Background 

With 10 million people affected and 1.5 million dying, tuberculosis (TB) is, by far, the leading cause of death from a single infectious agent. Over the last three decades, multidrug-resistant (MDR) TB has been the largest concern in antimicrobial resistance challenge globally. TB treatment requires a combination regimen of 4 to 7 drugs, takes at least 4 months for drug-susceptible and up to 18 months for drug-resistant forms. 

Recent clinical trial designs generally focused on developing single drugs rather than drug combinations. It is estimated to take 15-20 years to develop a new 3-4 drug combination regimen to treat all forms of TB, including MDR-TB. 

To advance anti-tuberculosis (TB) science and enable the progression of new, safe, and affordable treatment solutions for TB patients worldwide, a new consortium of 30 partners from 13 countries has officially launched. UNITE4TB is a public-private partnership with representation from academic institutions, small- and medium-sized enterprises (SMEs), public organisations, and pharmaceutical companies. Over the next 7 years, the consortium will be active in multiple trial sites on four continents (Europe, Asia, Africa and South America), with the goal of delivering novel phase 2 clinical trials that will accelerate the development of new TB drugs and regimens. Furthermore, UNITE4TB will upgrade current clinical trial methodology and enhance the efficiency with which new regimens are delivered. 

Objective 

The overall objective of this project is to identify novel 4-drug regimen(s) with non-inferior efficacy, shortened treatment duration and acceptable safety profile compared to the standard-of-care HRZE regimen. 

Study design 

PARADIGM4TB (UNITE4TB-01) is an adaptive platform, randomized, open-label, multi-center, seamless phase 2B (regimen selection) and 2C (duration randomization, multi-arm, multi-stage) clinical trial. 

To address the challenge of developing new TB treatment regimens, UNITE4TB follows a concept that is analogous to a car racetrack. 

Through its EFPIA and Associated Partners UNITE4TB ensures access to the majority of the most innovative TB compounds. These compounds, the key car parts, will enter the pitstop when they are phase 2-ready and be incorporated into a new treatment regimen (the race car). 

Potential combination regimens will then be launched onto the racetrack (a clinical trial platform with 40 trial sites on four continents) to participate in the race to select the best car or treatment regimen. 

New car parts (drugs) and cars (regimens) may enter the race when ready, making this a state-of-the-art adaptive trial design with conventional and new biomarkers of treatment success. Advanced pharmacokinetic and pharmacodynamic modelling techniques and artificial intelligence and machine learning techniques will be employed to select, test and deliver novel combination regimens with a high probability of success in subsequent phase 3 clinical trials.