Refining MDR-TB treatment regimens for ultra short therapy (TB-TRUST): study protocol for a randomized controlled trial

Abstract

Background: Multidrug-resistant tuberculosis (MDR-TB) are unsatisfied to treat, pressing more effective and innovative treatment regimens. New efficient regimens for MDR-TB have obtained high treatment success rates. However, those regimens without drug susceptibility testing (DST) are also likely to contribute to the emergence of resistance. Precision treatments guided by DST might optimize the patients' treatment outcome individually and minimize resistance amplification.

Methods: TB-TRUST is a phase III, multicenter, open-label, randomized controlled clinical trial of non-inferiority comparing the treatment success rate between the World Health Organization (WHO) shorter regimen and the refined ultra-short regimen for fluoroquinolones and second-line injectable drugs susceptible rifampicin-resistant TB. The control arm uses the WHO injectable-containing shorter regimen for 36-44 weeks depending on time of sputum smear conversion. The investigational arm uses a refined ultra-short regimen guided by molecular DST to pyrazinamide via whole-genome sequencing (WGS) to optimize the treatment of pyrazinamide-susceptible patients with levofloxacin, linezolid, cycloserine and pyrazinamide for 24-32 weeks and pyrazinamide-resistant with levofloxacin, linezolid, cycloserine and clofazimine for 36-44 weeks. The primary outcome is the treatment success rate without relapse at 84 weeks after treatment initiation. Secondary outcomes include the time of sputum culture conversion and occurrence of adverse events. Assuming α = 0.025 level of significance (one-sided test), a power of 80%, a < 10% difference in treatment success rate between control arm and investigational (80% vs. 82%), and a 5% lost follow-up rate, the number of participants per arm to show non-inferiority was calculated as 177(354 in total).

Discussion: Rapid molecular testing distinguishes patients who are eligible for shorter regimen with fluoroquinolone and the WGS-guided results shorten the treatment to 6 months for pyrazinamide susceptible patients. It's foreseeable that not only novel developed medicines, but also traditional powerful medicines with the susceptibility confirmed by DST are the key factors to ensure the effect of anti-MDR-TB drugs. As a DST-guided precision treatment, TB-TRUST are expected to optimize therapy outcome in more patients who cannot afford the expensive new medicines and minimize and even avoid resistance amplification with the rational use of anti-TB drugs.

Trail registration: ClinicalTrial.gov, NCT03867136 . Registered on March 7, 2019.

Keywords: Multicenter; Multidrug-resistant tuberculosis; Non-inferiority; Precision treatments; Randomized trial; Tuberculosis; Ultra-short regimen.

Conflict of interest statement

The authors declare that they have no conflict of interests.

Figures

Fig. 1

TB-TRUST study schematic. The study plan to recruit RR/MDR-TB patients who are susceptible to fluoroquinolones and second-line injectable agents. Recruited patients will be randomly divided into the ultra-short regimen group and the WHO shorter treatment with a ratio of 1:1. For patients in the ultra-short regimen, DST of WGS to pyrazinamide will be performed via using the culture isolates. During the first 4–8 weeks, patients are waiting for the result of pyrazinamide DST and receive five agents including levofloxacin, linezolid, cycloserine, pyrazinamide and clofazimine. After molecular pyrazinamide DST results are obtained, pyrazinamide-susceptible patients for 24–32 weeks depending on time to sputum smear conversion receiving agents including levofloxacin, linezolid, cycloserine, pyrazinamide, while pyrazinamide-resistant for 36–44 weeks receiving agents including levofloxacin, linezolid, cycloserine, clofazimine. The control arm uses the WHO injectable-containing shorter regimen for 36–44 weeks depending on time to sputum smear conversion. Follow-up visits were conducted every 2 weeks in the first 8 weeks after treatment initiation, and then followed every 4 weeks until the end of treatment, and every 12 weeks after discontinuation until 84 weeks.(Abbreviations in this figure: RR/MDR-TB: rifampicin-resistant/multidrug-resistant tuberculosis. SLID: second-line injectable drugs. NGS: next generation sequencing. PZA: pyrazinamide)