DRTB-HDT: a randomized controlled trial of two adjunctive host-directed therapies in rifampin-resistant tuberculosis

Abstract

Background: Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Current TB treatments are inadequate, requiring participants closely adhere to multi-drug regimens that are long, complex, and often poorly tolerated. In addition to these well-recognized shortcomings, current TB treatments, particularly those for rifampicin-resistant tuberculosis, leave a majority of cured participants with permanent, clinically significant lung impairment and radiographic evidence of bronchiectasis and fibrosis. This project will determine if two adjunctive host-directed therapies (HDTs) can prevent these poor outcomes.

Methods: Three hundred thirty participants with RIF-R TB and baseline risk factors for poor outcome will be enrolled in a randomized, controlled, 3-armed multi-centre trial, with clinical sites in Romania, Moldova, Georgia, Mozambique, and South Africa. All participants will receive standard multidrug therapy according to national guidelines. Those participants randomized to the experimental arms will in addition receive either CC-11050 (dovramilast) or metformin. Co-primary efficacy endpoints will examine effects on lung function (measured by spirometry) and infection (measured as time to stable sputum culture conversion). A sub-study will examine quantitative change in lung radiodensity by CT scan.

Discussion: These selected host-directed therapies candidates represent two complementary strategies: reducing inflammation vs inducing host cell anti-microbial activity, respectively. Both candidates are supported by data from preclinical and clinical studies. If successful, this ground-breaking project will increase Europe's capacity to control drug resistant tuberculosis by developing new treatments that increase the likelihood of cure and reduce the risk of life-long disability.

Trial registration: EudraCT Number: 2020-004295-18. South African National Clinical Trial Registration (SANCTR) Number: DOH-27-042021-8345.

Keywords: Clinical trial; Dovramilast (CC-11050); Drug Resistant Tuberculosis (DR-TB); Host-directed therapies; Metformin; Rifampicin-resistant tuberculosis (RR-TB); Tuberculosis.

Fig. 1

Study Schematic. RR-TB treatment may continue past week 72 if indicated by national policies. HIV + patients already on ART at the time of randomization will continue on ART. Participants enrolled during the final 18 months of the project funding period will have their final study visit (nominal month 18) during the final 1–2 months of funding

Fig. 2

Power calculations for FEV1

Fig. 3

Power calculations for HR-SCC. Values for N include 10% not evaluable