Periodic Reporting for period 3 - DRTB-HDT (STRATIFIED HOST-DIRECTED THERAPY FOR DRUG-RESISTANT TUBERCULOSIS: A RANDOMIZED CONTROLLED MULTI-CENTRE TRIAL)
Periodo di rendicontazione: 2023-01-01 al 2024-06-30
Tuberculosis (TB) has historically been the most common infectious cause of death globally, surpassed only recently (and presumably temporarily) by the ongoing Covid-19 pandemic. TB treatment is lengthy and often unsuccessful. Even if cured, most patients are left with impaired lung function and shortened longevity. Rifampin-resistant tuberculosis (RIF-R-TB) patients do not respond to the standard TB treatment with rifampin and are therefore at increased risk of death, treatment failure, and impaired post-TB lung function. This project investigates two complementary therapies alongside the standard RIF-R-TB treatment in a randomized, controlled phase 2 clinical trial in five countries (Moldova, Romania, Georgia, Mozambique and South Africa). Patients will receive either CC-11050 (a drug that reduces inflammation) or metformin (a drug that changes cellular metabolism) and be compared to patients receiving the standard RIF-R-TB treatment alone. The study will examine patients’ lung function (how much air can be forced out of the lungs in one deep sigh) and sputum culture conversion, meaning whether tuberculosis bacilli are coughed up and can still be detected in sputum after treatment. Thus the main objective of this project is to determine the efficacy, safety and tolerability of two adjunctive host-directed therapies in RIF-R-TB patients and identify baseline risk factors for poor treatment outcome. To achieve the second objective, the trial is accompanied by an analysis of the social and economic impact of treatment on TB patients.
After an initial delay of the project, the study protocol for the multi-center clinical trial has been developed and the enrollment of patients in the five countries has been initiated. Additional mandatory documentation such as a monitoring plan that covers both African and European sites equally as well as various standard operating procedures have been developed. In order to safely and centrally collect all necessary participant data, a database that complies with all general data protection regulation (GDPR) of the European Union has been developed and audited. Patient enrollment at the first site in South Africa has started in early 2023 and mid-recruitment has been reached in May 2024.The laboratories attached to the clinical sites, which will test patient isolates for drug susceptibility have been audited to make sure they are up to safety standards and ready for culture processing. The first patient samples for phenotypic Drug Susceptibility Testing (pDST) and Whole Genome Sequencing (WGS) have been shipped.
The social and economic impact of TB on patients has been modeled in an initial mathematical model which forms the basis for the final model that will be fueled by the collected data from the trial.
The social and economic impact of TB on patients has been modeled in an initial mathematical model which forms the basis for the final model that will be fueled by the collected data from the trial.
A manuscript, “The lifetime burden of disease due to incident tuberculosis: a global re-appraisal including post-TB sequelae”, was accepted at the Lancet Global Health in July 2021. The analysis concludes that “Many individuals who survive tuberculosis disease face ongoing disability and elevated mortality risks. However, these post-TB sequelae are generally omitted from policy analyses and burden of disease estimates. We estimated the global burden of TB, inclusive of post-TB morbidity and mortality.”
Through constructing a hypothetical cohort of individuals developing TB, the team was able to simulate lifetime health outcomes, stratified by country, age, sex, HIV status and treatment status. Globally, they estimated that 47 % of the total burden estimate (expressed in disability-adjusted life-years (DALYs)) can be attributed to post-TB sequelae. The analysis also showed that post-TB sequelae produce nearly half of the total disease burden caused by TB. Estimates of global disease burden are commonly used to calibrate research and development spending. Finding that the true TB burden is almost twice previous estimates will help stimulate additional research as well as political attention and more research effort.
Through constructing a hypothetical cohort of individuals developing TB, the team was able to simulate lifetime health outcomes, stratified by country, age, sex, HIV status and treatment status. Globally, they estimated that 47 % of the total burden estimate (expressed in disability-adjusted life-years (DALYs)) can be attributed to post-TB sequelae. The analysis also showed that post-TB sequelae produce nearly half of the total disease burden caused by TB. Estimates of global disease burden are commonly used to calibrate research and development spending. Finding that the true TB burden is almost twice previous estimates will help stimulate additional research as well as political attention and more research effort.