Concurrent Randomized, Double-Blind, Placebo-Controlled Trials to Validate Patient-Reported Outcome (PRO) Instruments and Assess Clinical Benefit of Treatment in Adults with Newly Diagnosed Nontuberculous Mycobacterial (NTM) Lung Infection Caused by Mycobacterium AviumComplex (MAC)

RATIONALE. MAC is the leading cause of NTM lung disease, which may be progressive and associated with significant symptom burden. Patients who initiate treatment for MAC lung disease often do not achieve microbiological benefit (culture conversion), and there is currently no validated PRO instrument that can evaluate clinical benefit of treatment. METHODS. ARISE (NCT04677543) and ENCORE (NCT04677569) are ongoing concurrent randomized, double-blind, placebo-controlled studies in which adults with a new diagnosis of MAC lung disease are randomized 1:1 to receive either amikacin liposome inhalation suspension 590 mg QD (ALIS) + azithromycin 250 mg QD (AZI) + ethambutol 15 mg/kg QD (ETH) or empty liposome control (ELC)+AZI+ETH. The primary objective of ARISE is to generate evidence demonstrating the domain specification, reliability, validity, and responsiveness of PRO endpoints at Month 7 [1 month off treatment]. The psychometric validation of the Quality of Life -Bronchiectasis (QOL-B) respiratory domain and/or Patient-Reported Outcome Measurement Information System -Fatigue-Short Form 7a (PROMIS F-SF 7a) within the MAC lung disease population will be used to generate data for the computation of a score for the primary endpoint in the ENCORE study (clinical benefit of treatment in respiratory symptoms at month 13 [1 month off treatment]). Microbiological secondary endpoints in ENCORE include the proportion of patients with durable culture conversion at 3 months off all MAC treatment. RESULTS. These studies are taking place at approximately 220 sites globally. A sample size of 50 patients per group in ARISE will provide 80% power for detecting a clinically meaningful difference at 1-month post treatment between patients achieving culture conversion during the study and those who did not. A sample size of 125 patients per group in ENCORE will provide sufficient power to assess superiority of ALIS+AZI+ETH over the active comparator (ELC+AZI+ETH) in the primary endpoint (clinical benefit of treatment in respiratory symptoms at month 13) and the durability of culture conversion at month 15. CONCLUSIONS. MAC lung disease has a significant unmet medical need as many patients may not attain microbiological benefit with treatment. Limited data are available to assess clinical benefit of treatment, and there are no PRO instruments that have been validated in this patient population. ARISE and ENCORE represent a unique parallel trial approach, while generating data sequentially, to potentially validate instruments in MAC lung disease and subsequently assess the clinical benefit of treatment.