Efficacy and safety of an innovative short-course regimen containing clofazimine for treatment of drug-susceptible tuberculosis: a clinical trial

ABSTRACT

In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

KEYWORDS:

• Short-course treatment
• clofazimine
• parabolic response surface
• pulmonary tuberculosis
• randomized clinical trial

Disclosure statement

Multi-Drug Therapies for Tuberculosis Treatment (US Patent: 10,080,749 B2). Multi-Drug Therapies for Tuberculosis Treatment (US Patent: 10,576,079 B2).

Additional information

Funding

This work was supported by grants of the Clinical Research Plan of SHDC [grant numbers 16CR1028B and SHDC2020CR6024], Bill and Melinda Gates Foundation [Global Health grant number OPP1070754], Shanghai Clinical Research Center for Infectious Disease (Tuberculosis) [grant number 19MC1910800], and Shanghai Medical Leading Talents Training Program [grant number 2019LJ13].