Background
Background: Short-course treatment (Rx) for drug-resistant TB (DR-TB) includes linezolid (LZD) as a key component but optimal LZD doses that maximize anti-TB activity and minimize toxicity are not established. ACTG A5356 is a Ph2 randomized, open-label trial of 26 wks of Rx for DR-TB with novel high vs standard dose LZD plus simplified bedaquiline (BDQ), delamanid (DLM) and clofazimine (CFZ; 2 wk loading dose). We proposed that high dose daily LZD x 4 wks then thrice weekly (TIW) would result in more rapid TB liquid culture (LCx) conversion with similar outcomes and tolerability vs daily lower dose LZD.
Methods
Methods: Eligible pts >18 yo, w/wo HIV, with pulmonary DR-TB and <7d of prior TB Rx were randomized 1:1 to LZD 600 mg/d wks 1-26 (Arm A) or 1200 mg/d wks 1-4, then 1200 mg TIW wks 5-26 (Arm B). All pts received daily BDQ 200 mg wks 1-8 then 100 mg wks 9-26, DLM 300 mg wks 1-26, and CFZ 300 mg wks 1-2, then 100 mg wks 3-26. Rx was extended to wk 38 if no LCx conversion by wk 16. Pts were followed thru wk 72. Primary endpoints were time to 1st stable negative LCx, permanent discontinuation (d/c) of >1 TB drug for adverse events (AEs), intolerance or death by wk 26.
Results
Results: 138 pts were enrolled at 13 sites in 7 countries from 09/2022-09/2024. Baseline (BL) median age was 34 yrs; 37% female; 21% PWH; 28% RRTB, 66% MDRTB, 5% Pre-XDRTB, 6% FQ-R. For 121 pts evaluable at wk 26, 71% in Arm A and 68% Arm B completed Rx by wk 26; 10% in Arm A vs 22% Arm B prematurely d/c’d study treatment. LCx conversion by wk 26 occurred in 97% Arm A and 92% Arm B; time to LCx conversion was longer in Arm B (p=0.05) (Fig. 1). Bilateral/diffuse disease (61% vs 53%) and aggregated cavity size ≥ 4cm (42% vs 37%) were more common in Arm B. HR for LCx conversion Arm B vs Arm A was 0.75 (95% CI 0.52-1.1). TB outcomes in Arm A vs Arm B by wk 26 were: favorable (fav)/cure (65% vs 53%); fav/Rx extended (2% vs 3%); unfav (3% vs 12%); unevaluable (31% vs 31%) (most due to Rx extension after wk 26). There were no differences for time to permanent d/c of >1 TB drug or Rx-related AEs; most common AEs were anemia (28%), peripheral neuropathy (13%), and prolonged QTc interval (Gr 3 12%).
Conclusions
Conclusions: Both arms were equally tolerated and had high rates of LCx conversion by wk 26, but the higher dose LZD arm was associated with less rapid LCx conversion and less favorable TB outcomes possibly due to more premature Rx d/c and some features associated with poorer outcomes compared with LZD 600 mg/d.
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