Efficacy of ultra-short course chemotherapy for new smear positive drug susceptible pulmonary tuberculosis: study protocol of a multicenter randomized controlled clinical trial

Tuberculosis (TB) is now the leading infectious disease killer worldwide. In 2015, there were an estimated 10.4 million new TB cases worldwide. China is one of 30 TB high burden countries with third largest TB population globally. In 2015, 0.9 million new cases were estimated with an incidence of 67/100,000, accounting for 8.7% of the global total [1, 2]. Currently, 6-month short course remains the standard of care for the treatment of drug-susceptible pulmonary TB (DS-PTB), and its efficacy has been evaluated and established in controlled trials. Although standard 6-month regimens for drug- susceptible TB are highly efficacious, the duration of treatment is still considerably longer than that of most of respiratory infections. Poor adherence leads to treatment failure which in turn drives the emergence of drug resistance. Shortened treatment for DS-PTB would improve treatment outcomes and reduce costs. So regimens for TB that are shorter and/or simpler than the current 6-month regimen are needed.

The effectiveness of fluoroquinolones (FQ) in vitro, their sterilizing effect in both mice and human in vivo and their success in treating multi-drug resistant TB(MDR-TB) raised hope that if used as first line drugs [3–6], they might contribute to shortening therapy duration of DS-PTB. In 2014, 3 independent clinical trials named REMoxTB, RIFAQUIN and OFLOTUB/Gatifloxacin (Gfx) simultaneously reported final results of shortening treatment duration for DS-PTB by using FQ-based regimens [7–9]. Unfortunately, noninferiority for these regimens was not shown as compared to the standard 6-month regimen, indicating that shortening treatment to 4 months was not effective in these settings. Challenges as we faced, optimizing regimens for DS-PTB with shorter duration are still promising. The first pharmacodynamic data showed that levofloxacin(Lfx) was less effective than moxifloxacin(Mfx) and Gfx. Lfx was given at a dose less than 500 mg/day in these early studies [10]. With the prescription increase at the dose of 1000 mg/day in recent studies, Lfx showed the best early bactericidal activity as active as Mfx at 400 mg during the first 7 days of treatment [3]. Other studies have also shown that Mfx and Gfx are better than ofloxacin, but do not contain comparison with Lfx [11]. It seems to reveal that Lfx at high doses, rather than low doses, has better pharmacodynamic qualities than either Mfx or Gfx. Additionally, Lfx is less expensive, more widely available, and may be less likely to prolong the QT interval compared to later generation of FQs. Previous study showed that Z inhibited the ribosome-sparing process of trans-translation. Trans-translation is essential for freeing scarce ribosomes in nonreplicating organisms. Therefore, Z could eradicate persisting organisms which are the major cause of recurrence of TB [12]. If Z is given during the whole course, it can improve the sterilizing activities against mycobacterial tuberculosis (MTB) and reduce relapse of TB. On the basis of the supportive evidence, a multicenter randomized controlled clinical trial is currently in progress to evaluate whether 4.5 months of an Lfx-containing regimen will be as effective as 6 months of the standard regimen for the treatment of DS-PTB. Meanwhile, given the strong bactericidal and sterilizing activities of H, R, E and Z, parallel treatment shortening trial is also in progress with the consideration of increasing drug combination at continuation phase as compared with the standard 6-month regimen.

To our knowledge, preferable dosage and treatment duration of Lfx’s contribution combined with first line anti-TB drugs is not well studied. Neither is the shortening regimen with full length of treatment using H and R. This study aims to assess the efficacy and safety of 2 shortened regimens (study regimens) for DS-PTB compared to the WHO standardized 6-month regimen (control regimen). Success of the ultra-short course TB regimens would further shorten the treatment duration of DS-PTB, improve compliance and cure rates, reduce rates of adverse reactions and cost, as well as minimize the risk of drug resistance.

