Adjunctive host-directed therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial

Abstract

Background Current tuberculosis treatments leave patients with clinically significant lung injury and increased allcause mortality post-cure. Adjunctive host-directed therapies could protect the lungs, improve long-term survival, and shorten treatment duration; however, few have been tested clinically. Therefore, we aimed to assess the safety and preliminary efficacy of four host-directed therapies for tuberculosis.Methods In this prospective, open-label, phase 2, randomised controlled trial, patients with pulmonary tuberculosis were recruited at three clinical sites in South Africa. Eligible patients were aged 18-65 years, HIV-1-negative, and had rifampicin-susceptible Mycobacterium tuberculosis, a sputum Xpert cycle threshold of less than 20, and moderately advanced or far advanced disease on chest radiography. By use of numbers generated in blocks of ten and stratification by site, eligible patients were randomly assigned (1:1:1:1:1) to receive one of the four oral host-directed treatments plus standard tuberculosis treatment or standard treatment alone (the control group). Host-directed treatments were: CC-11050 (200 mg twice daily, taken with food; day 1-112); everolimus (0•5 mg/day; day 1-112); auranofin (3 mg/day for seven doses, then 6 mg/day; day 1-112); and ergocalciferol (5 mg on day 1, then 2•5 mg on day 28 and day 56). All study participants received oral rifabutin-substituted standard tuberculosis treatment for 180 days. Patients and clinicians were not masked to treatment assignment. Spirometry and sputum culture with solid and liquid media were done at baseline and up to 180 days at specified intervals throughout treatment. The primary endpoint was safety and tolerability up to day 210. Secondary preliminary efficacy endpoints were treatment effects on sputum microbiology (culture status at day 56 and the hazard ratio for stable culture conversion up to day 180) and lung function (FEV 1 and forced vital capacity [FVC]) measured by spirometry at day 56, day 180, and day 540. Safety was analysed in the intention-to-treat population and preliminary efficacy primarily in the per-protocol population. The trial is registered at ClinicalTrials.gov, NCT02968927. Post-treatment follow-up was completed in 2020.

Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis

“…These lesions had minimal lung fibrosis and absence of acid-fast bacilli and necrosis (15). Subsequently, an open-label phase II randomized controlled trial in patients with pulmonary TB, adjunctive CC-11050 treatment was safe and resulted in improved lung function as measured by the increased recovery of forced vital capacity (FEV 1 ) (120). Finally, most of the PDE inhibitors showed efficacy as an adjunctive therapy to standard TB treatment, while many preclinically tested PDE inhibitors in monotherapy did not result in improved disease outcome.…”

Alveolar macrophages: novel therapeutic targets for respiratory diseases

“…Everolimus, another mTOR inhibitor, was recently tested as adjunctive host-directed therapy for TB (Ref. 119). Preliminary evidence suggests that it was well tolerated in patients simultaneously receiving standard-of-care antibiotic treatment and may improve lung function (clinicaltrials.gov: NCT02968927).…”

Autophagy Induction as a Host-Directed Therapeutic Strategy against Mycobacterium tuberculosis Infection

“…Lastly, a clinical trial (NCT02968927) was conducted in South Africato study the efficacy of multiple drugs such as everolimus (an analog of rapamycin), CC-11050, vitamin D3 and auranofin (an organogold compound) as adjunctive host directed TB therapies for TB. The study does confirm that CC11050 and everolimusshows safety and tolerability as well as improved forced expiratory volume (FEV) indicating a potential benefit to current TB treatment [ 153 , 154 ].…”