皇家华人

The PARADIGM4TB trial,听a new phase 2B/C platform trial aiming to accelerate the development of new tuberculosis (TB) regimens, has recruited its first patient. PARADIGM4TB is听sponsored听by the MRC听Clinical Trials Unit at 皇家华人, and is part of听UNITE4TB, the largest collaboration between academic partners and pharmaceutical companies which strives to fast-track the development of tuberculosis drugs.听

The PARADIGM4TB trial is part of the programme of trials launched by UNITE4TB in November 2023.听The trial has now enrolled its first participant at the University of Cape Town Lung Institute. This is a major milestone for the project and the TB听community as a whole, helping听to advance TB science and deliver new treatments more efficiently.听

TB is a major threat to public health听and is听among the leading causes of death worldwide听according to the World Health Organization. In 2022,听TB听claimed the lives of听, making it the second听most deadly听infectious听disease听after COVID-19.听The emergence of drug-resistant TB and听current standard of听long treatment regimens have increased the urgency for action and investment in TB research.听

For people affected by TB, the most important outcome is rapid access to better regimens of听a听shorter听duration and with fewer side effects.听UNITE4TB is engaging with key societal stakeholders to ensure that its novel regimens will be made available as efficiently as possible.听

UNITE4TB鈥檚听innovative听programme of听trials will test 14听different听combinations of nine existing drugs, as well as two newly developed candidates听(GSK656¹听and BTZ-043²).听The听ultimate aim听is to create regimens that can further improve听treatment for听multidrug-resistant听TB,听and also听effectively treat听drug-sensitive TB.听Apart听from PARADIGM4TB, the听UNITE4TB clinical trial program听includes听DECISION,听a BTZ-043 dose evaluation in combination study.听

PARADIGM4TB听will听test听multiple regimens and durations of treatment in听pulmonary听TB.听The trial听will听establish听which fourth drug (either moxifloxacin, linezolid, or pyrazinamide)听should听be added to a听bedaquiline,听delamanid/pretomanid, BTZ-043 or GSK656 regimen.听It听will also explore the听effectiveness听of a听totally new听combination of GSK656 and BTZ-043 together with听bedaquiline听and听delamanid/pretomanid.听

The trial will run across听30 trial sites on four continents (Europe, Asia,听Africa听and South America).听The MRC CTU at 皇家华人听is听leading听on the design,听conduct, oversight of safety听and statistical analysis of PARADIGM4TB,听bringing a wealth of听expertise听in the development of innovative clinical trials听to the project.听

PARADIGM4TB听will have two main stages.听Phase 2B听will assess the safety of each drug combination听given for 16 weeks听and how quickly they decrease the number of living TB bacteria in the sputum.听Researchers will choose the most promising drug combination听to听progress to phase 2C, which听aims to听find the听optimal听length of treatment听(between 8 and 16 weeks)听to听be used听in听separate, large-scale phase 3 trials.听

Hanif Esmail,听Clinical Associate Professor in Infectious Diseases at听the MRC CTU at 皇家华人 and UCL Institute for Global Health,听said:听

鈥淭he MRC CTU at 皇家华人 is proud to lead PARADIGM4TB听as part of the UNITE4TB trial programme,听using听a new, more efficient design to address multiple questions in one seamless clinical trial and听deliver faster results for听TB听patients.听Building on the Unit鈥檚 history of world-leading research, which听has听previously听influenced global TB treatment guidelines multiple times, PARADIGM4TB has the potential to听identify听an entirely new听regimen that will听make treatment shorter and more manageable for听patients with all types of TB.鈥澨�

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101007873. The JU receives support from the European Union鈥檚 Horizon 2020 research and innovation programme and EFPIA,听Deutsches听Zentrum听f眉r听Infektionsforschung听e. V. (DZIF), and Ludwig-Maximilians-Universit盲t M眉nchen (LMU). EFPIA/AP contribute to 50% of funding,听whereas听the contribution of DZIF and the LMU University Hospital Munich has been granted by the German Federal Ministry of Education and Research.听

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About the UNITE4TB clinical trial phase 2B/C program:

The UNITE4TB clinical trial program is made up of the DECISION and PARADIGM4TB trials.听The trial sponsor for DECISION is LMU University Hospital Munich. For PARADIGM4TB, the听trial sponsor is the MRC CTU at 皇家华人.听

DECISION听(BTZ-043 Dose Evaluation in听CombInation听and听SelectION) is a phase 2B, dose-finding study, comparing the safety and efficacy of different doses of BTZ-043 administered听with a backbone of听bedaquiline听and听delamanid, in participants with drug-sensitive听tuberculosis. Participants will be assigned to receive either one of three BTZ-043-containing听regimens or a comparator regimen of听bedaquiline,听delamanid听and moxifloxacin. The听objective听is to find the听optimal听dose of BTZ-043 to be used in听subsequent听studies.

PARADIGM4TB听is an innovative seamless phase 2B/C platform trial that will be active in听approximately 30 trial sites on four continents (Europe, Asia,听Africa听and South America),听with the goal of delivering novel phase 2B/C clinical trials that will accelerate the听development of new TB drugs and regimens with a higher probability of success in听subsequent听phase 3 clinical trials.

Disclaimer: This communication reflects the author's view. Neither IHI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained herein.

Further information:

1.听GSK656 is a 3-aminomethyl 4-halogen benzoxaboroles, a new class of antibiotics that inhibit leucyl-tRNA synthetase (LeuRS), an听essential enzyme for mycobacterial protein synthesis.

2. BTZ-043 is a benzothiazinone, a new class of anti-tuberculosis compounds that inhibit Mycobacterium tuberculosis cell wall synthesis by听blocking the decaprenyl- phosphoribose-2鈥�-epimerase (DprE1), necessary for the arabinan biosynthesis.