Promising Oral Regimens Offer New Hope for Rifampin-Resistant Tuberculosis Treatment

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Clinical Review | Infectious Diseases | TB

Time to read: 07:10
Time to listen: 13:20

Published on MedED: 3 March 2025
Originally Published: 29 January 2025
Source: N EJM
Type of article: Clinical Research Summary
MedED Catalogue Reference: MIC006
Category: Infectious Diseases
Cross-reference: TB
Keywords: rifampacin-resistant TB, RR-TB

Originally Published in NEMJ, 25 January, 2025. This is a summary of the clinical study and in no way represents the original research. Unless otherwise indicated, all work contained here is implicitly referenced to the original author and trial. Links to all original material can be found at the end of this summary. Access the Disclaimer

Key Take Away

The endTB trial presents promising results for shorter, all-oral regimens in the treatment of rifampin-resistant tuberculosis (RR-TB). The study demonstrated that three experimental regimens showed efficacy comparable to standard therapy, offering new, safer, and more convenient treatment options for patients globally.

Top

Study Context | Objectives | Study Design | Findings | Discussion| Limitations | Conclusion | Original Research | Funding | References

In Context

Rifampin-resistant tuberculosis (RR-TB) remains a significant global health issue, with approximately 410,000 new cases reported annually.

However, the World Health Organization estimates that only 40% of these cases are diagnosed and treated, with a treatment success rate of 65%.^1.Historically, treatment has involved lengthy regimens lasting 18 to 24 months, often including injectable aminoglycosides or polypeptides.

Due to the lack of contemporary randomized controlled trial evidence, regimens have typically been based on expert opinion and pooled observational studies.

To address this, three major trials were launched between 2016 and 2017 to evaluate shorter, all-oral regimens for treating RR-TB:
The STREAM 2 study tested a 9-month, 7-drug regimen containing bedaquiline, while the TB-PRACTECAL study explored three 6-month regimens with bedaquiline, linezolid, and pretomanid, either alone or in combination with moxifloxacin or clofazimine. ^2,3

The endTB trial, which is reviewed here, evaluated five 9-month regimens incorporating newer and repurposed drugs, including bedaquiline, delamanid, clofazimine, and linezolid.

Study Purpose

The endTB Phase 3 clinical trial aimed to find shorter, effective, and safe treatment regimens for rifampin-resistant tuberculosis by using newer drugs like bedaquiline and delamanid, along with repurposed drugs such as clofazimine and linezolid.

Its primary objective was to evaluate the efficacy and safety of five novel, all-oral, 9-month treatment regimens for fluoroquinolone-susceptible, rifampin-resistant tuberculosis (RR-TB), compared to the standard of care.

Clinicaltrial.gov: NCT02754765

Study Design

What Was Done

Participants were randomized to receive one of five experimental regimens or the standard therapy. The experimental regimens combined newer drugs—bedaquiline (B) and delamanid (D)—with repurposed drugs such as clofazimine (C) and linezolid (L), alongside standard TB medications like levofloxacin (Lfx), moxifloxacin (M), and pyrazinamide (Z). Each regimen was administered over 39 weeks (9 months).

Participants

The trial enrolled individuals aged 15 and older with fluoroquinolone-susceptible, pulmonary RR-TB confirmed by WHO-endorsed rapid tests.

A total of 754 participants were randomized across 12 sites in seven countries: Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa

Randomization

A Bayesian response-adaptive randomization method was employed, updating the probability of assignment to each treatment group monthly based on interim analyses of treatment responses at weeks 8 and 39.

Inclusion and Exclusion Criteria

• Inclusion: Participants were included irrespective of HIV status and CD4 lymphocyte count.

• Exclusion: Key exclusion criteria included pregnancy, elevated liver enzymes, uncorrectable electrolyte disorders, a QT interval corrected according to Fridericia’s formula (QTcF) of at least 450 msec, resistance or prior exposure (≥30 days) to bedaquiline, delamanid, clofazimine, or linezolid, and at least 15 days of treatment with any second-line antituberculosis drug during the current TB episode.

