Randomized Clinical Trial of Thrice-Weekly 4-Month Moxifloxacin or Gatifloxacin Containing Regimens in the Treatment of New Sputum Positive Pulmonary Tuberculosis Patients

M S Jawahar ,Fathima Rahman,Geetha Shanmugam,Allaudeen S Iliayas,Sudha Ganapathy,Dhanaraj Baskaran,Balambal Raman,Victor Mohan,Vaithilingam V Banurekha,Rajeswari Ramachandran,Vanaja Kumar,C N Paramasivan ,K Jagannath ,R Parthasarathy ,N Selvakumar ,Ravikumar Balasubramanian ,C Chandrasekar ,Marimuthu Makesh Kumar ,P Venkatesan ,George Priya Doss C ,S Ramesh Kumar ,N Charles ,Murugesan Raja Sakthivel ,N Poorana Gangadevi ,P R Narayanan

doi:10.1371/journal.pone.0067030

Abstract

BackgroundShortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India.MethodsNewly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens.ResultsOf 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification.Conclusions4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB.Trial RegistrationClinical Trials Registry of India CTRI/2012/10/003060

Highlights

Tuberculosis (TB) continues to be a major public health problem in much of the developing world
A randomized clinical trial by the National Institute for Research in TB (NIRT) formerly the Tuberculosis Research Centre (TRC) showed that 4- or 5-month regimens containing ofloxacin (O), isoniazid (H), rifampicin (R) and pyrazinamide (Z) daily for 3 months followed by H and R twice weekly for one or two months were very effective, with 99% of patients becoming sputum culture negative at the end of treatment, and only 4% and 2% respectively suffering recurrence of TB over 24 months of follow-up [2]
On review of interim data, the Data and Safety Monitoring Board (DSMB) recommended termination of the G arm initially (February 2006), and later the M arm (October 2006) due to high TB recurrence rates in these two arms compared to the control regimen arm

Summary

Introduction

Tuberculosis (TB) continues to be a major public health problem in much of the developing world. Shortening the duration of treatment for TB is a global research priority. Clinical trials that studied the efficacy of 3–4 month regimens in the 1970s and 1980s had high relapse rates [1]. A randomized clinical trial by the National Institute for Research in TB (NIRT) formerly the Tuberculosis Research Centre (TRC) showed that 4- or 5-month regimens containing ofloxacin (O), isoniazid (H), rifampicin (R) and pyrazinamide (Z) daily for 3 months followed by H and R twice weekly for one or two months were very effective, with 99% of patients becoming sputum culture negative at the end of treatment, and only 4% and 2% respectively suffering recurrence of TB over 24 months of follow-up [2]. Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India

Methods

Results

Conclusion