Infectious Disease · Medical Literature
A Pragmatic Trial of a 6-Month Strategy for Rifampicin-Resistant Tuberculosis.
Abstract
Safer, more effective treatment regimens for rifampicin-resistant tuberculosis are needed. We conducted a phase 3, open-label, pragmatic, randomized, controlled noninferiority trial in South Africa to assess a 6-month treatment strategy for pulmonary rifampicin-resistant tuberculosis. Participants with pulmonary rifampicin-resistant tuberculosis who were 6 years of age or older were randomly assigned to a regimen consisting of bedaquiline, linezolid, delamanid, and levofloxacin or clofazimine or both for 6 months (trial-strategy group) or the 9-month standard-of-care treatment regimen that was current in South Africa (control group). Persons who were pregnant or breastfeeding and those who had fluoroquinolone-resistant tuberculosis were included in the trial population. Treatment in both groups was adjusted on the basis of results of second-line drug susceptibility testing. The primary efficacy end point was a successful outcome (cure or completion of treatment) at the end of treatment and at 76 weeks after randomization. The noninferiority margin was 10 percentage points. The primary safety end point was an adverse event of grade 3 or higher. Among the 432 persons who were screened, 403 underwent randomization; 203 were assigned to the trial-strategy group, and 200 to the control group. A successful outcome was observed in 174 of 202 participants (86.1%) in the trial-strategy group and in 172 of 200 (86.0%) in the control group. The adjusted risk difference was -0.2 percentage points (95% confidence interval [CI], -6.9 to 6.5; P = 0.001 for noninferiority). Adverse events of grade 3 or higher occurred during treatment in 63 of 202 participants (31.2%) in the trial-strategy group and in 74 of 200 (37.0%) in the control group; 10 participants in each group died. Among participants in South Africa with rifampicin-resistant tuberculosis, the 6-month trial strategy was noninferior to the standard-of-care strategy with respect to a successful outcome. The safety profiles of the two strategies were similar. (Funded by the U.S. Agency for International Development and others; BEAT Tuberculosis ClinicalTrials.gov number, NCT04062201.).
Clinical relevance
In patients aged ≥6 years with pulmonary rifampicin-resistant tuberculosis—including pregnant or breastfeeding women and those with fluoroquinolone resistance—is a 6-month all-oral regimen of bedaquiline, delamanid, linezolid, and levofloxacin and/or clofazimine (BDLLfxC) noninferior in efficacy and comparable in safety to the South African 9-month standard-of-care regimen? __SNAPSHOT__ {"studyDesign":"Phase 3, open-label, pragmatic, randomized controlled noninferiority trial (BEAT Tuberculosis)","setting":"Two urban sites in South Africa (Isango Lethemba TB Research Unit, Eastern Cape; King Dinizulu Hospital Complex, KwaZulu-Natal); enrollment August 2019–October 2022","sampleSize":"432 screened; 403 randomized (trial-strategy group: n=203, control group: n=200); 1 participant in the trial-strategy group never initiated treatment","population":"Participants aged ≥6 years with pulmonary rifampicin-resistant tuberculosis (RR-TB), inclusive of those who were pregnant or breastfeeding, had fluoroquinolone-resistant TB, or had isoniazid resistance. Treatment was adjusted based on second-line drug susceptibility testing results. Enrolled under real-world programmatic conditions representative of the South Africa National TB Programme.","intervention":"6-month all-oral trial strategy: bedaquiline + linezolid + delamanid + levofloxacin and/or clofazimine (BDLLfxC), adjusted based on second-line drug susceptibility testing results","comparator":"9-month (or longer) standard-of-care oral regimen current in South Africa at time of enrollment, also adjusted based on second-line drug susceptibility testing","primaryOutcome":"Dual primary efficacy endpoint: successful outcome (cure or treatment completion) at both end of treatment and at 76 weeks after randomization, assessed by adjusted risk difference with a noninferiority margin of 10 percentage points. Primary safety endpoint: proportion of participants experiencing an adverse event of grade 3 or higher.","followUp":"76 weeks after randomization (approximately 18 months)","fundingSource":"United States Agency for International Development (USAID); executed by the University of the Witwatersrand in collaboration with the South African National Department of Health. The abstract also acknowledges the U.S. Department of Health and Human Services/NIH/NIAID/DAIDS grading standards. No industry funding identified."}
Key findings
Among 403 randomized participants, successful outcomes were achieved in 174/202 (86.1%) in the trial-strategy group and 172/200 (86.0%) in the control group. The adjusted risk difference was −0.2 percentage points (95% CI: −6.9 to +6.5 percentage points), with the upper boundary of the CI well within the prespecified 10-percentage-point noninferiority margin; noninferiority was demonstrated (p=0.0014 for noninferiority). Regarding safety, the primary safety endpoint (grade ≥3 adverse events during treatment) occurred in 63/202 (31.2%) in the trial-strategy group versus 74/200 (37.0%) in the control group. Serious adverse events occurred in 38 participants (18.8%) in the trial-strategy group and 44 (22.0%) in the control group during treatment. Ten deaths occurred in each group. Linezolid-attributed anemia was the most common serious adverse event: 33 participants (16.3%) in the trial-strategy group and 29 (14.5%) in the control group. Transfusion was required in 20/202 (9.9%) trial-strategy versus 11/200 (5.5%) control participants. Peripheral neuropathy causing permanent linezolid discontinuation occurred in 10 (5.0%) trial-strategy versus 7 (3.5%) control participants. Optic neuritis was observed in 9 participants overall (2.2%): 7 (3.5%) in the trial-strategy group and 2 (1.0%) in the control group. Asymptomatic QTcF prolongation >500 msec occurred in 5 (2.5%) trial-strategy and 7 (3.5%) control participants. Severe hepatic adverse events occurred in 4 (2.0%) trial-strategy versus 9 (4.5%) control participants. NNT and NNH are not calculable from reported data for most comparisons; transfusion NNH for trial-strategy vs. control = 23 (calculated, based on 9.9% vs. 5.5%).
