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Introduction

Tuberculosis (TB) remains a global health challenge, and its current treatment regimen, known as “directly observed therapy, short course” (DOTS), is ironically anything but short, and significant infrastructure is required to deliver and observe therapy. As such, researchers are constantly exploring shorter treatment regimens that can reduce the burden on healthcare systems and patients.

Recently, while on the NUS website, I chanced upon an article and learnt that a ground-breaking international study had been conducted by a research team from NUS YLLSoM, NUH, and Singapore Clinical Research Institute (SCRI), led by Professor Nicholas Paton.

The results of the study were published in the New England Journal of Medicine (NEJM) last month and revealed that a tubcerculosis (TB) treatment strategy with an initial 8-week treatment period followed by retreatment of a small minority who were not cured, showed the same efficacy level as the standard 6-month treatment, but halved the average total time on treatment.

The recent publication of the TRUNCATE-TB trial (the aforementioned trial led by Prof Paton’s team) results in NEJM offers us promising news on this front.

TRUNCATE-TB trial

The trial aimed to test a new two-month (8-week) treatment strategy for TB that responds well to drugs (specifically rifampin-sensitive TB). The study included 674 participants and compared the standard 24-week treatment with two experimental treatment plans. These experimental plans were evaluated after eight weeks to see if the disease persisted. Additionally, participants were closely monitored to check for disease relapse until week 96. The main goal was to measure the combination of death, ongoing treatment, or active disease at week 96.

Key findings of TRUNCATE-TB

Group	Primary Outcome Events	Adjusted Difference	97.5% CI
Control (Standard Treatment) – (i.e. 8 weeks of RHEZ, followed by 16 weeks of rifampin and isoniazid)	3.9%	N/A	N/A
Rifampin–Linezolid Intensified Regimen (i.e. high-dose rifampin, linezolid, isoniazid, pyrazinamide, ethambutol)	11.4%	7.4%	-1.7 to 13.2
Bedaquiline–Linezolid Intensified Regimen (i.e. bedaquiline. linezolid, isoniazid, pyrazinamide, ethambutol)	5.8%	0.8%	-3.4 to 5.1

With these results, only the bedaquiline–linezolid intensified regimen was found to be noninferior to the standard treatment (c.f the rifampin-linezolid intensified regimen wasn’t deemed noninferior because the upper bound of the 97.5% CI for the incidence of primary outcome events was 13.2%, which was higher than 12%; for a strategy to be deemed noninferior according to the study protocol, the difference between the strategy group and the standard-treatment group in the risk of the primary outcome had to be less than 12%).

In the group which received the bedaquiline-linezolid intensified regimen, 85.7% of participants didn’t need treatment beyond eight weeks. On average, the total treatment time in this group was 84.8 days, which is less than half of the standard treatment group’s 180.2 days. However, an important thing to note is that as of the time of writing, bedaquiline is currently not registered as an approved drug in Singapore. It has been FDA-registered for more than a decade though, and is indicated in the management of MDR-TB (multidrug-resistant TB).

Although there were concerns about toxic effects and antibiotic resistance associated with the bedaquiline and linezolid regimen, the trial reported limited toxic effects, suggesting that earlier concerns might be overstated. There were two cases of acquired drug resistance in the bedaquiline–linezolid group, which does not raise substantial concerns in the context of the trial.

Potential Impact and Challenges

The two-month treatment strategy could greatly benefit patients, healthcare systems, and TB control efforts. However, challenges remain, such as the high level of treatment adherence and thorough patient assessments needed for the strategy, which may not be possible in many TB control programs.

Despite these challenges, the TRUNCATE-TB trial is a significant advancement in adaptive clinical trial design and offers an encouraging treatment strategy for drug-sensitive TB.

Adaptive clinical trial design allows for modifications during the trial based on the data being collected, such as dropping treatment arms or adjusting sample sizes. In the TRUNCATE-TB trial, the researchers used early stopping rules and modified entry criteria for higher-risk patients, among other adaptive strategies.

One of the adaptive strategies employed by the researchers was the use of early stopping rules for certain treatment groups. The trial initially had five treatment groups, and the plan was to drop two of these groups based on early stopping rules. However, none of the groups met those standards. As a result, the researchers decided to stop enrollment in two groups on the basis of logistical criteria, such as pill burden and regulatory concerns, in order to preserve statistical power for the remaining groups.

This approach allowed the researchers to focus on the remaining treatment groups, which were more promising and had fewer logistical challenges. By employing early stopping rules and adapting the trial design based on the data, the researchers could optimize the use of resources and increase the efficiency of the study. This flexibility is an important aspect of adaptive clinical trial design, allowing for improvements and modifications during the course of the trial.

Conclusion

For the longest time, as a medical student, pretty much all I’ve ever known about the medical management of TB is the standard RHEZ cocktail that can be used: (‘H’ and ‘Z’ here refer to isoniazid and pyrazinamide respectively) or RIPE (the letters of this acronym correspond to the first letter of common anti-TB drugs: rifampin, isoniazid, pyrazinamide, and ethambutol). The results of this TRUNCATE-TB seem to be yet another one of the many reminders that medical practice and the latest standard of care are constantly evolving, and that we need to keep up with the most important updates. As such, in some sense, I pity future generations of medical students, who will only have an increasing amount of content that they need to learn – the historical streptomycin, the standard RHEZ cocktail, and now: regimen-intensifying agents such as bedaquiline and linezolid.

In sum, the TRUNCATE-TB trial shows that a two-month treatment strategy with the bedaquiline–linezolid intensified regimen is noninferior to the standard six-month regimen for drug-sensitive TB. While there are challenges to implementing this strategy in real-world settings, the results offer a beacon of hope for reducing the impact of TB treatment on patients and healthcare systems not just on our little red dot, but in other TB-endemic countries.