Endpoints

• Primary Endpoint: A favourable outcome at week 73, defined as the absence of unfavorable outcomes and either two consecutive negative cultures (including one between weeks 65 and 73) or favourable bacteriologic, radiologic, and clinical evolution. Unfavorable outcomes included death from any cause, modification of the treatment regimen, or initiation of new treatment for RR-TB

• Secondary Endpoints: Favourable outcomes at weeks 39 and 104.

• Safety Endpoints: Grade 3 or higher adverse events, serious adverse events, death, discontinuation of at least one trial drug due to adverse events, and adverse events of special interest (e.g., hepatotoxicity, hematologic toxicity, optic neuritis, peripheral neuropathy, and QTcF prolongation) occurring by week 73.

Findings

The study, conducted from February 2017 to October 2021, included 754 participants.

Of these, 37.8% (264) were women, with a median age of 32 years; 3.6% (25) were under 18 years old.

HIV infection was present in 14% (98), while 81.3% (568) had sputum smear results graded 1+ or higher, and 57.1% had cavitary disease on chest radiography.

Quick reference

The experimental regimens combined newer drugs—bedaquiline (B) and delamanid (D)—with repurposed drugs such as clofazimine (C) and linezolid (L), alongside standard TB medications like levofloxacin (Lfx), moxifloxacin (M), and pyrazinamide (Z).

Regimen	Combination
BLMZ	Bedaquiline, Linezolid, Moxifloxacin,Pyrazinamide
BDLLfxZ	Bedaquiline , Delamanid ,Linezolid, Levofloxacin
BCLLfxZ	Bedaquiline,Clofazimine, Linezolid Levofloxacin
DCMZ	Delamanid , Clofazimine , Moxifloxacin,, Pyrazinamide
DCLLfxZ	Delamanid, Clofazimine, Linezolid, Levofloxacin, Pyrazinamide
BPaLM	In stage 2 of the trial, a 24-week regimen of Bedaquiline, Pretomanid, Linezolid, and Moxifloxacin was investigated.

The following findings were recorded:

Efficacy

In the standard-therapy group, favorable outcomes were seen in 80.7% of the modified intention-to-treat population (95% CI, 72.4–87.3), and 95.9% of the per-protocol population (95% CI, 88.6–99.2).

These outcomes remained consistent across secondary endpoints at weeks 39 and 104, as well as in adjusted and sensitivity analyses.

By week 73, no significant treatment differences were noted across subgroups, though geographic region, prior exposure to second-line antituberculosis agents, cavitary disease, HIV status, and low BMI may influence treatment response.

Over time, outcomes improved, with the BCLLfxZ regimen showing a longer time to unfavorable outcomes compared to standard therapy (hazard ratio: 0.48, 95% CI, 0.23–0.98), suggesting a potential therapeutic benefit.

Safety

By week 73, the proportion of participants experiencing grade 3 or higher adverse events ranged from 54.8% (BLMZ group) to 61.4% (BDLLfxZ group), with 62.7% in the standard-therapy group.

Serious adverse events were similar across groups, ranging from 13.1% in the BCLLfxZ group to 16.7% in the DCMZ and standard-therapy groups. Mortality rates remained low, with 2% (15) of participants dying by week 73, and 2.4% (18) by week 104. No deaths were attributed to trial medications.

Safety Analysis at Week 73

Grade 3 or higher adverse events occurred in 34.7% (313/901) of participants, while 31.0% (54/174) had at least one serious adverse event.

Adverse events of special interest were reported in 23.9% of participants.

Hepatotoxicity occurred in 7.1% of participants in the standard-therapy group, with rates in experimental groups ranging from 6.3% (BDLLfxZ) to 18.3% (BLMZ).

