Antimicrobial resistance (AMR) is of great public health concern, causing numerous losses of lives worldwide and threatening to reverse many of the considerable strides modern medicine has made over the last century. There is a need to stratify antibiotic and alternative treatments in terms of the actual benefit for the patient, improving patient outcome and limit the impact on AMR. High quality, effective and appropriate diagnostic tests to steer appropriate use of antibiotics are available. However, implementation of these tests into daily healthcare practice is hampered due to lack of insight in the medical, technological and health economical value and limited knowledge about psychosocial, ethical, regulatory and organisational barriers to their implementation into clinical practice. VALUE-Dx will define and understand these value indicators and barriers to adoption of diagnostics of Community-Acquired Acute Respiratory Tract Infections (CA-ARTI) in order to develop and improve health economic models to generate insight in the whole value of diagnostics and develop policy and regulatory recommendations. In addition, efficient clinical algorithms and user requirement specifications of tests will be developed fuelling the medical and technological value of CA-ARTI diagnostics. The value of diagnostics will be tested and demonstrated in a unique pan-European clinical and laboratory research infrastructure allowing for innovative adaptive trial designs to evaluate novel CA-ARTI diagnostics. Close and continuous interaction with the VALUE-Dx multi-stakeholder platform provides for optimal alignment of VALUE-Dx activities with stakeholder opinions, expert knowledge and interests. A variety of dissemination and advocacy measures will promote wide-spread adoption of clinical and cost-effective innovative diagnostics to achieve more personalized, evidence-based antibiotic prescription in order to transform clinical practice, improve patient outcomes and combat AMR.

P. vivax is considered the most difficult human malaria to eliminate because of the inability of conventional diagnostics to detect individuals with latent liver forms. These individuals account for 80% of all infections and can readily infect mosquitoes. Currently countries can test knowing this has little impact or and the treat everyone which exposes individuals to drugs with potentially dangerous side effects. Parasite specific antibody responses have been shown to correlate with the likelihood of hypnozoite carriage and can be used to identify individuals who should be treated. Aim is to implement a Cluster-Randomised Trial in Ethiopia and Madagascar to demonstrate the effectiveness of a new anti-malaria intervention based on Plasmodium vivax serological testing and treatment (PvSTATEM) with primaquine to prevent the relapse infections responsible for maintaining P. vivax transmission. Simultaneously, we will assess social and health system acceptability of such an approach as well as refine new mobile technologies which interface with point-of-care diagnostic tests and guide treatment decisions. We aim to reduce malaria burden at both the individual and population level in two countries which experience the highest levels of P.vivax in Africa. We expect to have a significant effect in reducing morbidity and improving health. We will ensure community engagement and assess the adoption of new technologies that align with those existing in the health system. The proposal is built on equal partnership and shared capacity to address a substantial public health burden.

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.