OR01
Looking for early treatment response biomarkers in TB platform trials: the EU-PEARL experience
J Espinosa Pereiro(4) T Mielke(1) M Posch(5) F Saluzzo(2,6) A Spitaleri(2,6) A Ghodousi(2) J Gonzalez Moreno(1) A Sanchez Montalva(4) N Heinrich(3) D M Cirillo(2,6)
1:Janssen, Pharmaceutical Companies of Johnson and Johnson; 2:Vita-Salute San Raffaele University; 3:Ludwig-Maximilians-Universitat München; 4:Vall d'Hebron Research Institute (VHIR); 5:Medical University Wien; 6:San Raffael Scientific Institute
The EU-PEARL IMI2 project aims to create an adaptive design for tuberculosis (TB) phase 2b/c platform trials to accelerate the development of TB treatment regimens. As a long follow-up is needed to monitor non-favourable events in TB, interim decision-making enhances trials efficiency in identifying the most promising regimens.
A systematic review performed by EU-PEARL, analysing more than 1300 biomarker entries, showed that early microbiological endpoints can be used as surrogates for efficacy. In subsequent design discussions and simulations, three ready-to-implement endpoints have been evaluated.
Proportion of participants with a negative sputum culture at 8 weeks after randomisation has been widely used. However, it does not allow real-time evaluation of the intervention performance, delaying the identification of promising/futile regimens.
Time-to-culture conversion allows for continuous data accrual. Nonetheless, in the performed simulations, interim analyses occurred relatively late. Therefore, the efficiencies targeted with adaptive designs were not reached.
Median decline in bacterial load, estimated by time-to-positivity, can be used to predict culture conversion, evaluating earlier the microbiological response. However, modelling this outcome for interim decision-making may hinder the reliability of the marker.
The proportion of participants with serious adverse events has been included as part of a composite decision rule when previous safety data are scarce. Further simulations are ongoing.
Early pathogen biomarkers combined with safety outcomes are a starting point, but the thorough validation of new surrogate endpoints to early predict treatment response is deeply needed. Integrated Research Platforms represent a unique milieu for this purpose, offering a number of comparable studies that may accelerate the validation process.