Amikacin Liposome Inhalation Suspension for Mycobacterium avium Complex Lung Disease: A 12-Month Open-Label Extension Clinical Trial

Kevin L Winthrop, Patrick A Flume, Rachel Thomson, Kevin C Mange, Dayton W Yuen, Monika Ciesielska, Kozo Morimoto, Stephen J Ruoss, Luigi R Codecasa, Jae-Joon Yim, Theodore K Marras, Jakko van Ingen, Richard J Wallace Jr, Barbara A Brown-Elliott, Chris Coulter, David E Griffith, Kevin L Winthrop, Patrick A Flume, Rachel Thomson, Kevin C Mange, Dayton W Yuen, Monika Ciesielska, Kozo Morimoto, Stephen J Ruoss, Luigi R Codecasa, Jae-Joon Yim, Theodore K Marras, Jakko van Ingen, Richard J Wallace Jr, Barbara A Brown-Elliott, Chris Coulter, David E Griffith

Abstract

Rationale: Patients with refractory Mycobacterium avium complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population.Objectives: Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT.Methods: Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed.Results: In the ALIS-naive cohort, 83.3% of patients (n = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% (n = 32) had serious TEAEs; 26.7% (n = 24) achieved culture conversion by Month 6 and 33.3% (n = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients (n = 34/73) experienced respiratory TEAEs, and 27.4% (n = 20) had serious TEAEs; 9.6% (n = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% (n = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts.Conclusions: In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).

Keywords: ALIS; Mycobacterium avium; amikacin liposome inhalation suspension; culture conversion; nontuberculous mycobacteria.

Figures

Figure 1.
Figure 1.
INS-312 study design. Adults with treatment-refractory MAC lung disease who were originally enrolled in the CONVERT study and did not achieve conversion or had recurrent MAC infection by Month 6 exited CONVERT at Month 8, and eligible patients were permitted to enroll in the INS-312 open-label safety extension. Patients originally randomized to receive ALIS+GBT in CONVERT (prior-ALIS cohort) continued their assigned treatment. Patients originally randomized to receive GBT alone in CONVERT (ALIS-naive cohort) had ALIS added to their ongoing GBT at INS-312 baseline. *INS-312 baseline coincided with the EOT visit in CONVERT. †All patients, including those who terminated the study early, had their EOT visit and safety follow-up visit at EOS. ALIS = amikacin liposome inhalation suspension; BL = baseline; EOS = end of study; EOT = end of treatment; GBT = guideline-based therapy; MAC = Mycobacterium avium complex; QD = once daily.
Figure 2.
Figure 2.
Patient disposition (EOS). Patient flow through the study is shown. Completion was defined as successfully completing 12 months of the same treatment regimen beginning with INS-312 baseline and completing the 28-day off-treatment EOS follow-up visit. Adverse events are reported and classified based on Medical Dictionary for Regulatory Activities preferred terms. *Primary reason for study discontinuation as noted by the investigator on the case report form. †Bronchospasm (n = 2), dysphonia (n = 2), acute respiratory failure (n = 1), cough (n = 1), dyspnea at rest (n = 1), laryngeal granuloma (n = 1), pneumothorax (n = 1), pulmonary fibrosis (n = 1), respiratory failure (n = 1), balance disorder (n = 1), cerebral infarction (n = 1), hypoacusis (n = 1), vision blurred (n = 1), ascites (n = 1), chest pain (n = 1), electrocardiogram QT prolonged (n = 1), decreased appetite (n = 1), breast cancer (n = 1). ǂAllergic alveolitis (n = 1), laryngitis (n = 1), Mycobacterium avium complex infection progression (n = 1). ALIS = amikacin liposome inhalation suspension; EOS = end of study; GBT = guideline-based therapy.
Figure 3.
Figure 3.
(A) Cumulative proportion of patients in the ALIS-naive cohort with culture conversion, shown by the first month of conversion: safety population. The cumulative proportion of patients achieving culture conversion is displayed by the first month at which sputum cultures were negative for MAC. Month 10 was the latest time point at which a patient could achieve the first of three consecutive sputum cultures negative for MAC and be considered a converter by Month 12. Patients with cultures negative for MAC at INS-312 baseline, Months 1 and 2, were considered converters at baseline. A patient with missing monthly culture data was considered positive for MAC unless they were unable to produce sputum even after induction. (B) Proportion of patients with culture conversion over time (safety population). The study month at which patients first experienced a MAC-negative sputum culture is shown by Kaplan-Meier analysis. Open circles indicate patients who were censored. ALIS = amikacin liposome inhalation suspension; MAC = Mycobacterium avium complex.
Figure 4.
Figure 4.
(A) Cumulative proportion of patients in the prior-ALIS cohort with culture conversion, shown by the first month of conversion: safety population. The cumulative proportion of patients achieving culture conversion is displayed by the first month at which sputum cultures were MAC negative. Month 10 was the latest time point at which a patient could achieve the first of three consecutive negative sputum cultures and be considered a converter by Month 12. A patient with missing monthly culture data was considered MAC positive unless they were unable to produce sputum even after induction. (B) Proportion of patients with culture conversion over time (safety population). The study month at which patients first experienced a MAC-negative sputum culture is shown by Kaplan-Meier analysis. Open circles indicate patients who were censored. ALIS = amikacin liposome inhalation suspension; MAC = Mycobacterium avium complex.

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