Comparison of ethambutol versus streptomycin during the intensive phase in treatment of tuberculous meningitis: an open-label randomized clinical trial

Background The choice of the fourth drug in anti-tubercular therapy for adults with tuberculous meningitis (TBM) remains uncertain. This trial compared the effectiveness and safety of ethambutol (ETM) versus streptomycin (STM) during the intensive phase. Methods This is an investigator-initiated, single-center, open-label, randomized controlled trial conducted during October 2020-June 2025. The study was stopped early because of slow recruitment. Patients were randomized to receive either STM (15 mg/kg intramuscular daily; ~90 injections) with isoniazid (H) 5 mg/kg (~300 mg/d), rifampicin (R) 10 mg/kg (~600 mg/d), and pyrazinamide (Z) 25 mg/kg (~1500 mg/d), or ETM (15 mg/kg orally daily) with HRZ for 6 months, followed by RH for 12 months in both arms. Primary outcome was mortality at 6 months. Secondary outcomes included in-hospital mortality and neurologic disability at 3 and 6 months. The disability was assessed using the modified Rankin Scale (mRS) as good (mRS ≤ 2) or poor (mRS > 2). Adverse events were noted. Results Of 131 patients screened, 49 were excluded. The results therefore are based on 82 patients. The two arms were matched for baseline characteristics. At 6 months, 26 patients had died: 12/42 (28.6%) in the STM arm and 14/40 (35%) in the ETM arm (hazard ratio: 0.78; 95% confidence interval: 0.36-1.70; P = 0.54). In intention-to-treat analysis, there were no differences in in-hospital mortality and disability at 3 and 6 months. Two patients each developed ototoxicity and vision loss in the STM and the ETM arm, respectively. Conclusions In adults with TBM, there was no difference in mortality or disability at 6 months between ETM and STM arms, but the study may lack statistical power to detect a difference.The trial was registered in the Clinical Trials Registry of India, CTRI/2020/07/026423 (registered on: 7 July 2020). Key messages What is already known on this topic: The choice of the fourth drug in anti-tubercular therapy (ATT) for adults with tuberculous meningitis (TBM) remains uncertain. Despite extensive use, direct comparisons of ethambutol (ETM) versus streptomycin (STM) in TBM through randomized controlled trials are lacking. What this study adds: In adults with TBM, there was no difference in mortality or disability at 6 months between ETM- or STM-based ATT regimens during the intensive phase. How this study might affect research, practice, or policy: The safety profile of both drugs was comparable; hence, the choice of fourth drug may instead be guided by safety and feasibility.