Tuberculosis (TB) is a leading causes of morbidity and mortality worldwide. Current TB treatments are long, complex and often poorly tolerated; moreover, cases of the rifampicin-resistant (RIF-R) form of TB magnify this global health threat. The EU-funded DRTB-HDT project will determine if two adjunctive host-directed therapies can prevent the poor outcomes of treatment in cases of RIF-R TB. Patients with RIF-R TB and risk factors for poor outcome will participate in a randomised, controlled, three-armed multicentre trial. All patients will receive standard multidrug therapy; the experimental arms will additionally receive either CC-11050 or metformin. These selected drug candidates represent two complementary host-directed therapy strategies: reducing inflammation or inducing host cell anti-microbial activity, respectively. If the trial is a success, DRTB-HDT will improve the capacity to control RIF-R TB, thereby increasing the likelihood of its cure.