Current 6-month regimens for new smear positive DS-PTB are used in more than 90 countries and are designed and evaluated cost-effective [13]. With the exciting results of shortened regimens for MDR-TB cases from the previous 24 months to 9 months length of therapy [14–16], researchers have been paving the way to explore the probably shorter regimens for DS-PTB inferior to the current standard ones. In the 1970s, the introduction of R resulted in a 15 to 20% increase of sputum conversion at 8 weeks and shortening duration of treatment from 18 months to 9 months. The later introduction of Z led to a further 13% increase of sputum conversion at 8 weeks, allowing therapy to be further reduced from 9 months to 6 months [17–20]. Based on these findings, Medical Research Council (MRC) led the controlled clinical trial of five short-course (4-month) chemotherapy regimens for PTB patients including 2HRSZ/2HRZ, 2HRSZ/2HR, 2HRSZ/2HZ, 2HRSZ/2H, 2HRZ/2H. However, all the shortened regimens failed to present expected primary outcome, instead, with 16%, 11%, 32%, 30% and 40% recurrence after 24 months of treatment completion [21, 22]. For years with new drugs progress for TB chemotherapy, especially the favorable pharmacodynamics and bactericidal activity of FQ on MTB, shortening the treatment duration for DS-PTB by using a FQ-based regimen is of great hot topic 3 independent shortening clinical trials have been reported simultaneously with a failure to show noninferiority to the 6-month standard regimen attributed to the higher recurrence rate observed with the 4-month regimens, despite rapid culture conversion during treatment [7–9]. These findings raised questions that the shortening FQ-containing regimens did not work as adequately as the murine model did which may overpredict the sterilizing potency of the regimens.

Since Lfx administered with high dose is of comparable efficacy compared with Mfx and Gfx against MTB, it is possible to introduce Lfx to the regimen for shorter duration of DS-PTB. However, there is also concern that Lfx may fail as first-line anti-TB drugs because of its widely applied for common infections such as urinary and gastrointestinal tracts, wounds, and other lung infections. In high-TB-burden countries, a great number of cases with undiagnosed TB are likely to take an FQ, which could be selected for resistance in at least a fraction of MTB they harbor [23]. Several studies focus on FQ resistance and its association with previous FQ exposure indicated a low prevalence. Researchers from Korea found 2.6% FQ resistance in patients exposed to FQs while 3.4% resistance in patients without FQ exposure [24]. A study from Taiwan found no correlation of FQ resistance with either FQ exposure or duration of FQ exposure, but saw a positive correlation with previous anti-TB treatment and resistance to any other drugs [25]. Previous study from the same research team comparing sputum taken both before and after a course of FQs treatment showed that patients who received an FQ before standard anti-TB treatment had a poor prognosis, most likely as a result of the emergence of drug resistant. 11.1% of the MTB obtained FQ resistance after taking an FQ for 1–3 weeks [26]. The fifth national TB epidemiology survey in China of 2010 reported that Lfx resistant TB accounted for 9.1% among new TB patients [27]. A high prevalence of FQ-resistant TB may void the possibility of Lfx as first line drug for shortening DS-PTB treatment duration. Appropriate bacteriological and histopathological tests for TB should be performed as early as possible before Lfx-containing regimen is recommended. If the study regimen is successful, it is expected to provide a new standard of care for DS-PTB which would cut down the number of required clinic visits and the burden on the health care system and could also decrease the percentage of patients who fail to complete the full course of current longer therapy. If the study regimens are shown to be noninferior or superior to the control regimen, that would represent an even greater advance for patients with DS-PTB and TB control programmes globally. However, there are a few negative aspects that need to be considered before an FQ-containing first-line regimen could be broadly recommended. The FQs are fairly effective drugs for common nonspecific respiratory syndromes and community-acquired pneumonia, and curtailing this usage to ensure they remain effective as first-line TB drugs may not prove beneficial to all-cause morbidity and mortality at the community level. Also, using FQs as standard first-line therapy would reduce their effectiveness against MDR-TB, and could perhaps result in the emergence of more XDR-TB. Its implementation might be suggested only where the prevalence of Lfx-resistant TB is low and FQs are not routinely used for nonspecific respiratory symptoms when TB cannot be effectively excluded would reduce concerns above.