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.

Insignificant difference in culture conversion between bedaquiline-containing and bedaquiline-free all-oral short regimens for multidrug-resistant tuberculosis

“…It was effective to introduce 9-month Lzd-Mfx-Cfz-Cs-Pza, which is much cheaper than the bedaquiline-containing regimen (roughly 26 vs. 63 US dollars a day in the 9-month regimen). Actually, we have been conducting another randomized controlled study, named TB-TRUST (NCT03867136), to assess the efficacy and feasibility of this bedaquiline-free regimen (Weng T et al, 2021).…”

Adverse effects induced by second-line antituberculosis drugs: an update based on last WHO treatment recommendations for drug-resistant tuberculosis

“…Exploration of initiatives for MDR-TB treatment started decades ago but increased in size and scope only in the past few years (47). The WHO 2018 guidelines for DR-TB (10) proposed a three-drug combination treatment plan comprising Mfx, Lzd and Bdq, which represented the arrival of the era of totally oral treatment (47).…”

“…Exploration of initiatives for MDR-TB treatment started decades ago but increased in size and scope only in the past few years (47). The WHO 2018 guidelines for DR-TB (10) proposed a three-drug combination treatment plan comprising Mfx, Lzd and Bdq, which represented the arrival of the era of totally oral treatment (47). In 2020, the WHO consolidated guidelines on TB (Module 4) revised current policy recommendations on the treatment strategy for DR-symptoms (nausea, vomiting and dizziness) (13,31) are the most common ADE.…”

“…TB (11). The 2020 recommendations have witnessed two important trends in the MDR-TB treatment: to shorten the duration of MDR-TB treatment and to research the strengths of effective novel and repurposed oral agents (15,47).…”

Pyrazinamide Resistance and pncA Mutation Profiles in Multidrug Resistant Mycobacterium Tuberculosis

“…All these regimens include PZA. [10][11][12][13][14][15][16] The potential synergistic activities between PZA and important second-line as well as novel drugs (such as bedaquiline, delamanid, and pretomanid) highlight its importance in both current and future MDR-TB treatment strategies.…”