Azithromycin for Bronchial Asthma in Adults
Adults with persistent asthma symptoms as defined by current guidelines were randomized to receive 12 weekly doses of azithromycin or placebo as adjunctive therapy between June 2006 and November 2009. Self-reported questionnaire data were collected for 1 year after randomization. Patients were recruited and enrolled from community practice-based settings throughout North America. Study clinician members and/or staff of 5 practice-based research networks (PBRNs) and one community-based allergist enrolled patients from their practices for this study. The PBRNs included one nationwide network (American Academy of Family Physicians National Research Network) and 4 regional networks (Ambulatory Network for Scholarship and Research, Illinois; Cleveland Ambulatory Research Network, Ohio; Oklahoma Physicians Resource/Research Network; and the Wisconsin Research and Education Network). Further participant details are provided in the Acknowledgments. During this "real-world" study, we encountered eligible patients, most of whom had severe treatment-resistant or refractory asthma, who declined randomization in favor of being treated with azithromycin. Rather than exclude these patients entirely, we elected to enroll them as a parallel observational cohort. Patients who opted to participate in this "open-label" (OL) arm received a prescription for azithromycin from their personal physician and were followed for the same outcomes as the randomized arm.
Eligibility criteria can be found in Table 1. Community-based clinicians enrolled and randomized eligible patients and remained available to assess side effects or severe adverse reactions, but they were not involved in follow-up data collection. All subjects continued to receive usual asthma care from their doctor. All study sites received approval from their respective human subject committees, and subjects provided written, informed consent.
An independent statistician prepared the randomization codes used for subject assignment to the azithromycin or placebo study arms. The investigators, study subjects, and study site personnel were blinded to treatment allocation. Study medication was azithromycin 600 mg, 1 tablet daily for 3 days followed by 1 tablet weekly for 11 weeks, or identical matching placebo tablets. Each study site received coded study medication bottles (1:1 allocation) in blocks of 6 and was instructed to distribute them (numbered 1 to 6) in numerical ascending order to eligible consenting study subjects. After 3 weeks of taking study medication, subjects were asked to guess their allocation.
Internet trial registration (http://clinicaltrials.gov/show/NCT00266851) and another Internet site (http://asthmastory.com) identified asthma patients wanting to participate in AZMATICS. When they learned that they had a 50% chance of receiving a placebo, many of these patients declined to be randomized but remained interested in the use of azithromycin for treatment of their asthma. Institutional review board approval was obtained to enter eligible subjects requesting azithromycin into a parallel, OL observational cohort. OL subjects obtained a 12-week prescription for weekly azithromycin from their personal physician and were monitored for the same baseline and outcome data that were being collected for the randomized cohort. Because 600-mg azithromycin tablets were not uniformly available, OL treatment consisted of 2 azithromycin tablets (250 mg each), to achieve a 500-mg daily dose for 3 days, followed by 3 tablets to achieve a 750-mg, once-weekly dose for 11 additional weeks.
Subjects submitted follow-up data via Internet questionnaires. During the first 3 months after randomization (the study medication administration period), subjects reported weekly via the Internet whether they had taken their assigned study medication during the previous week. In addition to study medication adherence, subjects also reported weekly on side effects for the first 3 months. Outcome data were recorded every 1.5 months (6 weeks) through 12 months. Outcome measures are listed in Table 1.
All analyses were by intention to treat, and no subjects with available data were excluded from any analysis. Repeated-measures (RM) analysis of variance (ANOVA)—with intervention and time as fixed effects; subjects as random effects; and age, sex, and ever-smoking as covariates—was conducted for each of the continuous variables. After finding significant effects in the RM ANOVA models, we explored the effects with tests at specific time points. We used Fisher exact test for categorical variables, Wilcoxon rank sum tests for continuous variables (reported as median and range), and t tests for continuous variables (reported as mean and standard deviation). We controlled for the effects of age, sex, ever-smoking, and asthma controller medication using ANOVA for normally distributed continuous outcomes and logistic regression for binary outcomes. On the basis of our pilot results, a total sample size of 58 had 80% power (for α = 0.05) to detect a 0.66-unit (13%) difference in overall asthma symptoms (the primary outcome). AZMATICS used a Data Safety Monitoring Board that met approximately every 6 months. The Data Safety Monitoring Board did not identify any reason for early termination.
