In an adaptive, open trial of several treatment strategies, an 8-week treatment regimen with bedaquiline and linezolid for rifampin-susceptible tuberculosis (TB) was found to be comparable to the standard 6-month treatment.
In clinical trials, treatment for six months has resulted in 95 percent cure rates of rifampin-susceptible tuberculosis; however, the researchers note that success rates are significantly lower outside of controlled trials, where “long-term adherence is difficult for some persons and resource constraints limit the provision of adherence support.”
Based on reported success with 3- and 4-month investigational regimens, particularly those containing fluoroquinolnes or rifapentine, and even 2-month regimens for patients with smear-negative tuberculosis, Nicholas Paton, MD, Yong Loo Lin Schole of Medicine, Singapore, and colleagues from the TRUNCATE-TB trial team searched for a shorter treatment with a greater likelihood of adherence.
“Consequently the ongoing half year routine might prompt overtreatment in most of people to forestall backslide in a minority of people,” Paton and partners commented.
Véonique Dartois, PhD, Center for Discovery and Innovation, Nutley, New Jersey, and NEJM Editor-in-Chief Eric Rubin, MD, PhD, point out in an accompanying editorial in the New England Journal of Medicine that the common description of the standard treatment, “directly observed therapy, short course,” is a misnomer for a regimen that is anything but short.
“Because patients receive treatment on a daily basis for six months, an infrastructure is required to deliver and monitor therapy. According to Dartois and Rubin, “a push for shorter treatments has resulted from this logistic burden.”
The TRUNCATE-TB trial used an adaptive approach with multiple treatment arms, including prolonging treatment for clinical disease that persisted after the investigated 8-week regimen; and remission of relapse using the standard six-month treatment plan, with antibiotic susceptibility testing taken into account. At week 96, death, ongoing treatment, or active disease were the primary treatment outcomes; with a 12 percentage point noninferiority margin.
Between March 21, 2018 and January 20, 2020, Paton and colleagues recruited 675 adult participants with TB symptoms or chest radiograph evidence and positive nucleic acid amplification testing for TB without rifampin resistance at 18 locations across five countries. Either the control group, which received standard treatment for six months (eight weeks of isoniazid, rifampin, ethambutol, and pyrazinamide followed by 16 weeks of isoniazid and rifampin), or one of four other groups, which received intensified 5-drug regimens, were assigned to the subjects at random.
In order to maintain sufficient statistical power to determine whether a retained investigational regimen was superior to standard treatment, the initial trial strategy called for eliminating two groups based on early stopping rules. However, the criteria for early stopping were not met, so two groups were eliminated due to logistical considerations like pill burden and regulatory concerns.
According to Paton and colleagues, the standard treatment group achieved primary treatment success in 7.9% of 181 patients; 11.4% (21 of 184) in the strategy group used a rifampin-linezolid regimen for the first time (the adjusted difference of 7.4% and 97.5% CI1.7 to 13.2 did not meet the criteria for noninferiority); and 5.8% (11 of 189) in the group with a bedaquiline-linezolid initial regimen that met noninferiority (adjusted difference 0.8%, 97.5 percent CI -3.4-5.1). In comparison to 180 days of standard treatment, the rifampin-linezolid strategy group had a mean total of 106 days to cure and the bedaquiline-linezolid regimen had a mean total of 85 days.
The researchers discovered that the incidence and severity of adverse events in the three groups were comparable, indicating that there was no evidence of drug resistance caused by the intensified treatment strategies. They find support in previous trials with a 4-month rifamycin-based regimen, in which drug resistance was detected in less than 1 percent of participants, despite the fact that their sample size was insufficient to establish the risk of drug resistance.
Dartois and Rubin expressed satisfaction with the findings, especially the fact that the bedaquiline-linezolid regimen was well tolerated. In point of fact, “this is one of many trials that suggests that the initial concerns about bedaquiline may be overstated, at least for patients who undergo prescreening with electrocardiography,” as they stated.
Dartois and Rubin stated, “Perhaps the biggest accomplishment of this trial is a step forward in the adaptive clinical trials design that may help to accelerate the development of regimens and quickly test many more 2-month therapies that are selected on the basis of recent treatment-shortening trial results.”
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