https://www.cidrap.umn.edu/tuberculosis/trial-data-support-3-shorter-regimens-drug-resistant-tb
Trial data support 3 shorter regimens for drug-resistant TB
Chris Dall, MA
January 31, 2025
Tuberculosis
The phase 3 trial, conducted by an international team of researchers with the endTB (Evaluating Newly Approved Drugs for Multidrug-Resistant Tuberculosis) project, compared outcomes in patients who received five different 9-month, all-oral drug regimens for fluoroquinolone-susceptible, rifampicin-resistant TB or the standard, 18- to 24-month therapy. The results showed that three of the regimens were noninferior to the standard therapy, producing favorable outcomes in 85% to 90% of participants.
One of the investigators involved in the trial calls the results a "milestone" in efforts to shorten and simplify treatments for multidrug-resistant/rifampicin-resistant (MDR/RR)-TB, which affects an estimated 410,000 people annually, predominantly in low- and middle-income countries. The standard regimen, which includes injectable drugs and drugs with severe side effects, has shown only a 65% success rate historically.
"Traditional MDR/RR-TB treatment is often a long and difficult battle with considerable side effects," co-principal investigator and endTB project director Lorenzo Guglielmetti, PhD, MSc, of Medecins sans Frontieres, said in an interview posted on the endTB project website. "The new regimens tested in the endTB trial can drastically improve the patients’ quality of life. They make it easier for patients to complete the full treatment and ultimately increase the chances of full recovery. "
3 of 5 alternative regimens found noninferior
For the trial, investigators enrolled participants ages 15 and older with confirmed fluoroquinolone-susceptible, rifampicin-resistant TB from Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa from February 2017 through October 2021. Participants were randomly assigned to receive standard therapy or one of five 9-month regimens containing combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z).
The endTB trial is one several trials over the past decade aimed at evaluating shorter, less toxic drug regimens for MDR/RR-TB. As Guglielmetti explains, it's also part of a larger project to evaluate the safety and efficacy of bedaquiline and delaminid, which are two newer drugs for MDR/RR-TB.
"These new drugs were the first new TB drugs developed in almost 50 years—a great promise for the fight against TB—but pharmaceutical companies did not see the value in completing their development by creating treatment regimens for a disease that predominately affects poorer communities," he said.
Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat (mITT) analysis and 562 in the per-protocol analysis. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was –12 percentage points.
The new regimens tested in the endTB trial can drastically improve the patients’ quality of life. They make it easier for patients to complete the full treatment and ultimately increase the chances of full recovery.
In the primary outcome analysis, favorable outcomes occurred in 80.7% of the mITT population in the standard therapy group. Among participants in four of the five alternative groups, the results from the mITT analysis showed noninferiority, with the following risk differences compared with standard therapy: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, −0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, −4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, −7.5 to 12.5).
The results in the per-protocol analysis were similar, except for DCMZ, which was not found to be noninferior.
The proportion of participants with grade 3 or higher adverse events was similar across the regimens, with grade 3 or higher hepatotoxic events more common in the experimental groups, except for the BDLLfxZ group.
Regimens are now recommended by the WHO
The investigators note that the 85% to 90% treatment success rate in patients treated with the alternative regimens is similar to the 89% success rate found in trials for the 6-month, all-oral BPaLM (bedaquiline, pretomanid, and linezolid, with or without moxifloxacin), which was recommended for MDR/RR-TB patients by the World Health Organization (WHO) in 2022.
The study authors also point out that while BPaLM is recommended only for use in nonpregnant people ages 14 and older, the three regimens (BLMZ, BCLLfxD, and BDLLfxZ) can be used in nearly all adults, children, and pregnant women, and all the drugs in the regimens have pediatric formulations.
"These findings support the use of three new, all-oral, shorter-duration regimens for rifampin-resistant tuberculosis in addition to BPaLM," they wrote.
The WHO endorsed use of the three regimens in August 2024.
