Five All-Oral Regimens Show Efficacy in the Phase 3 endTB Trial for Rifampin-Resistant TB
Carole Mitnick, ScD highlights the importance of trust in the success of the endTB trial and addresses the ongoing toxicity concerns with new shorter treatment regimens.
A phase 3 trial has shown that certain 9-month all-oral regimens are as effective as the standard 18-24 month treatment for fluoroquinolone-susceptible, rifampin-resistant tuberculosis (RR-TB). The trial's primary endpoint was a favorable outcome at week 73, defined by negative sputum cultures or improvements in bacteriological, clinical, and radiological measures.
The study found that four of the five new regimens performed similarly to the standard treatment, with over 80% of standard therapy patients achieving favorable outcomes. Regimens combining bedaquiline, clofazimine, levofloxacin, and pyrazinamide (BCLLfxZ) and bedaquiline, delamanid, linezolid, moxifloxacin, and pyrazinamide (BDLLfxZ) were noninferior to the standard therapy, with differences in favorable outcomes ranging from 2.5% to 9.8%.
The multinational trial included 754 participants, with 699 in the modified intention-to-treat analysis and 562 in the per-protocol analysis. The regimens tested included bedaquiline, delamanid, linezolid, levofloxacin, moxifloxacin, clofazimine, and pyrazinamide. The study also found that the incidence of grade 3 or higher adverse events, including hepatotoxicity, was similar across all regimens, with hepatotoxic events reported in 11.7% of participants overall and 7.1% in the standard therapy group.
Building Trust for Trial Success
In our interview with Carole Mitnick, ScD, a professor at Harvard Medical School and senior research associate at Partners in Health, she discussed the role that trust played in the endTB trial's success. "TB trials are long, long efforts that require, in particular for drug-resistant TB, that require participation of volunteers for close to two years," Mitnick said. "And the endTB trial was really only possible because of the foundation of trust that had been cultivated over decades among investigators, the collaborating institutions of Partners in Health, Doctors Without Borders, Interactive Research Development, and Harvard Medical School with communities from which volunteers come."
Mitnick emphasized that this trust is currently under threat, noting, "I just have to mention that that trust is currently being destroyed by the destruction of USAID and the abrupt halt to scores of clinical trials and the care they afford to people who generously volunteer to participate in trials for the greater good. So that's really foundational to anything, to the efficacy results, to the safety results, is this trust, this foundation of trust."
Safety Profile of the Regimens
Mitnick explained that some issues remain with the new regimens. "The endTB clinical trial examined five all-oral alternatives to the current standard of care. And those regimens were considerably shorter, so nine months versus a standard of care that's 18 to 24 months, and they improved the toxicity profile of some of the adverse events that occur with those longer regimens," she said.
She continued, "Historically, those regimens used injectable agents from the drug class known as aminoglycosides and polypeptides which caused kidney problems, which caused deafness, and so those are completely out of the picture. Now, with these endTB regimens, some other issues are overlapping between the endTB regimens that were found to be non-inferior to the standard of care and the standard of care, those include hepatotoxicity. Many of the drugs used in TB treatment are metabolized by the liver, and therefore can cause liver damage. Same holds true for peripheral neuropathy, so numbness and tingling in fingers and toes, which is an issue with linezolid, and that's true in both the standard of care and in the endTB regimens."
Toxicity Concerns with New Regimens
Despite the promising results, Mitnick emphasized that the newer regimens still come with significant toxicity concerns. "So the three regimens that are non-inferior to the standard of care all do come with some toxicity," she said. "This is an area where we need much, much improvement in the treatment of drug-resistant and even in drug-susceptible TB."
Mitnick identified liver toxicity as a primary concern. "I think the primary concern that people see with toxicity at newer regimens even is liver toxicity, which exists with the existing regimen as well," she explained. "And also effects that are linked to the drug linezolid, meaning peripheral neuropathy, the numbness and tingling and pain, I should say, in extremities, as well as serious kind of dysregulations of blood, of the production of red blood cells."
Stay tuned for Part 2 of our interview with Mitnick where we discuss the main implications, takeaways from the study, and more.
