TB Treatment Shortened With Intensified, Adaptive Approach

An 8-week regimen with bedaquiline and linezolid for rifampin-susceptible tuberculosis (TB) was found noninferior to the standard 6-months of treatment in an adaptive, open trial of several treatment strategies.

Although 6 months of treatment has produced 95% cure rates of rifampin-suceptible TB within clinical trials, the investigators note that there is markedly less success outside the controlled trial environment, where “long-term adherence is difficult for some persons and resource constraints limit the provision of adherence support.”

Nicholas Paton, MD, Yong Loo Lin Schole of Medicine, Singapore, and colleagues with the TRUNCATE-TB trial team undertook their search for a shorter treatment with greater likelihood of adherence based on reported success with 3- and 4-month investigational regimens, particularly those containing fluoroquinolnes or rifapentine, and even with 2-month regimens for patients with smear-negative tuberculosis.

“Thus the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” Paton and colleagues remarked.

In an accompanying editorial in the New England Journal of Medicine, Véonique Dartois, PhD, Center for Discovery and Innovation, Nutley, New Jersey, and NEJM Editor-in-Chief, Eric Rubin, MD, PhD, point out that the common description of the standard treatment, “directly observed therapy, short course”, is a misnomer for a regimen that is anything but short.

“Patients are treated, generally on a daily basis, for 6 months, which necessitates an infrastructure to deliver and observe therapy. This logistic burden has led to a push for shorter treatments,” Dartois and Rubin observe.

The TRUNCATE-TB trial involved several treatment arms and employed an adaptive approach that included extending treatment for clinical disease persisting after the investigated 8 week regimen; and retreatment of relapse with the standard 6 month regimen, adjusted for antibiotic susceptibility testing. The primary treatment outcome was a composite of death, ongoing treatment, or active disease at week 96; with a noninferiority margin of 12 percentage points.

Paton and colleagues enrolled 675 adult subjects with symptoms or chest radiograph evidence of TB and positive nucleic acid amplification testing for TB without rifampin resistance, at 18 sites in 5 countries during the period of March 21, 2018 through January 20, 2020. Subjects were randomly assigned to either the control group receiving 6 month standard treatment (8 weeks of isoniazid, rifampin, ethambutol and pyrazinamide followed by 16 weeks of isonizid and rifampin), or to one of 4 other groups with intensified, 5-drug regimens.

The initial trial plan was to drop 2 groups on the basis of early stopping rules, to preserve sufficient statistical power to ascertain noninferiority of a retained investigational regimen against standard treatment. The criteria allowing early stopping was not met, however, and so 2 groups were dropped instead for logistic criteria such as pill burden and regulatory concerns.

Paton and colleagues report that primary treatment outcome was attained in 3.9% (7 of 181) of the standard treatment group; 11.4% (21 of 184) in the strategy group with an initial rifampin-linezolid regimen (the adjusted difference of 7.4% and 97.5% CI1.7 to 13.2 did not meetnoninferiority); and 5.8% (11 of 189) in the group with bedaquiline-linezolid initial regimen meeting noninferiority (adjusted difference 0.8%, 97.5% CI -3.4-5.1).In contrast to 180 days of standard-treatment, the mean total days to cure was 106 days in the rifampin-linezolid stategy group and 85 days with the bedaquiline-linezolid regimen.

The investigators found that incidence and severity of adverse events were similar in the 3 groups, and indicate that there was no evidence that the intensified treatment strategies prompted drug resistance.Although acknowledging that their sample size was small for establishing risk of drug resistance, they find support in previous trials with 4-month rifamycin-based regimen, in which drug resistance was detected in less than 1% of participants.

Dartois and Rubin welcomed the findings, particularly that the bedaquiline-linezolid regimen was well tolerated. "In fact, this is one of many trials that suggest that the original concerns about bedaquiline might be overstated, at least for patients who undergo prescreening with electrocardiography,” they indicated.

“Perhaps the biggest accomplishment of this trial is a step forward in the adaptive clinical trials design that may help to accelerate regimen development and to rapidly test many more 2-month therapies that are selected on the basis of recent treatment-shortening trial results,” Dartois and Rubin remarked.