Practice implications
The BEAT-TB trial established that a 6-month all-oral regimen (BDLLfxC) is noninferior to the South African 9-month standard of care in achieving successful treatment outcomes (cure or completion) at both end of treatment and 76-week follow-up, with approximately 86% success in both groups. Importantly, the trial enrolled a clinically meaningful broad population that included children ≥6 years, pregnant and breastfeeding women, and individuals with fluoroquinolone-resistant TB—groups systematically excluded from most prior pivotal trials. This pragmatic, internally controlled design in a high-burden, resource-constrained programmatic setting substantially strengthens the external validity of findings compared to prior single-arm studies (Nix-TB, ZeNix) and supports real-world applicability. The WHO has already incorporated BDLLfxC as a second recommended 6-month all-oral option for RR-TB and pre-XDR-TB based in part on this evidence. Regarding safety, the overall grade ≥3 adverse event burden was numerically lower in the trial-strategy group, though linezolid-related anemia (requiring transfusion in ~10% of the 6-month arm) and optic neuritis (more frequent in the trial-strategy group) require clinical vigilance. The trial did not establish superiority, did not assess long-term relapse beyond 76 weeks, and was conducted exclusively in South Africa, limiting generalizability to other high-burden settings. This summary is based on abstract and preprint data; the full published manuscript should be consulted for complete per-protocol analyses, subgroup results, and supplementary safety data. __LIMITATIONS__ Open-label design: lack of blinding introduces potential for ascertainment bias in outcome classification and adverse event reporting.,Single-country trial (South Africa): limits generalizability to other high-burden TB settings with different drug resistance patterns, healthcare infrastructure, and population characteristics.,Noninferiority design with a 10 percentage point margin: the margin, while clinically pre-specified, means a true 10% inferiority of the 6-month regimen relative to standard of care could not be excluded.,Follow-up duration of 76 weeks may be insufficient to detect late relapse, particularly relevant for regimens combining multiple bactericidal agents with differing half-lives.,Regimen heterogeneity: both arms allowed treatment modification based on drug susceptibility testing, introducing variability in actual treatment received that may limit comparisons of specific drug combinations.,Pediatric (6–14 years) and pregnant/breastfeeding subgroups: trial included these populations but subgroup-specific efficacy and safety data are not reported in the abstract; adequacy of representation and power for subgroup conclusions cannot be assessed.,Linezolid-related toxicity (anemia requiring transfusion in ~10% of 6-month arm; optic neuritis in 3.5%) represents a clinically important safety signal requiring individualized monitoring plans.,This summary draws primarily from the published abstract and a preprint version; full per-protocol analysis, secondary outcomes, and subgroup data require review of the complete manuscript. __BOTTOM_LINE_CATEGORY__ practice_changing __BOTTOM_LINE__ The BEAT-TB trial demonstrates that a 6-month all-oral regimen of bedaquiline, delamanid, linezolid, and levofloxacin/clofazimine achieves approximately 86% successful treatment outcomes for pulmonary rifampicin-resistant TB—noninferior to the South African 9-month standard of care—across a broad patient population including children ≥6 years, pregnant or breastfeeding women, and patients with fluoroquinolone resistance. Clinicians should anticipate meaningful linezolid-related toxicity, particularly anemia (transfusion required in ~10%) and optic neuritis, necessitating proactive monitoring. These findings have already informed WHO guideline updates recommending BDLLfxC as a second 6-month all-oral option; however, full-manuscript review is warranted before implementation across settings beyond South Africa.