In a recent study published in The Lancet Respiratory Medicine, researchers reported the TB-PRACTECAL clinical trial outcomes, which evaluated the efficacy and safety of oral bedaquiline, linezolid, and pretomanid (BPaL)-based regimens for pulmonary tuberculosis resistant to rifampicin.
Study: Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial. Image Credit: fizkes/Shutterstock.com
The TB-PRACTECAL clinical trial investigated novel anti-tubercular medicinal performances in delivering efficient 24-week therapeutic regimens for tuberculosis infection resistant to rifampicin.
The trial had three potential regimens: BPaL with or without clofazimine (BPaLC) or moxifloxacin (BPaLM). The BPaLM regimen showed the most promising results, and the World Health Organization (WHO) suggested a six-month BPaLM course for rifampicin-resistant TB without fluoroquinolone resistance in 2022 and a BPaL regimen for pulmonary tuberculosis resistant to rifampicin with further resistance in 2022.
About the study
In the present study, researchers presented the final TB-PRACTECAL clinical trial assessment, comparing the effectiveness and safety of the BPaLM treatment regimen to conventional therapy.
The study included individuals aged ≥15 years with pulmonary tuberculosis resistant to rifampicin at seven community locations and hospitals in South Africa, Belarus, and Uzbekistan.
The trial progressed from the 2B phase (stage 1.0) to the third phase (stage 2.0), with two groups for investigation. In the first stage of the trial, participants were 1:1:1:1 randomized to receive standard care, 24-week orally administered BPaL, BPaLC, or BPaLM, and in the second stage, they received 1:1 BPaLM treatment and regular care.
The study's primary outcome was the proportion of individuals in the altered intention-to-treat population and the per-protocol population with unfavorable outcomes (treatment discontinuation, treatment failure, disease recurrence, individuals lost to follow-up or death) 72 weeks post-randomization.
The safety population was determined using a non-inferiority margin of 12%. Individuals aged ≥15 years with a pulmonary infection by Mycobacterium tuberculosis, confirmed by culture-based drug susceptibility tests or molecular tests, were included.
The team excluded pregnant individuals, those with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels 3.0-fold higher than the normal range, those having Fridericia-corrected QT (QTcF) intervals higher than 450 ms, those with structural cardiac disease or those who were at an elevated risk of being resistant to pretomanid, linezolid, or bedaquiline.
With binary options, gender was self-documented. All patients assigned to the exploratory groups were administered the BPaL regimen, including 600 mg of linezolid once a day for 16 weeks, followed by 300 mg for eight weeks.
In addition, the BPaLM regimen included 400 mg of moxifloxacin daily, and the BPaLC regimen included 100 mg of clofazimine each day. Safety and efficacy were monitored every 28 days for 24 weeks and subsequently every 56 days for the remaining 84 weeks.
From January 2017 to March 2021, the team assessed 680 individuals for eligibility, with 552 randomly allocated to the conventional treatment and BPaLM intervention groups.
The adjusted intention-to-treat fraction included 507 individuals, of whom 41% were female. The median age was 35, and 28% had human immunodeficiency virus (HIV) infections.
Unfavorable outcomes occurred in 12% of the 137 BPaLM group participants and 41% of the 137 regular care group participants (risk difference of 29 percentage points). Thirty-three percent of 151 patients receiving BPaLM experienced grade 3.0 or more severe adverse events compared to 48% of regular care recipients (risk difference of 25 percentage points).
By week 72, five fatalities occurred in the regular care group, one of which (COVID-19-related pneumonia) was not associated with therapy and four of which (suicide, acute pancreatitis, sudden cardiac arrest, and sudden death) were deemed treatment-related.
At 72 weeks post-randomization, the primary study outcome was the unfavorable status of either treatment cessation, treatment failure, tuberculosis recurrence, loss to follow-up, or death. Secondary efficacy assessment outcomes included unfavorable outcomes at 24 weeks and 108 weeks post-randomization.
Other outcomes included culture conversion after 12 weeks, time-to-culture conversion, and TB recurrence within 48 weeks of randomization (in the investigation groups).
In the BPaLC and BPaL groups, post-hac analyses were conducted to evaluate the long-term results. Unadjusted risk differences for BPaLC were 17 percentage points and 27 percentage points for BPaL at week 72 in the modified intention-to-treat group, showing non-inferiority.
At week 108, the adjusted intention-to-treat population revealed that BPaLC remained non-inferior to usual treatment. However, illness recurrence occurred in a small percentage of patients in the BPaLC group, and three of four isolates from individuals who had disease recurrence developed new resistance to bedaquiline.
Overall, the study findings showed that the 24-week, all-oral BPaLM regimen added by the WHO to the treatment guidelines for pulmonary tuberculosis resistant to rifampicin is safe, effective, and non-inferior to standard care.
Children and adolescents may prefer BPaL-based regimens with better outcomes, shorter duration, lower pill burdens, and improved quality of life.