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

<div><p>Background</p><p>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.</p><p>Methods</p><p>Newly 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.</p><p>Results</p><p>Of 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.</p><p>Conclusions</p><p>4-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.</p><p>Trial Registration</p><p>Clinical Trials Registry of India <a href="http://clinicaltrials.gov/ct2/show/CTRI/2012/10/003060" target="_blank">CTRI/2012/10/003060</a></p></div

Flow diagram of patients from screening to analysis.

<p>Flow diagram of patients from screening to analysis.</p

Status at end of treatment in 416 patients according to initial drug susceptibility profile (Intent – to –treat analysis).

*<p>Response could not be assessed in 7 lost patients – Gatifloxacin (4), Moxifloxacin (1), Control (2).</p>∧<p>4 patients –Treatment changed for toxicity (Seizure - 3, Cardiac –1), unfavouable bacteriological response –3.</p><p><a href="mailto:@" target="_blank">@</a> Treatment changed for pneumothorax −1, unfavouable bacteriological response −1.</p><p>$ Treatment changed for hepatotoxicity –1, unfavouable bacteriological response −4.</p

Status at end of treatment in 403 patients according to initial drug susceptibility profile (Per-protocol analysis).

#<p>Treatment changed for toxicity.</p><p><a href="mailto:@" target="_blank">@</a> Treatment changed for pneumothorax -1.</p

TB recurrence during 24 months of post-treatment follow-up in 395 patients according to regimen and initial drug susceptibility profile (Intent-to-treat analysis).

<p>TB recurrence during 24 months of post-treatment follow-up in 395 patients according to regimen and initial drug susceptibility profile (Intent-to-treat analysis).</p

TB recurrence during 24 months of post-treatment follow-up in 389 patients according to regimen and initial drug susceptibility profile (Per-protocol analysis).

<p>TB recurrence during 24 months of post-treatment follow-up in 389 patients according to regimen and initial drug susceptibility profile (Per-protocol analysis).</p

Kaplan – Meier analysis of post-treatment TB recurrence-free survival over 24 months in the study regimens.

<p>Kaplan – Meier analysis of post-treatment TB recurrence-free survival over 24 months in the study regimens.</p

Adverse reactions attributable to anti -TB drugs in 416 patients (Intent- to – treat group).

*<p>Gatifloxacin terminated (Seizure –3, cardiac −1).</p><p><a href="mailto:@" target="_blank">@</a> Treatment changed for heptotoxicity −1.</p

Sputum culture negativity based on three specimens each month, among 416 patients.

<p>Sputum culture negativity based on three specimens each month, among 416 patients.</p

Baseline characteristics of 416 pulmonary TB patients according to regimen.

<p>Baseline characteristics of 416 pulmonary TB patients according to regimen.</p