Hematologic toxicity was reported in 10.3% of participants in the standard-therapy group, while experimental groups reported rates between 7.4% (BCLLfxZ) and 10.5% (DCLLfxZ).

Peripheral neuropathy occurred in 4.8% of the standard-therapy group, and between 2.4% (DCLLfxZ) and 7.1% (BDLLfxZ) in the experimental groups. QTcF interval prolongation was noted in 4.2% of the DCMZ group and 3.3% in the BCLLfxZ group.

Discussion

The three experimental regimens (BLMZ, BCLLfxZ, BDLLfxZ) demonstrated noninferior efficacy compared to standard therapy, achieving favorable outcomes in over 85% of participants at week 73, surpassing global averages and matching the BPaLM regimen (89%).

Deaths were rare, even with coexisting conditions and cavitary disease. Grade 3 or higher adverse events were common but generally unrelated to trial drugs.

Hepatotoxicity was more frequent in the experimental groups, except for BDLLfxZ, likely due to drugs like pyrazinamide, bedaquiline, and linezolid, known to elevate liver enzymes. The occurrence of linezolid-related toxic effects was lower in experimental groups, possibly due to dose reductions after 16 weeks. QTcF interval prolongation over 500 msec was infrequent and primarily occurred in participants receiving regimens with clofazimine, bedaquiline, or moxifloxacin, aligning with existing safety data for these drugs.

Limitations

The researchers note several limitations, including the fact that both trial staff and participants were aware of group assignments due to differences in treatment duration.

Additionally, the WHO guidelines were updated twice during the trial. Still, according to the clinical study, the impact on regimen composition was minimal, as 81.5% of standard-therapy regimens already aligned with the updated recommendations.

Conclusion

In conclusion, the findings of this trial provide strong support for the use of three new, all-oral, shorter-duration regimens—BLMZ, BCLLfxZ, and BDLLfxZ— for the treatment of rifampin-resistant tuberculosis, complementing the WHO-endorsed BPaLM regimen. These regimens are suitable for use in both adults and children, including pregnant individuals, as they contain drugs with pediatric formulations and are considered safe during pregnancy.

While bedaquiline-sparing regimens like DCMZ and DCLLfxZ were evaluated, they showed less favorable outcomes compared to standard therapy containing bedaquiline, particularly in terms of recurrence rates.

The adoption of these endTB regimens could simplify treatment options and offer alternatives to drugs with challenging side effects or resistance. However, further research into bedaquiline-sparing regimens, rapid resistance testing, and vigilant monitoring for hepatotoxicity and QT prolongation is needed.

Overall, this trial highlights the potential for more effective, simplified, all-oral treatments for rifampin-resistant tuberculosis, improving prospects for patients globally.

Importance of this study for South Africa

South Africa faces a significant challenge with rifampicin-resistant tuberculosis (RR-TB), which contributes to a high burden of disease, with an estimated 21,000 new cases annually. A critical issue is the substantial rate of loss to follow-up (LTFU), where patients miss prolonged periods of treatment. This leads to the development of further resistance and increased transmission of drug-resistant TB.⁵

Current treatments, though effective, are often toxic and cause severe side effects such as myelosuppression, peripheral neuropathy, and optic nerve damage. There is an urgent need for shorter, less toxic, and more effective treatment regimens to address these concerns^.4,5

Access the Study

Guglielmetti, L., Khan, U., Velásquez, G. E., Gouillou, M., Abubakirov, A., Baudin, E., Berikova, E., Berry, C., Bonnet, M., Cellamare, M., Chavan, V., Cox, V., Dakenova, Z., de Jong, B. C., Ferlazzo, G., Karabayev, A., Kirakosyan, O., Kiria, N., Kunda, M., Lachenal, N., … endTB Clinical Trial Team (2025). Oral Regimens for Rifampin-Resistant, Fluoroquinolone-Susceptible Tuberculosis. The New England journal of medicine, 392(5), 468–482. https://doi.org/10.1056/NEJMoa2400327

