PCDF Research Forum

Efficacy and Safety of Azithromycin Maintenance Therapy in Primary Ciliary Dyskinesia (BESTCILIA): A Multicenter, Double-blind, Randomized, Placebo-controlled Phase 3 Trial

Kobbernagel et al

Summary by Andrew Sadowski

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Quick Summary

The authors tested 6 months of preventative azithromycin on PCD patients. The patients were split into two groups: an experimental group who received the antibiotic and a control group who was given a placebo. The experimental group had fewer exacerbations (events that require antibiotic intervention) and less disease-causing bacteria in their sputum (lung mucus). The experimental group also reported higher rates of diarrhea and loose stool compared to the placebo group. The authors recommend further study into azithromycin (for extended periods) to assess the long-term effects but concluded that the drug is likely safe and effective for periods of 6 months.



Researchers conducted a double-blind, randomized, placebo-controlled trial to evaluate maintenance azithromycin (an antibiotic) use in PCD patients. The specific aim of this paper was to clinically test if maintenance azithromycin is effective in those with PCD.



Patients were enrolled based on the following criteria: were between ages 7-50, had an FEV1 (or volume of air one can exhale in one second) greater than or equal to 40%, had received antibiotics in the past two years and had not taken azithromycin within the last month. Patients screened who had positive specific bacteria growth in sputum cultures were excluded from the study. The study was designed to look at azithromycin as a preventative treatment in stable patients, and not as a hospital-level treatment during an active infection/flare up.



For the primary endpoint, the authors reported that there were 87 exacerbations during the trial period. 31 of these events occurred in the treatment group and 56 occurred in the placebo group, indicating that patients in the control group had about a 2x chance of having an exacerbation. An important number to look at when looking at this type of data is the p value. The p value is a number that indicates what are the chances that the results could happen by pure chance. The higher the p value, the greater the likelihood that the results are driven by random chance instead of by the administered therapy. In this case, the p value for the difference in respiratory exacerbations was 0.004, which means there is a 0.4% chance the results are random. Therefore, it is likely that azithromycin is the reason for decreased exacerbations in the treatment group.

There are two other important points to highlight from the results. The first is the data researchers obtained from the sputum samples of the patients throughout the study. The cultures were tested for total number of bacteria, as well as macrolide-resistant bacteria (macrolide is a class of antibiotic, which includes azithromycin). The average number of bacteria in the sputum of azithromycin-treated patients was 0.93, while the placebo group was 2.41, with a p value of 0.007. This indicates azithromycin reduced the amount of bacteria in sputum cultures of patients over 6 months. The authors also looked at antibiotic resistance over the course of the study and found no significant difference in antibiotic (macrolide) resistance between placebo and experimental arms of the study.

Worth noting, the most common adverse event reported in the treatment group was diarrhea/loose stool, reported by 23% of the azithromycin arm and only 5% of the placebo group. Tinnitus – a constant ringing noise in the ears – was noted by 2 patients receiving the drug. However, the number was too small to say whether the tinnitus was a result of the azithromycin.



One of the primary takeaways is that the authors did not see a difference in lung function between the two groups in this study. This could be due to length of study, speculating that 6 months may not be a long enough timeframe to see changes in lung function from preventative azithromycin use.

The researchers concluded that 6 months of azithromycin therapy is safe and effective at reducing lung exacerbations, but questions remain in the context of using the drug for long-term treatment of PCD. Researchers recommend testing for periods longer than 6 months to evaluate if there are any adverse events or if antibiotic resistance develops. In addition, the authors recommend that clinicians investigate azithromycin use in PCD patients with chronic P. aeruginosa infection. Lastly, azithromycin trials in patients with cystic fibrosis (CF) with P. aeruginosa showed significant efficacy, both in reduced exacerbations and increased measures of lung function. That may be another reason to further explore azithromycin use in PCD.