Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive Tuberculosis: the "TRUNCATE-TB" trial

TB incidence rates are falling only very slowly in many high burden countries that have healthcare systems for TB that are overstretched and experiencing large funding gaps. Current tools and systems are clearly not able to solve the problem in the near future and alternatives must be explored - as a matter of urgency - that allow healthcare systems to use resources more effectively and economically to treat and cure more patients with drug-sensitive disease. Multi-drug-resistant (MDR)-TB is also an increasing problem, and a further advantage of improving treatment for drug-sensitive TB may be that it reduces the drive towards generating new cases of MDR-TB.

We propose a new strategic approach: instead of the current standard of care of 6 months treatment for drug-sensitive TB, we propose an approach that focuses resources on optimizing individual treatment for just 2 months, then stopping and following patients in order to re-treat the small proportion of those who relapse subsequently (which is expected to be with drug-sensitive organisms). In addition to saving programme resources, stopping after 2 months may reduce the drug pressure for generating MDR-TB as patients not taking medication cannot breed drug resistance. If relapse rates are relatively low, it is possible that such a strategy could be highly cost effective.

With recent advances in TB drug development, it is now likely that we can find one or more 2-month combination regimens with low rate of relapse that can be used in such a strategy. Previous trials show that, even with standard drugs, rates of relapse with shorter course TB treatment are low (usually below 10%). With the new drugs that have new mechanisms of action, it is likely that 2-month treatment combinations can be constructed that will have very low rates of relapse - this has already been shown in a mouse model of TB. The only way to test which of the many promising regimens may achieve good cure rate of TB with just 2 months of treatment is to do human trials in which treatment is stopped at this time point and patients are followed for relapse.

The Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for drug-sensitive TB (TRUNCATE TB) trial is a randomized open label, multi-arm multi-stage, parallel group trial in which we will compare four novel strategies - each using a different initial 2 month treatment combination including one or more novel drugs, and a subsequent 6-month retreatment course with standard drugs for those who relapse - against a 6 month treatment course with standard drugs from the outset.

TRUNCATE TB will recruit 1300 patients with confirmed drug-sensitive pulmonary TB and allocate them at random to receive one of the novel 2 month treatment combinations or 6 months standard-of-care treatment. All patients will be followed for 2 years to detect exacerbation of symptoms and be evaluated for relapse. Information on clinical outcomes, microbiological clearance of TB, adverse events, quality of life and healthcare utilisation and costs will be collected. Treatments will be compared for their overall outcome (what proportion of people still have TB in their sputum at 2 years after study entry). If the strategies are equivalent on this outcome then the various advantages and disadvantages of the strategies can be compared including safety, patient acceptability and quality of life, resource use and costs, and drug resistance. We will also look for markers of response that could permit refinements of the strategy (e.g. by identifing groups of patients, if any, in whom 2 months' treatment can be reliably predicted to be inadequate). The trial will be conducted at approximately 12 large TB treatment centres within an Asian TB trials network.

This trial addresses a question of high relevance to real-world TB programme settings. It has the potential to transform the way TB programmes operate and to have a major impact on global health.

TRUNCATE-TB is a randomized, open-label, parallel group, non-inferiority trial testing a new strategic approach to the treatment of drug-sensitive pulmonary TB. Patients will be randomized to receive 6 months' initial standard-of-care treatment, or to one of several strategy arms comprising 2 months' treatment with a novel combination followed by 6 months' re-treatment with the standard-of-care combination for those who relapse.

A multi-arm multi-stage (MAMS) design will be used that allows multiple regimens to be tested against a single control group and which allows for treatment arms to be dropped or added during the trial. This represents an efficient and cost-effective approach to evaluating several candidate regimens that may provide high rates of sterilization after 2 months' treatment. The trial will have a pilot phase in which 300 patients will be enrolled to gather detailed initial safety data, as well as test feasibility of recruitment and follow-up and allow an initial intermediate assessment for efficacy and possible arm drop. The definitive phase of the trial will complete the recruitment of a total of 1300 patients.

Eligible patients must have a pulmonary TB confirmed by molecular test, without rifampicin resistance. HIV infected participants will be eligible (recruited only in the definitive phase), but must have a CD4 above 200 cells/mm3 and be off anti-retroviral therapy at study entry. Patients will be followed for 96 weeks (prolonged if late-re-treatment). The primary endpoint is TB sputum culture status at 96 weeks after randomization. Secondary endpoints include drug resistance, treatment failure or relapse, programme resource use and cost and the safety of the treatment regimens.

The trial will be conducted at approximately 12 sites in Asia, forming a sustainable Asian TB clinical trials network that will make a significant future contribution to the urgent need for increased TB clinical trials capacity.

Patients with TB will benefit from this research if it leads to a new standard-of-care TB treatment regimen of 2 months' duration rather than the current 6 months' duration. This would dramatically reduce the burden on TB patients, potentially reduce the duration of side effects and treatment-related costs and improve quality of life. In addition to efficacy, each of these will be outputs from the trial.

Doctors and healthcare practitioners treating TB will benefit from this research as it will provide valuable new clinical information on treatment regimens for drug-sensitive TB that incorporate novel drugs, and it will potentially lead to a new substantially shorter combination regimens and reduce workload for practitioners. The research will also yield clinical information on clinical factors (alone or combined with novel biomarkers) which may predict those who are likely to benefit from shorter TB treatment regimens or who may need longer treatment. This clinical information may be of value in settings where TB treatment can be individualised. Shorter treatment is likely to improve adherence and therefore reduce the risk of acquired resistance, reducing the exposure of healthcare practitioners to drug-resistant TB.

TB Programme directors and staff and global policy-makers (e.g. WHO, The Union) will benefit from this research because it will provide novel data on outcomes of TB treatment that will be directly relevant to public health policy discussions since this is a trial evaluating a programme strategy and not just regimen efficacy and may transform the way that TB is managed within global and national programmes

For national and international funding organisations involved in supporting TB programmes, this research will provide important information that may enable them to deploy resources more cost-effectively. The advent of a new strategy may also help to catalyse fund raising to support a fresh initiative to reduce the global burden of TB.

Communities where TB is prevalent will benefit from this research because it may lead to improved treatments for TB that better control the epidemic, thereby decreasing the risk of new TB infection. The reduced risk of acquired resistance will reduce the number of resistant TB cases in the community.

The pharmaceutical industry may benefit from this research because it will provide additional information about novel TB drugs used in different combinations (post-licensing data) as well as develop a novel trial methodology that may be of use in clinical drug development. The research may also provide a platform to validate new biomarkers for predicting TB treatment outcome. The trial network that is established will provide pharma with a platform that they could subsequently use for future TB trials.

Academics across a range of fields including microbiology, drug development, infectious diseases, clinical trials, statistics and methodology, health services research will benefit from the research: increased understanding of the mechanism of TB sterilisation; identification of biomarkers for clinical outcomes, drug discovery and development; approaches to the investigation of combination therapies for infectious diseases; statistical and methodological approaches to clinical trials

Researchers in low and middle income countries where this work will be conducted will benefit from the experience of conducting a state-of-the-art investigator-initiated TB clinical trial through on-trial training, following protocols and also through playing an active role in discussions around the design and implementation of the trial. The trial aims to strengthen trials infrastructure and training and form a cohesive TB clinical trials network that will contribute to enhancing desperately-needed TB clinical trials capacity as well capacity for trials in other infections.