Conflict of Interest, Funding and Support

Conflict of Interest Disclosures
Full declaration available online

Funding/Support
The study was supported by grants from Unitaid (SPHQ15-LOA-045) to Partners In Health, the Research Foundation, Flanders (FWO G0A7720N to Dr. de Jong), the National Institute of Allergy and Infectious Diseases (K08 AI141740 to Dr. Velásquez), Wellcome Trust (206379/Z/17/Z to Dr. McIlleron), and in-kind support from Médecins Sans Frontières, Partners In Health, and Interactive Research and Development for trial implementation and administration.ng

1. World Health Organization. (2023). Global tuberculosis report 2023. World Health Organization. Retrieved 2 March 2025. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023

2. Goodall RL, Meredith SK, Nunn AJ, et al. Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial. Lancet 2022;400:1858-1868.

3. Nyang’wa B-T, Berry C, Kazounis E, et al. A 24-week, all-oral regimen for rifampin-resistant tuberculosis. N Engl J Med 2022;387:2331-2343.

4. Guglielmetti, L. (n.d.). Novel nine-month regimens for rifampicin-resistant tuberculosis: Results of the endTB trial. WHO EURO Virtual Medical TB Consilium, 26th webinar. Retrieved from https://vmc.euro.who.int/vmc/public/Files/Public/Webinars/2%20Results%20of%20the%20endTB%20trial%20%281%29.pdf

5. Morgan, H., Ndjeka, N., Hasan, T., Gegia, M., Mirzayev, F., Nguyen, L. N., Schumacher, S., Schlub, T. E., Naidoo, K., & Fox, G. J. (2024). Treatment of Multidrug-resistant or Rifampicin-resistant Tuberculosis With an All-oral 9-month Regimen Containing Linezolid or Ethionamide in South Africa: A Retrospective Cohort Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 78(6), 1698–1706. https://doi.org/10.1093/cid/ciae145

5. McNabb, K.C., Bergman, A.J., Patil, A. et al. Travel distance to rifampicin-resistant tuberculosis treatment and its impact on loss to follow-up: the importance of continued RR-TB treatment decentralization in South Africa. BMC Public Health 24, 578 (2024). https://doi.org/10.1186/s12889-024-17924-0

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Key Take Away

The endTB trial presents promising results for shorter, all-oral regimens in the treatment of rifampin-resistant tuberculosis (RR-TB). The study demonstrated that three experimental regimens showed efficacy comparable to standard therapy, offering new, safer, and more convenient treatment options for patients globally.

Top

Study Context | Objectives | Study Design | Findings | Discussion| Limitations | Conclusion | Original Research | Funding | References

In Context

Rifampin-resistant tuberculosis (RR-TB) remains a significant global health issue, with around 410,000 new cases reported annually.

However, the World Health Organization (WHO) estimates that only 40% of these cases are diagnosed and treated, with a treatment success rate of 65% (WHO, 2023). Historically, treatment has involved lengthy regimens lasting 18 to 24 months, often including injectable aminoglycosides or polypeptides. ¹

Due to the lack of contemporary randomized controlled trial evidence, regimens have typically been based on expert opinion and pooled observational studies.

To address this, three major trials were launched between 2016 and 2017 to evaluate shorter, all-oral regimens for treating RR-TB.

The STREAM 2 study tested a 9-month, 7-drug regimen containing bedaquiline, while the TB-PRACTECAL study explored three 6-month regimens with bedaquiline, linezolid, and pretomanid, either alone or in combination with moxifloxacin or clofazimine. ^2,3

The endTB trial, which is reviewed here, evaluated five 9-month regimens incorporating newer and repurposed drugs, including bedaquiline, delamanid, clofazimine, and linezolid.

Study Purpose

Clinicaltrial.gov: NCT02754765

Study Design

Its primary objective was to evaluate the efficacy and safety of five novel, all-oral, 9-month treatment regimens for fluoroquinolone-susceptible, rifampin-resistant tuberculosis (RR-TB), compared to the standard of care.

