A randomized trial to evaluate the toxicity and efficacy of 1200mg and 1800mg rifampicin daily for 4 months in the treatment of pulmonary tuberculosis (360G-Wellcome-109349_Z_15_Z)

Tuberculosis (TB) is one of the major causes of death in the world, responsible for 1.5 million deaths annually. Currently, the most effective form of control of tuberculosis is treatment of clinical disease. The current WHO recommended 6 month regimen for the treatment of TB is too long. An estimated 15% of patients worldwide do not successfully complete treatment. If treatment duration could be reduced, adherence and cure rates would improve, and treatment costs would decrease. Of the four drugs in standard tuberculosis treatment, rifampicin and pyrazinamide are responsible for most of the sterilising activity. Increasing the dose of rifampicin both results in significantly greater M. tuberculosis killing in pre clinical studies, and also in greater early bactericidal activity in the sputum of patients with pulmonary tuberculosis. Preliminary results suggest that, unlike pyrazinamide, higher doses of rifampicin are safe. The principal objectives of the trial are: 1)To determine whether an increase in the daily dose of rifampicin from 600 mg to 1200 or 1800mg results in more rapid sterilisation of the lungs, allowing a reduction of treatment duration to 4 months. 2) To assess whether the increased dose results in an increase in serious (grade 3 or 4) adverse events. In this multicentre randomised, controlled clinical trial, 654 smear positive patients with pulmonary tuberculosis will be randomly allocated to either the standard 6 month regimen, or a 4 month regimen with rifampicin at 1200 or 1800mg daily and other drugs at standard dose. They will be followed up for 12 months after stopping treatment, with monthly clinical, sputum and laboratory examinations. If the new regimen is shown to be effective and safe, results will be presented to the WHO and to National Tuberculosis Control Programmes and to the wider academic community, to inform treatment guidelines and routine practice. If positive,the results of this trial will have major public health benefit.