Amikacin safe, improves respiratory symptoms in M. avium complex lung disease

Key takeaways:

• The quality of life-bronchiectasis respiratory domain was validated for this patient population via two types of validity.
• Patients receiving amikacin did not report any new or unexpected safety signals.

SAN DIEGO — Amikacin for 6 months improved respiratory symptoms in adults with newly diagnosed or recurrent Mycobacterium avium complex lung disease, according to a presentation at the American Thoracic Society International Conference.

Healio previously reported on the findings from the phase 3 ARISE trial investigating the efficacy of amikacin liposome inhalation suspension (ALIS; Arikayce, Insmed) for treatment of MAC lung disease among newly diagnosed patients in September 2023.

In this randomized, double-blind, multi-region trial, researchers assessed 99 adults with newly diagnosed or recurrent MAC lung disease who had not started antibiotics to validate the quality of life-bronchiectasis (QOL-B) respiratory domain, a patient-reported outcome instrument, as well as determine how respiratory symptoms and microbiologic outcomes differ between those receiving once-daily ALIS and those receiving once-daily placebo for 6 months.

“There is no currently validated fit-for-purpose [patient-reported outcome] instrument for people with MAC lung disease,” Charles L. Daley, MD, chief of the division of mycobacterial and respiratory infections and professor in the department of medicine at National Jewish Health, said during his presentation.

“[The QOL-B respiratory domain] has been validated in those with non-CF bronchiectasis but not in those with MAC,” he added.

Notably, after the 6-month treatment period, researchers waited 1 month to evaluate QOL-B patient-reported outcomes.

In terms of microbiologic outcomes, researchers cultured two sputum samples in agar and broth from each patient each month and looked for culture conversion, or “no MAC growth on agar and broth media in all sputum cultures at two consecutive visits,” Daley said.

Of the total cohort, 48 patients (median age, 71.5 years; 66.7% women; 85.4% white; 72.9% first diagnosis of MAC) received ALIS plus macrolide-based background regimen, and 51 patients (median age, 67 years; 88.2% women; 76.5% white; 72.5% first diagnosis of MAC) received placebo plus macrolide-based background regimen.

At baseline, both groups had a mean QOL-B respiratory domain score within the 60-to-70-point range out of 100 (ALIS, 63.04 points vs. placebo, 66.9 points). With this tool, Daley noted that a higher score signaled fewer respiratory symptoms and better health-related quality of life.

Validation, respiratory symptoms

Using the Patient Global Impression of Severity-Respiratory (PGI-S R) as an anchor during validation of the QOL-B respiratory domain, researchers observed that the QOL-B respiratory domain demonstrated both known-groups validity and concurrent validity.

When researchers compared the QOL-B respiratory domain least-squares means estimate with the number of patients that fell into the five PGI-S R severity groups, the ordering went in “the same direction,” showcasing known-groups validity, Daley said.

Researchers observed concurrent validity by placing the QOL-B respiratory domain against four other respiratory and fatigue patient-reported outcome scales and comparing direction and level of correlation.

“We looked to see, did they move in the right direction in the right amounts?” Daley said. “It turns out, they do.”

Moving forward, researchers utilized empirical cumulative distribution function curves and determined that an additional 14.8 points was the estimated clinically meaningful within-patient change threshold for the QOL-B respiratory domain score.

According to this threshold for meaningful change, a greater proportion of patients receiving ALIS vs. placebo achieved improvement (43.8% vs. 33.3%).

In an adjusted analysis, the ALIS group also had a larger change in QOL-B respiratory domain from baseline to month 7 vs. the placebo group (least-squares mean, 12.24 vs. 7.76).

“The findings demonstrate that the QOL-B respiratory domain has reliability, validity and responsiveness for assessing symptoms in adults with newly diagnosed or recurrent MAC lung disease,” Daley said.

“This looks like an instrument that can be used in clinical trials,” he added.

Microbiologic outcomes, safety

When evaluating culture conversion rates at month 6 and month 7, researchers observed higher rates in the ALIS group vs. the placebo group during both assessments (month 6, 80.6% vs. 63.9%; month 7, 78.8% vs. 47.1%).

Daley further highlighted that patients receiving ALIS had a faster median time to first culture conversion compared with patients receiving placebo (1 month vs. 2 months).

“[In the ALIS arm,] the conversion is occurring at a higher frequency and sooner,” he said.

Among those who met the study’s criteria for culture conversion, fewer patients in the ALIS group vs. the placebo group had recurrence of MAC (12.8% vs. 50%).

Daley added, “Fortunately, no patients in either arm developed macrolide or amikacin resistance during the course of the trial.”

With regard to safety, patients receiving ALIS did not report any new or unexpected safety signals, according to Daley.

The majority of patients in each group experienced a treatment-emergent adverse event (ALIS, 91.7%; placebo, 80.4%). For those receiving ALIS, dysphonia occurred the most often (41.7%), followed by cough (27.1%), diarrhea (27.1%) and COVID-19 (12.5%).

Seven serious treatment-emergent adverse events (n =7) occurred in the ALIS group, which was comparable to the eight serious treatment-emergent adverse events (n = 3) observed in the placebo group.

For adverse events that fell under the category of ototoxicity, such as dizziness, tinnitus and vertigo, Daley said both treatment groups had low rates and did not differ from each other much.

“The next thing we're waiting for is a 15-month confirmatory study that is ongoing now,” Daley said. “This is evaluating the efficacy and safety of ALIS in the same patient population. The difference is this is a 12-month treatment and then evaluation 3 months off-treatment, so double the length of ARISE.”