What are the NIX TB (New Isoniazid (Isoniazid) for Tuberculosis) trial, TB Practecal (Tuberculosis Practical) trial, and ZeNix (Zenyth, possibly a brand name, with generic name not specified) trial in tuberculosis treatment?

Summary of NIX-TB, TB PRACTECAL, and ZeNix Trials

NIX-TB Trial

The NIX-TB trial demonstrated that a 6-month, all-oral BPaL regimen (bedaquiline, pretomanid, linezolid) achieved approximately 90% treatment success in patients with pre-extensively drug-resistant (pre-XDR) TB or multidrug-resistant TB with treatment failure. 1

Study Design and Population

• Single-arm trial without a control group, enrolling 109 participants in South Africa 1
• Targeted patients with fluoroquinolone-resistant MDR-TB or those who had failed previous treatment 1
• Linezolid was dosed at 1200 mg daily for the full 6 months 1

Efficacy Outcomes

• Treatment success rate of 97.0% when comparing success versus failure or recurrence 1
• Success rate of 93.2% when comparing treatment success versus death 1
• Overall favorable outcome rate of 90.5% versus failure, recurrence, or death 1
• Only 1.8% of patients were lost to follow-up 1

Safety Profile

• Toxicity was substantial: 81% experienced peripheral neuropathy and 48% developed myelosuppression 1
• 25.7% experienced at least one serious adverse event 1
• 49% had at least one grade 3-4 adverse event related to study drugs 1
• Almost one-third of patients stopped linezolid early due to adverse events 1
• One death occurred from acute hemorrhagic pancreatitis (0.9%) 1

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ZeNix Trial

The ZeNix trial optimized linezolid dosing within the BPaL regimen, demonstrating that 600 mg daily for 6 months provided the best risk-benefit ratio with favorable outcomes ranging from 84-93% across different dosing groups. 1

Study Design

• Evaluated different linezolid doses (600 mg or 1200 mg daily) and durations (2 or 6 months) within the BPaL regimen 1
• Designed specifically to address the optimal dose and duration of linezolid following the high toxicity observed in NIX-TB 1
• No control arm, similar to NIX-TB 1

Key Findings

• The 600 mg daily for 6 months group showed superior tolerability while maintaining efficacy 1
• Favorable outcomes ranged between 84% and 93% across different linezolid dose groups 1
• Six of nine participants with baseline phenotypic bedaquiline resistance achieved favorable outcomes 1
• Confirmed the efficacy results of NIX-TB while demonstrating reduced toxicity with lower linezolid dosing 1

Clinical Impact

• WHO currently recommends 600 mg daily linezolid throughout treatment, though this is based on very low certainty of evidence 1
• Concerns remain about amplification of resistance in patients with extensive disease and unfavorable linezolid pharmacokinetics 1

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TB PRACTECAL Trial

The TB PRACTECAL trial demonstrated that the 24-week, all-oral BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) was superior to standard care for rifampicin-resistant TB, with only 12% unfavorable outcomes compared to 41% with standard care. 2

Study Design and Population

• Open-label, randomized, controlled, multi-arm, multicenter, non-inferiority trial 2
• Conducted at seven sites in Uzbekistan, Belarus, and South Africa 2
• Enrolled participants aged 15 years and older with pulmonary rifampicin-resistant TB 2
• Stage two compared BPaLM (24 weeks) versus standard care (36-80 weeks) in a 1:1 ratio 2

Efficacy Results

• Unfavorable outcomes occurred in only 16 (12%) of 137 participants in the BPaLM group versus 56 (41%) of 137 in the standard care group 2
• Risk difference of -29.2 percentage points (96.6% CI -39.8 to -18.6), demonstrating both non-inferiority and superiority (p<0.0001) 2
• Trial was stopped early due to superiority of the BPaLM regimen 1

Safety Outcomes

• Only 23% of BPaLM recipients had grade 3 or higher adverse events or serious adverse events, compared to 48% receiving standard care 2
• Risk difference of -25.2 percentage points (96.6% CI -36.4 to -13.9) favoring BPaLM 2
• Five deaths occurred in the standard care group by week 72, with four judged treatment-related 2
• No treatment-related deaths in the BPaLM group 2

Regulatory Impact

• WHO added BPaLM to treatment guidance in 2022 as the preferred regimen for fluoroquinolone-susceptible MDR/RR-TB 1, 2
• The regimen is recommended even though the trial included participants with fluoroquinolone-resistant TB 1
• Expected to become the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant TB 2

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Comparative Context

Common Limitations

• All three trials had relatively small sample sizes and lacked traditional control arms (NIX-TB and ZeNix) or were conducted in limited geographic settings 1
• Monitoring linezolid side effects outside clinical trial settings in high-endemic, low-resource areas may be challenging 1
• Drug susceptibility testing capacity for bedaquiline, linezolid, and pretomanid remains urgently needed 1

Emerging Concerns

• Bedaquiline resistance acquisition has been reported in programmatic settings in South Africa 1
• The optimal linezolid dosing remains based on very low certainty of evidence 1
• Pretomanid's full adverse event profile, particularly hepatotoxicity and reproductive toxicity in humans, requires further documentation 1