A new phase 2 clinical trial is investigating whether host-directed therapies can improve outcomes for patients with rifampicin-resistant tuberculosis (RR-TB), addressing both the challenge of bacterial eradication and the permanent lung damage that affects most tuberculosis survivors.
The DRTB-HDT trial will evaluate two adjunctive treatments—metformin and dovramilast (CC-11050)—alongside standard RR-TB therapy in 330 participants across eight international sites. The study represents a significant shift toward targeting host immune responses rather than focusing solely on antimicrobial activity.
Addressing Critical Treatment Gaps
Rifampicin-resistant tuberculosis affected 400,000 people worldwide in 2023, directly causing 150,000 deaths. Despite recent improvements in treatment regimens, only 63% of patients who began RR-TB treatment in 2020 achieved cure. Even among those cured, the majority experience permanent lung impairment and radiographic evidence of bronchiectasis and fibrosis.
"RR-TB participants are at greatest risk of these residual defects," the researchers noted, attributing this to delayed eradication of infection and prolonged pulmonary inflammation. The resulting disability reinforces poverty, shortens longevity, and increases mortality from pneumonia and other non-tuberculosis infections.
Dual-Mechanism Approach
The trial tests two distinct host-directed therapy approaches identified in a 2014 workshop jointly sponsored by the US NIH and Bill and Melinda Gates Foundation. The interventions fall into complementary categories: enhancing antimicrobial activity in host phagocytic cells and reducing inflammation or targeting tissue destruction mechanisms.
Metformin, a widely prescribed diabetes medication and AMPK activator, has demonstrated multiple relevant effects in preclinical studies. Research showed metformin reduced Mycobacterium tuberculosis growth in macrophages and enhanced conventional antimicrobial efficacy in infected mice. Additional studies found metformin accelerates resolution of established lung fibrosis by promoting myofibroblast deactivation and apoptosis.
Three retrospective studies involving nearly 10,000 diabetic participants found metformin reduced tuberculosis risk compared to other diabetes treatments. Additional retrospective analyses showed clinical benefits in tuberculosis patients with diabetes, including reduced risk of cavitary disease and improved treatment outcomes.
Dovramilast (CC-11050) targets inflammatory pathways, down-regulating genes in multiple networks including those associated with IL-17, IL-23, and NFkB in tuberculosis-infected mice. The compound accelerated bacterial clearance from lungs when combined with isoniazid therapy in chronic infection models. In a phase 2 study of 40 HIV-negative participants with moderate or advanced rifampicin-susceptible tuberculosis, 200 mg CC-11050 administered during the first four months of treatment improved FEV1 recovery at month 6 compared to controls.
Trial Design and Endpoints
The randomized, open-label, three-arm trial will assign participants at a 1:1:1 ratio to receive either metformin, dovramilast, or standard care alone. All participants will receive recommended RR-TB treatment according to WHO guidelines, with those in experimental arms receiving additional host-directed therapy for the first six months.
The study employs two co-primary endpoints that must both be met for treatment success. The first assesses lung function using forced expiratory volume in one second (FEV1) at month 6, expressed as a percentage of predicted value based on age, sex, height, and race. The second measures time to stable culture conversion, defined as the time to the first of two sequential cultures obtained at least two weeks apart showing no Mycobacterium tuberculosis growth.
"FEV1 is an independent predictor of all-cause mortality in the general population," the researchers explained. "It is the most widely used single measurement to assess disease progression or response to treatment in persons with chronic obstructive pulmonary disease, with a change of 100 ml described as the minimal clinically important effect."
Statistical Power and Safety Monitoring
Power calculations indicate the study will have at least 80% power to detect treatment effects similar to those observed in previous host-directed therapy studies for both co-primary endpoints. With 100 evaluable participants per arm, the trial can detect a 6% difference in FEV1% and demonstrate non-inferiority for culture conversion at a hazard ratio of 1.36.
Safety monitoring will focus on treatment-emergent serious adverse events, clinical and laboratory measurements, and disease exacerbation including paradoxical reactions. A Data Monitoring Committee composed of external tuberculosis clinical trial experts will review study data regularly and can recommend discontinuation if safety or efficacy appears worse than control.
Regulatory and Monitoring Framework
The trial operates under comprehensive monitoring by two independent organizations following ICH-GCP E6 (R2) guidelines. All informed consents will undergo 100% source data verification, with half of participants receiving verification of key data including inclusion criteria, adverse events, and primary endpoints.
The study addresses potential drug interactions carefully, particularly for metformin, which will be temporarily suspended for surgical procedures and radiological studies involving iodinated contrast. Gatifloxacin is prohibited in metformin recipients due to hypoglycemia risk, while strong CYP3A4 inhibitors are prohibited for participants receiving dovramilast or bedaquiline.
Results from this trial could inform future phase 3 studies and potentially transform treatment approaches for rifampicin-resistant tuberculosis by addressing both infection eradication and preservation of lung function. The study protocol and anonymized participant data will be made available to qualified investigators through the NIH TB Portals system following completion and publication of primary results.
