What is the treatment regimen for the ENDTB (End Tuberculosis) trial?

The endTB Trial Treatment Regimen

The endTB trial evaluated five 9-month all-oral regimens for multidrug-resistant tuberculosis (MDR-TB), with the most effective regimens containing bedaquiline, linezolid, levofloxacin, and pyrazinamide (BCLLfxZ), which demonstrated superior outcomes compared to standard therapy. 1

Overview of the endTB Trial

The endTB (Evaluating Newly Approved Drugs for Multidrug-Resistant Tuberculosis) trial is a phase III, multi-country, adaptive, randomized controlled clinical trial designed to evaluate shorter treatment regimens for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. 2

Trial Design

• Type: Phase III, pragmatic, multi-country, adaptive, randomized controlled trial
• Population: Patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis
• Comparison: Five 39-week (9-month) multi-drug regimens vs. standard of care
• Follow-up: 73 to 104 weeks post-randomization

Specific Regimens Tested

The endTB trial evaluated five experimental 9-month all-oral regimens containing various combinations of:

1. BCLLfxZ: Bedaquiline (B) + Clofazimine (C) + Linezolid (L) + Levofloxacin (Lfx) + Pyrazinamide (Z)
2. BLMZ: Bedaquiline (B) + Linezolid (L) + Moxifloxacin (M) + Pyrazinamide (Z)
3. BDLLfxZ: Bedaquiline (B) + Delamanid (D) + Linezolid (L) + Levofloxacin (Lfx) + Pyrazinamide (Z)
4. DCMZ: Delamanid (D) + Clofazimine (C) + Moxifloxacin (M) + Pyrazinamide (Z)
5. BDLfxZ: Bedaquiline (B) + Delamanid (D) + Levofloxacin (Lfx) + Pyrazinamide (Z) 1

Key Results

The most recent results from the endTB trial showed that four of the five regimens were non-inferior to standard therapy in the modified intention-to-treat analysis:

• BCLLfxZ: 9.8 percentage points better than standard therapy (95% CI, 0.9 to 18.7)
• BLMZ: 8.3 percentage points better (95% CI, -0.8 to 17.4)
• BDLLfxZ: 4.6 percentage points better (95% CI, -4.9 to 14.1)
• DCMZ: 2.5 percentage points better (95% CI, -7.5 to 12.5) 1

The BCLLfxZ regimen (Bedaquiline + Clofazimine + Linezolid + Levofloxacin + Pyrazinamide) showed the best outcomes, with 90.5% favorable outcomes compared to 80.7% in the standard therapy group.

Safety Profile

• The proportion of participants with grade 3 or higher adverse events was similar across the regimens
• Hepatotoxicity (grade 3 or higher) occurred in 11.7% of participants overall
• Linezolid-associated toxicity was common but manageable, often requiring dose adjustments 1

Clinical Implications

The endTB trial results represent a significant advancement in MDR-TB treatment by:

1. Shortening treatment duration: From 18-24 months to just 9 months
2. Eliminating injectable agents: All regimens are fully oral, avoiding the toxicity of aminoglycosides
3. Improving outcomes: Higher success rates than standard therapy
4. Reducing toxicity: Better safety profile compared to traditional regimens

Related Trials

The endTB-Q trial is a companion study specifically designed for patients with pre-XDR TB (fluoroquinolone-resistant MDR-TB), using a regimen containing bedaquiline, linezolid, clofazimine, and delamanid for 6-9 months. 3

The TB-PRACTECAL trial also demonstrated that a 6-month regimen with bedaquiline, linezolid, pretomanid, and moxifloxacin (BPaLM) was superior to standard of care for MDR/RR-TB, with 89% favorable outcomes versus 51% in standard care. 4

WHO Recommendations

Based on these findings, the WHO now recommends:

1. A 6-month BPaLM regimen as the preferred treatment option for fluoroquinolone-susceptible MDR/RR-TB
2. A 9-12 month bedaquiline-based regimen as a second option for MDR/RR-TB without fluoroquinolone resistance 4

The endTB trial has significantly contributed to transforming MDR-TB treatment from lengthy, injectable-based regimens to shorter, more effective, and less toxic all-oral regimens, marking a major advancement in the global fight against drug-resistant tuberculosis.