Tuberculosis (TB) today rivals HIV/AIDS as the leading cause of death from infectious diseases. The number of TB patients has never been higher and the growing proportion of drug-resistant TB is threatening control strategies both in the developing and developed world, Eastern Europe being a particularly worrying point in case. The anTBiotic consortium aims to fuel the long-term TB clinical pipeline while immediately offering new options to clinicians when confronted with multidrug-resistant (MDR)-TB. More specifically, the proposed studies aim to: a) Establish the proof of concept of anti-TB efficacy in humans of a pioneering, first-in-class, low-dose GSK oxaborole clinical drug candidate; b) Identify a combination of β-lactam antibiotics suitable for the treatment of MDR TB orally or as a once daily intravenous or intramuscular application and c) Incorporate the best β-lactam combination into an explorative salvage regimen for untreatable patients with extensively drug-resistant TB The anti-TB activity in humans will be established in a two-week EBA clinical studies that combine established (CFU, TTP) and new clinical markers (biomarkers, PET/CT). These datasets will help ascertain anti-TB efficacy in humans and generate confidence on their validity in longer-term drug combination trials. A variety of modelling approaches to predict optimal dosing will be used. Finally, we intend to use at least one of these novel anti-TB entities as part of a pioneering, non-controlled clinical trial in highly drug resistant subjects in Europe and South Africa. This final clinical intervention will hopefully be of immediate benefit to drug-resistant patients in the EU and elsewhere in addition to generating a strong precedent for further adoption worldwide.

Current anti-tuberculosis (TB) drug regimens face serious limitations at times of increasing antimicrobial drug resistance. Fortunately, for the first time for centuries, several novel anti-TB compounds are available for clinical evaluation. As the traditional approach to testing these in multiple combination regimens is too slow and inefficient new approaches of clinical phase 2 study designs are required if we are to meet the targets of the WHO EndTB strategy to save the lives of millions into the near future. Our consortium brings together a unique group of European and international leaders in TB research and leading industry partners. Together we will provide the necessary comprehensive range of expertise to meet the demands of the UNITE4TB scientific research agenda. Specifically, we will develop a new global standard for phase 2 TB clinical trial designs, utilising simulation tools to identify optimal doses in phase 2A trials and apply a multi-arm multi-stage adaptive randomised controlled 2B/C trial design capable of rapid and simultaneous evaluation of the best candidate regimens. Our innovative phase 2 trials will be performed to the highest regulatory standards, incorporating state-of-the-art microbiology, biomarker investigation and clinical pharmacology. We will take advantage of existing global TB clinical trial networks with the capacity to enrol patients at an unprecedented pace and number across four continents. Artificial intelligence/machine learning technologies will be applied to validate state-of-the art molecular and imaging tools as treatment decision biomarkers with the aim of establishing new, real-time outcome measures. Our consortium will evaluate 3-5 new chemical entities (NCEs) at phase 2A and up to 17 novel combination regimens in phase 2B/C. Our objective is to identify those that have the greatest chance of success in subsequent definitive phase 3 clinical trials and of becoming the global gold-standard TB regimens of the future.