What Was Done

Participants

The trial enrolled individuals aged 15 and older with fluoroquinolone-susceptible, pulmonary RR-TB confirmed by WHO-endorsed rapid tests.

A total of 754 participants were randomized across 12 sites in seven countries: Georgia, India, Kazakhstan, Lesotho, Pakistan, Peru, and South Africa

Randomization

Inclusion and Exclusion Criteria

• Inclusion: Participants were included irrespective of HIV status and CD4 lymphocyte count.

Endpoints

• Secondary Endpoints: Favourable outcomes at weeks 39 and 104.

• Safety Endpoints: Grade 3 or higher adverse events, serious adverse events, death, discontinuation of at least one trial dr
ug due to adverse events, and adverse events of special interest (e.g., hepatotoxicity, hematologic toxicity, optic neuritis, peripheral neuropathy, and QTcF prolongation) occurring by week 73. 4

Findings

The study, conducted from February 2017 to October 2021, included 754 participants.

Of these, 37.8% (264) were women, with a median age of 32 years; 3.6% (25) were under 18 years old.

HIV infection was present in 14% (98), while 81.3% (568) had sputum smear results graded 1+ or higher, and 57.1% had cavitary disease on chest radiography.

The following findings were recorded:

Efficacy

These outcomes remained consistent across secondary endpoints at weeks 39 and 104, as well as in adjusted and sensitivity analyses.

Safety

By week 73, the proportion of participants experiencing grade 3 or higher adverse events ranged from 54.8% (BLMZ group) to 61.4% (BDLLfxZ group), with 62.7% in the standard-therapy group.

Safety Analysis at Week 73

Grade 3 or higher adverse events occurred in 34.7% (313/901) of participants, while 31.0% (54/174) had at least one serious adverse event.

Adverse events of special interest were reported in 23.9% of participants. Hepatotoxicity occurred in 7.1% of participants in the standard-therapy group, with rates in experimental groups ranging from 6.3% (BDLLfxZ) to 18.3% (BLMZ).

Hematologic toxicity was reported in 10.3% of participants in the standard-therapy group, while experimental groups reported rates between 7.4% (BCLLfxZ) and 10.5% (DCLLfxZ).

Discussion

Deaths were rare, even with coexisting conditions and cavitary disease. Grade 3 or higher adverse events were common but generally unrelated to trial drugs.

The researchers note several limitations, including the fact that both trial staff and participants were aware of group assignments due to differences in treatment duration.

Additionally, the WHO guidelines were updated twice during the trial, but according to the clinical study, the impact on regimen composition was minimal, as 81.5% of standard-therapy regimens already aligned with the updated recommendations.

Conclusion

The adoption of these endTB regimens could simplify treatment options and offer alternatives to drugs with challenging side effects or resistance.

However, further research into bedaquiline-sparing regimens, rapid resistance testing, and vigilant monitoring for hepatotoxicity and QT prolongation is needed.

Overall, this trial highlights the potential for more effective, simplified, all-oral treatments for rifampin-resistant tuberculosis, improving prospects for patients globally.

Importance of this study for South Africa

South Africa faces a significant challenge with rifampicin-resistant tuberculosis (RR-TB), which contributes to a high burden of disease, with an estimated 21,000 new cases annually. A critical issue is the substantial rate of loss to follow-up (LTFU), where patients miss prolonged periods of treatment.This leads to the development of further resistance and increased transmission of drug-resistant TB.⁵

Current treatments, though effective, are often toxic and cause severe side effects such as myelosuppression, peripheral neuropathy, and optic nerve damage. There is an urgent need for shorter, less toxic, and more effective treatment regimens to address these concerns^.4,5

Access the Study

3. Nyang’wa B-T, Berry C, Kazounis E, et al. A 24-week, all-oral regimen for rifampin-resistant tuberculosis. N Engl J Med 2022;387:2331-2343.

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