Doxycycline as host-directed therapy in pulmonary tuberculosis: a Phase 2 randomized double-blind, placebo-controlled trial

Matrix metalloproteinases (MMPs) have previously been implicated as key players of tissue destruction in tuberculosis (TB) and is a target for host-directed therapy in TB. Here, we conducted a Phase 2 randomized, double-blind, placebo-controlled trial investigating doxycycline, a licensed broad spectrum MMP inhibitor in TB patients. 30 pulmonary TB patients who just started TB treatment (= 7 days) were enrolled and randomly assigned to receive either doxycycline 100 mg or placebo twice a day for 14 days, in addition to standard care. Changes in host transcriptome and biological markers of tissue destruction were assessed at 14- and 56-days. Whole blood RNA sequencing suggests doxycycline aided in the restoration of normal gene expression, as demonstrated by the greater down-regulation of TB-dominant interferon response and innate immune response genes, and the up-regulation of B-cell markers that were depleted in active TB. The down-regulation of immune response genes persisted for 6 weeks after the final dose, and was similarly observed in the suppression of MMP-1 in plasma samples. In respiratory samples, doxycycline suppressed MMP-1, -8, -9, -12 and -13, as well as Type I collagen and elastin destruction. 2 weeks of adjunctive doxycycline with standard anti-tubercular treatment was also well-tolerated with no serious adverse events related to the study drug. These findings serve as the basis for large scale studies on adjunctive doxycycline in TB. Total RNA extraction, quality check, sequencing library preparation and RNA-sequencing of the whole blood clinical trial samples were performed at Singapore Immunology Network (SIgN), A*STAR, Singapore as part of a project agreement and paid for by National University Health System (grant no.: NUHSRO/2014/039/BSL3-SeedFunding/Jul/01). Full bioinformatics analysis of the RNA-sequencing data was performed at University of Southampton, United Kingdom.