B107-23 The MAC2v3 Randomized Pragmatic Trial of Macrolide-based 2- Versus 3-drug Treatment for Mycobacterium Avium Complex Pulmonary Disease: Initial Results

Background

ATS/IDSA treatment guidelines recommend a 3-drug regimen (azithromycin, ethambutol, and a rifamycin) for Mycobacterium avium complex pulmonary disease (MAC-PD). However, it is unclear how rifamycins contribute to efficacy and tolerability of this regimen. We sought to evaluate whether a 2-drug regimen was non-inferior and more tolerable than a 3-drug regimen.

Methods

The MAC2v3 open-label, pragmatic trial randomized patients with non-cavitary treatment-naïve MAC-PD to thrice weekly azithromycin 500mg, ethambutol 20mg/kg +/- rifampin 600mg, stratified by bronchoalveolar lavage or ≥ 2 sputum cultures to meet diagnostic criteria. After randomization physicians treated patients pragmatically with standard of care monitoring and sputum collection guidance. Therapeutic regimen alterations were allowable. Patient-reported outcomes (PROs) and monthly adherence (patient-log or coordinator confirmed) were collected. Our primary outcome was culture negativity, i.e. 2 consecutive negative cultures without reversion at 12 months, evaluated as non-inferiority (10% margin) in a per-protocol population (PP, i.e. adherence as completing >80% of doses on assigned regimen). Additionally, our statistical analysis plan PP definition considered treatment intensification (i.e. addition of amikacin, clofazimine, rifamycin) as treatment failure (PP-I). Secondary outcomes evaluated in a modified intention-to-treat population included: regimen tolerability (adherence above), PROs (QOL-Bronchiectasis respiratory symptoms scale [QOLB-RSS]), development of macrolide resistance. We conducted linear mixed effects modeling with jackknife 95% confidence intervals (CI) for categorical (risk difference [RD]) and continuous outcomes, modeling site as random effect and diagnostic strata as fixed effect.

Results

We randomized n = 473 patients. Mean age was 69 years, 395 (80%) were female, and 376 (84%) were white. Of these, n = 456 started treatment (Figure); n = 259 PP-I and n = 205 PP were evaluable for culture outcomes. The culture negative RD comparing 2-drug to 3-drug groups was -5.0% (95% CI -15.5,5.1) in the PP-I population and -2.4 (95% CI -15.8,11.4) in the PP population, favoring the 3-drug group. The tolerance RD was 18.7% (95% CI 9.5,28.2), favoring the 2-drug group. QOLB-RSS scores increased over the 12 month period (p < 0.001), with no difference between treatment groups (p = 0.40). Among those with positive cultures after 6 months, drug susceptibility testing was obtained in 37/103 (36%) 2-drug and 48/77 (31%) 3-drug, with 1 macrolide-resistant isolate in each group.

Conclusion

The primary non-inferiority culture negative RD was within the 10% margin but did not achieve statistical significance. The 2-drug regimen was significantly better tolerated, QOLB-RSS improved similarly in both groups, and macrolide resistance was rare. A regimen of azithromycin and ethambutol can be cautiously considered to treat non-cavitary MAC-PD.

This abstract is funded by: PCORI