Tuberculosis Treatment Trials

Tuberculosis remains a major problem in many countries; in sub-Saharan Africa numbers of cases reported have increased dramatically following the advent of the HIV-AIDS epidemic. Treatment regimens for drug-sensitive tuberculosis which are highly effective under controlled trial conditions have been available for many years but need to be given for at least 6 months. Many patients fail to complete treatment since they feel much better after 2-3 months treatment. Shorter and simpler effective regimens are needed. The CTU recently completed two international multi-centre trials assessing the possibility of treatment shortening and/or simplifying treatment. A trial assessing ultra-short treatment has been funded and is planned to commence in the near future. There is an urgent need to find effective treatments for multi-drug resistant tuberculosis (MDR-TB), current regimens are given for long durations, are toxic, expensive and results are generally poor. A large multi-centre trial is currently in progress which is assessing a promising regimen which has been developed in Bangladesh; the trial includes two regimens containing the first new tuberculosis drug to be licensed for about 50 years. There have been very few trials of tuberculosis treatment in children, one such trial in children with limited disease is expected to start soon and trials in drug-resistant tuberculosis and TB-meningitis are planned.

Outline the overall aim and importance of the research, the specific research objectives, plan and methodology, including experimental design Address any clinical and translational research issues, specific goals/plans for medical/public health exploitation/applications, and refer to any IPR implications (see Guidance Notes).
In 1993 the WHO declared TB a global emergency. Despite this, TB remains a considerable cause of mortality and morbidity, with 8.6 million new TB cases and 1.3 million TB deaths in 2012. TB kills more adults than any other infectious disease with 5000 people dying from the disease every day globally. Effective short course treatment for drug-sensitive TB was developed by the MRC TB & Chest Diseases Unit in the 1970s and 80s. However, many patients fail to complete treatment, drug-resistance is on the increase and there is an urgent need for new drugs. Since the formation of the MRC Clinical Trials Unit in 1998 a programme of trials has been initiated in collaboration with a number of international organisations. Initially the focus has been on shortening and/or simplifying the treatment of drug-sensitive TB, assessing in non-inferiority designs alternatives to the standard 6-month regimen. Most recently two trials assessing the role of fluoroquinolones in treatment shortening have been assessed. Additional questions addressing this question are currently being conducted or planned including a strategy trial of ultra short course chemotherapy and trials in children. The Multi-Arm Multi-Stage (MAMS) trial design was developed in the MRC CTU and allows for early stopping of poorly performing arms in a multi-arm trial. We designed a Phase IIB TB trial with a MAMS design which recently reported results and are planning to implement the design in future trials. The treatment of drug-resistant TB, in particular multi-drug resistant disease, has a very poor evidence base and a large multi-centre phase III trial, the first ever to be conducted, is evaluating regimens which are considerably shorter than the recommended WHO standard of care. Two of these regimens include the newly licensed drug bedaquiline.