The optimal choice of the fourth drug in first-line anti-tubercular therapy for adults with tuberculous meningitis (TBM) is unresolved. Despite longstanding clinical use of both ethambutol (ETM) and streptomycin (STM), direct randomized comparisons in TBM were lacking. This investigator-initiated trial aimed to compare effectiveness and safety of ETM versus STM when used during the intensive phase of treatment.
This was a single-center, open-label, randomized controlled trial conducted between October 2020 and June 2025. The study was stopped early because of slow recruitment. The trial was published in Postgraduate Medical Journal (2026) and is registered in the Clinical Trials Registry of India (CTRI/2020/07/026423, registered 7 July 2020).
A total of 131 patients were screened for eligibility; 49 were excluded and 82 patients were randomized. The two randomized arms were matched for baseline characteristics according to the report.
Patients randomized to the STM arm received streptomycin 15 mg/kg intramuscularly daily (approximately 90 injections) combined with isoniazid (H) 5 mg/kg, rifampicin (R) 10 mg/kg, and pyrazinamide (Z) 25 mg/kg during the intensive phase. Patients in the ETM arm received ethambutol 15 mg/kg orally daily combined with the same HRZ backbone. In both arms, intensive-phase therapy lasted 6 months followed by RH for 12 months.
The predefined primary outcome was mortality at 6 months. Secondary outcomes included in-hospital mortality and neurologic disability at 3 and 6 months. Disability was assessed using the modified Rankin Scale (mRS) and categorized as good (mRS ≤ 2) or poor (mRS > 2). Adverse events were recorded during the study.
Of 131 screened patients, 82 were randomized and included in the analysis. At 6 months, 26 patients had died overall. Mortality by arm was 12 of 42 patients (28.6%) in the STM arm and 14 of 40 patients (35%) in the ETM arm. The reported hazard ratio for death at 6 months was 0.78 with a 95% confidence interval of 0.36–1.70 and a P value of 0.54.
The investigators report no statistically significant difference in the primary outcome between ETM- and STM-based regimens. The trial was halted early for slow recruitment, and the authors note the study may lack statistical power to detect modest differences.
In intention-to-treat analyses there were no differences between the arms for in-hospital mortality or neurologic disability at 3 and 6 months, using the mRS-defined thresholds (good mRS ≤ 2; poor mRS > 2). The paper reports matched baseline characteristics between groups but does not provide additional subgroup effect sizes in the abstract.
Adverse-event reporting in the trial identified two patients in the STM arm who developed ototoxicity and two patients in the ETM arm who experienced vision loss. The authors summarize the overall safety profiles as comparable between the two drugs in this cohort.
In this randomized, open-label trial of adults with TBM, there was no observed difference in 6-month mortality or disability between regimens that used ethambutol or streptomycin as the fourth intensive-phase drug. The safety profiles reported were similar, with rare occurrences of ototoxicity in the STM arm and vision loss in the ETM arm.
Key limitations reported by the investigators include early termination of recruitment due to slow enrollment, which may have limited the statistical power to detect a true difference between arms. The single-center, open-label design and the early stop are relevant when interpreting generalizability and effect-size confidence.
The authors suggest that, given comparable outcomes and safety in this trial, selection of the fourth drug in intensive-phase regimens for TBM may be guided by safety considerations and feasibility, though larger trials would be required to confirm equivalence or detect smaller differences in mortality or disability.
The trial registration number is CTRI/2020/07/026423 (Clinical Trials Registry of India; registered 7 July 2020). The study is reported in Postgrad Med J. 2026 Aug 21;102(1211):826–832. DOI: 10.1093/postmj/qgag021. PubMed identifier (PMID) is 41989851.