NSAIDS-XDR-TB clinical trial: A randomized pilot study to estimate the potential efficacy and safety of using adjunctive ibuprofen for the treatment of pre-XDR and XDR tuberculosis

BackgroundDrug-resistant tuberculosis (TB) remains a formidable global health challenge. Host-directed therapies (HDTs) offer the potential to mitigate tissue damage, reduce treatment duration, and improve clinical outcomes by modulating immune responses. We assessed the safety and potential efficacy of adjunctive ibuprofen--an inexpensive, well-tolerated non-steroidal anti-inflammatory drug--in patients with pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) TB. MethodsIn this prospective, open-label, randomized pilot study (NCT02781909) conducted in Georgia, 28 adults with bacteriologically confirmed pulmonary pre-XDR or XDR-TB were randomized 1:1 to receive either standard-of-care (SoC) TB treatment alone (n=14) or SoC plus 400 mg ibuprofen daily during the first 2 months (n=14). Participants were followed for 6 months. The primary endpoints were early sputum culture conversion and radiological improvement. Secondary endpoints included WHO-defined final treatment outcomes, safety, health-related quality of life (HQoL), and changes in inflammatory markers. FindingsBy week 2, culture negativity was achieved in 27% of control participants versus 9% in the ibuprofen group (risk difference 18%, 95% CI -13 to 50). The median time to culture conversion was 4 months in both groups. At month 2, favourable X-ray evolution was observed in 64% of controls compared with 54% of the ibuprofen group (risk difference 9%, 95% CI -32 to 50), with 90% of participants in each group showing improvement by month 6. Final treatment outcomes were comparable ({approx}71% cured) and the incidence of safety-related events did not differ significantly. Notably, the ibuprofen group exhibited greater proportional reductions in inflammatory markers--including a statistically significant decrease in the monocyte-to-lymphocyte ratio at months 2 and 5, along with reductions in interferon gamma levels and the enrichment score for Thompson_FAIL_13 gene signature at month 6. InterpretationAlthough adjunctive ibuprofen did not improve primary microbiological or radiological endpoints, its excellent safety profile and significant anti-inflammatory effects support its potential role as an immune-modulating adjunct in the treatment of drug-resistant TB. These findings warrant further investigation in larger studies to optimize dosing and evaluate clinical benefits. FundingCatalan Government (2021 SGR 00920), Spanish Government-FEDER Funds (CPII18/00031, PI20/01424 and CB06/06/0031, and European Unions Horizon 2020 research and innovation program under grant agreement No. 847762 (SMA-TB project). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDrug-resistant tuberculosis (TB) remains a major global health challenge. Host-directed therapies (HDTs) have emerged as a means to shorten treatment, improve outcomes and limit tissue damage from excessive inflammation. In preclinical models of active TB, non-steroidal anti-inflammatory drugs (NSAIDs) enhanced bacterial control and reduced lung pathology. Clinical data on NSAIDs as HDTs are scarce, confined to small studies in tuberculous meningitis and TB patients with diabetes, which reported encouraging but preliminary benefits. Added value of this studyThis is the first randomized trial of adjunctive ibuprofen in patients with pre-XDR and XDR-TB. Whilst ibuprofen did not confer microbiological or clinical benefit at two and six months, it was safe, well tolerated and significantly lowered systemic inflammatory markers. Baseline imbalances in disease severity and high inter-patient variability likely obscured any clinical effect despite reduced inflammation. Implications of all the available evidenceOur findings demonstrate that ibuprofen is a safe adjunct in drug-resistant TB and can mitigate harmful inflammation. Future work should explore optimised dosing regimens, alternative HDT candidates and more sensitive or tailored endpoints--potentially focusing on patient subgroups most likely to benefit. Such refinements will be essential to reveal the true clinical value of HDTs across diverse TB populations.