Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease

Abstract

Rationale: Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease.

Objectives: In this phase II study, we investigated the efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease.

Methods: During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events.

Measurements and main results: The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 [32%] of 44 vs. 4 [9%] of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. -25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation.

Conclusions: Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236).

Keywords: culture conversion; efficacy; nontuberculous mycobacteria; safety.

Figure 1.

Mean change from baseline on the semiquantitative scale (SQS) for mycobacterial culture growth through the end of the open-label phase (missing value equals failure; modified intent-to-treat population). The SQS is a mycobacterial culture reporting method expressed on a seven-step scale that uses outcomes ranging from no growth at 6 weeks (step 1), growth in liquid media only (step 2), agar positive (1–49 colonies) (step 3), 1+ (step 4), 2+ (step 5), 3+ (step 6), and 4+ (step 7). Change from baseline ranges from +6 (worsening) to −6 (improvement) steps. Death, regardless of cause, was considered a failure and is represented by a +7-step worsening. *All patients in the open-label phase received liposomal amikacin for inhalation (LAI). PBO = placebo.

Figure 2.

Proportion of patients with negative sputum cultures for nontuberculous mycobacteria in the double-blind phase (last observation carried forward; modified intention-to-treat population). A greater proportion of patients achieved negative sputum cultures at Day 84 on liposomal amikacin for inhalation (LAI) (14 [32%] of 44) versus placebo (4 [9%] of 45) (P =  0.006). Mabs = Mycobacterium abscessus; MAC = Mycobacterium avium complex; PBO = placebo.

Figure 3.

Patients achieving culture conversion through the end of the open-label phase. Of the 23 patients who achieved culture conversion by the 28-day end-of-study follow-up visit, 4 (LAI = 2 patients; placebo = 2 patients) converted at baseline (Day 1) prior to the administration of study drug. Nineteen patients achieved culture conversion after baseline (Day 1), 10 of whom were randomized to LAI in the double-blind phase and 7 after entering the open-label phase (1 of 7 on prior LAI and 6 of 7 on prior placebo). The remaining two patients achieved culture conversion while receiving add-on placebo. All of the converters with Mycobacterium avium complex were patients without cystic fibrosis. Two of the converters with Mycobacterium abscessus infection (LAI, one patient; PBO, one patient) had cystic fibrosis, and two were patients without cystic fibrosis. Four patients who achieved culture conversion had a subsequent positive liquid media–only culture result: three of these cultures were different species from the baseline isolate, or “new infections” (M. avium at baseline and Mycobacterium timonense 28 d after LAI; M. avium at baseline and Mycobacterium chimaera at 12 mo after LAI; M. avium at baseline and Mycobacterium intracellulare at Day 168), and one was the same or “relapse.” ^†New infection; ^‡relapse. BL = baseline; f/u = follow-up; LAI = liposomal amikacin for inhalation; Mabs = Mycobacterium abscessus; MAC = Mycobacterium avium complex; ND = not done; NG = no growth at 6 weeks; NTM = nontuberculous mycobacteria; PBO = placebo; Rx = medication; SQS = semiquantitative scale.

Figure 4.

Mean distance walked in the 6-minute-walk test (last observation carried forward; modified intention-to-treat population). LAI = liposomal amikacin for inhalation; PBO = placebo.