Methods
Adults with persistent asthma symptoms as defined by current guidelines were randomized to receive 12 weekly doses of azithromycin or placebo as adjunctive therapy between June 2006 and November 2009. Self-reported questionnaire data were collected for 1 year after randomization. Patients were recruited and enrolled from community practice-based settings throughout North America. Study clinician members and/or staff of 5 practice-based research networks (PBRNs) and one community-based allergist enrolled patients from their practices for this study. The PBRNs included one nationwide network (American Academy of Family Physicians National Research Network) and 4 regional networks (Ambulatory Network for Scholarship and Research, Illinois; Cleveland Ambulatory Research Network, Ohio; Oklahoma Physicians Resource/Research Network; and the Wisconsin Research and Education Network). Further participant details are provided in the Acknowledgments. During this "real-world" study, we encountered eligible patients, most of whom had severe treatment-resistant or refractory asthma, who declined randomization in favor of being treated with azithromycin. Rather than exclude these patients entirely, we elected to enroll them as a parallel observational cohort. Patients who opted to participate in this "open-label" (OL) arm received a prescription for azithromycin from their personal physician and were followed for the same outcomes as the randomized arm.
Study Eligibility
Eligibility criteria can be found in Table 1. Community-based clinicians enrolled and randomized eligible patients and remained available to assess side effects or severe adverse reactions, but they were not involved in follow-up data collection. All subjects continued to receive usual asthma care from their doctor. All study sites received approval from their respective human subject committees, and subjects provided written, informed consent.
Randomization and Masking
An independent statistician prepared the randomization codes used for subject assignment to the azithromycin or placebo study arms. The investigators, study subjects, and study site personnel were blinded to treatment allocation. Study medication was azithromycin 600 mg, 1 tablet daily for 3 days followed by 1 tablet weekly for 11 weeks, or identical matching placebo tablets. Each study site received coded study medication bottles (1:1 allocation) in blocks of 6 and was instructed to distribute them (numbered 1 to 6) in numerical ascending order to eligible consenting study subjects. After 3 weeks of taking study medication, subjects were asked to guess their allocation.
Open-label Treatment
Internet trial registration (http://clinicaltrials.gov/show/NCT00266851) and another Internet site (http://asthmastory.com) identified asthma patients wanting to participate in AZMATICS. When they learned that they had a 50% chance of receiving a placebo, many of these patients declined to be randomized but remained interested in the use of azithromycin for treatment of their asthma. Institutional review board approval was obtained to enter eligible subjects requesting azithromycin into a parallel, OL observational cohort. OL subjects obtained a 12-week prescription for weekly azithromycin from their personal physician and were monitored for the same baseline and outcome data that were being collected for the randomized cohort. Because 600-mg azithromycin tablets were not uniformly available, OL treatment consisted of 2 azithromycin tablets (250 mg each), to achieve a 500-mg daily dose for 3 days, followed by 3 tablets to achieve a 750-mg, once-weekly dose for 11 additional weeks.
Study Outcomes
Subjects submitted follow-up data via Internet questionnaires. During the first 3 months after randomization (the study medication administration period), subjects reported weekly via the Internet whether they had taken their assigned study medication during the previous week. In addition to study medication adherence, subjects also reported weekly on side effects for the first 3 months. Outcome data were recorded every 1.5 months (6 weeks) through 12 months. Outcome measures are listed in Table 1.
Statistical Analysis
All analyses were by intention to treat, and no subjects with available data were excluded from any analysis. Repeated-measures (RM) analysis of variance (ANOVA)—with intervention and time as fixed effects; subjects as random effects; and age, sex, and ever-smoking as covariates—was conducted for each of the continuous variables. After finding significant effects in the RM ANOVA models, we explored the effects with tests at specific time points. We used Fisher exact test for categorical variables, Wilcoxon rank sum tests for continuous variables (reported as median and range), and t tests for continuous variables (reported as mean and standard deviation). We controlled for the effects of age, sex, ever-smoking, and asthma controller medication using ANOVA for normally distributed continuous outcomes and logistic regression for binary outcomes. On the basis of our pilot results, a total sample size of 58 had 80% power (for α = 0.05) to detect a 0.66-unit (13%) difference in overall asthma symptoms (the primary outcome). AZMATICS used a Data Safety Monitoring Board that met approximately every 6 months. The Data Safety Monitoring Board did not identify any reason for early termination.
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