Trial data support 3 shorter regimens for drug-resistant TB
Chris Dall, MA
January 31, 2025
Tuberculosis
A randomized clinical trial conducted in seven countries has identified three new options for shorter, all-oral treatment of drug-resistant tuberculosis (TB), researchers reported this week in the New England Journal of Medicine.The phase 3 trial, conducted by an international team of researchers with the endTB (Evaluating Newly Approved Drugs for Multidrug-Resistant Tuberculosis) project, compared outcomes in patients who received five different 9-month, all-oral drug regimens for fluoroquinolone-susceptible, rifampicin-resistant TB or the standard, 18- to 24-month therapy. The results showed that three of the regimens were noninferior to the standard therapy, producing favorable outcomes in 85% to 90% of participants.
One of the investigators involved in the trial calls the results a "milestone" in efforts to shorten and simplify treatments for multidrug-resistant/rifampicin-resistant (MDR/RR)-TB, which affects an estimated 410,000 people annually, predominantly in low- and middle-income countries. The standard regimen, which includes injectable drugs and drugs with severe side effects, has shown only a 65% success rate historically.
"Traditional MDR/RR-TB treatment is often a long and difficult battle with considerable side effects," co-principal investigator and endTB project director Lorenzo Guglielmetti, PhD, MSc, of Medecins sans Frontieres, said in an interview posted on the endTB project website. "The new regimens tested in the endTB trial can drastically improve the patients’ quality of life. They make it easier for patients to complete the full treatment and ultimately increase the chances of full recovery. "
3 of 5 alternative regimens found noninferior
For the trial, investigators enrolled participants ages 15 and older with confirmed fluoroquinolone-susceptible, rifampicin-resistant TB from Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa from February 2017 through October 2021. Participants were randomly assigned to receive standard therapy or one of five 9-month regimens containing combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z).
The endTB trial is one several trials over the past decade aimed at evaluating shorter, less toxic drug regimens for MDR/RR-TB. As Guglielmetti explains, it's also part of a larger project to evaluate the safety and efficacy of bedaquiline and delaminid, which are two newer drugs for MDR/RR-TB.
"These new drugs were the first new TB drugs developed in almost 50 years—a great promise for the fight against TB—but pharmaceutical companies did not see the value in completing their development by creating treatment regimens for a disease that predominately affects poorer communities," he said.
Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat (mITT) analysis and 562 in the per-protocol analysis. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was –12 percentage points.
The new regimens tested in the endTB trial can drastically improve the patients’ quality of life. They make it easier for patients to complete the full treatment and ultimately increase the chances of full recovery.
In the primary outcome analysis, favorable outcomes occurred in 80.7% of the mITT population in the standard therapy group. Among participants in four of the five alternative groups, the results from the mITT analysis showed noninferiority, with the following risk differences compared with standard therapy: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, −0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, −4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, −7.5 to 12.5).
The results in the per-protocol analysis were similar, except for DCMZ, which was not found to be noninferior.
The proportion of participants with grade 3 or higher adverse events was similar across the regimens, with grade 3 or higher hepatotoxic events more common in the experimental groups, except for the BDLLfxZ group.
Regimens are now recommended by the WHO
The investigators note that the 85% to 90% treatment success rate in patients treated with the alternative regimens is similar to the 89% success rate found in trials for the 6-month, all-oral BPaLM (bedaquiline, pretomanid, and linezolid, with or without moxifloxacin), which was recommended for MDR/RR-TB patients by the World Health Organization (WHO) in 2022.
The study authors also point out that while BPaLM is recommended only for use in nonpregnant people ages 14 and older, the three regimens (BLMZ, BCLLfxD, and BDLLfxZ) can be used in nearly all adults, children, and pregnant women, and all the drugs in the regimens have pediatric formulations.
"These findings support the use of three new, all-oral, shorter-duration regimens for rifampin-resistant tuberculosis in addition to BPaLM," they wrote.
The WHO endorsed use of the three regimens in August 2024.