; 600 mg x 3 days, then 600 mg weekly x 11 weeks; Other Names: Zithromax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Overall Asthma Symptoms From Baseline	5-point scale: 0=none, 1=mild, 2=moderate, 3=severe, 4=worst ever, the lower scores indicate improvement in asthma symptoms	Within the past 24 hours; measured every 1.5 months for one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Asthma Control Over Baseline	Mini-Juniper Asthma Control Questionnaire without pulmonary function. This is a 6-item survey scored on a 7 point scale where 0 is none, or no symptoms and 6 is severe or symptoms all of the time. Answers are averaged for a final score of 0-6. Data are reported as a change from baseline.	Within the past week; every 3 months
Change is Asthma-specific Quality-of-Life (AQL)	Juniper Asthma Quality of Life Questionnaire is a 32-item survey, recall of the past 2 weeks, scored on a 7 point Likert scale where 1 is severely impaired, and 7 is not impaired at all. Scores are averaged for a final range of 1-7. Change from Baseline is reported here.	Within the past 2 weeks; every three months
Asthma Exacerbations	A steroid burst, an unscheduled or emergency visit and/or a hospitalization for asthma, reported at Weeks 0, 6, 12, 18, 24, 30, 36, 42, 48, and any time during follow up.	up to 12 months

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Pfizer; American Academy of Family Physicians; Dean Foundation
• Investigators: Principal Investigator: David L Hahn, MD, MS, Wisconsin Research and Education Network (WREN)

Publications and helpful links

General Publications

• Hahn DL, Plane MB. Feasibility of a practical clinical trial for asthma conducted in primary care. J Am Board Fam Pract. 2004 May-Jun;17(3):190-5. doi: 10.3122/jabfm.17.3.190.
• Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract. 1995 Oct;41(4):345-51.
• Hahn DL. Chlamydia pneumoniae, asthma, and COPD: what is the evidence? Ann Allergy Asthma Immunol. 1999 Oct;83(4):271-88, 291; quiz 291-2. doi: 10.1016/S1081-1206(10)62666-X.
• Hahn DL, Plane MB, Mahdi OS, Byrne GI. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials. 2006 Jun;1(2):e11. doi: 10.1371/journal.pctr.0010011. Epub 2006 Jun 30.
• Hahn DL, Grasmick M, Hetzel S, Yale S; AZMATICS (AZithroMycin-Asthma Trial In Community Settings) Study Group. Azithromycin for bronchial asthma in adults: an effectiveness trial. J Am Board Fam Med. 2012 Jul-Aug;25(4):442-59. doi: 10.3122/jabfm.2012.04.110309.

Helpful Links

• Patient perspective/literature review
• Infectious asthma research/annotated bibliography
• Book that reviews the topic of infection as a treatable cause for asthma

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: December 15, 2005
• First Submitted That Met QC Criteria: December 15, 2005
• First Posted (Estimate): December 19, 2005

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: July 30, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Asthma; Randomized clinical trial; Adults; Azithromycin
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: H-2005-0258

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No