Host-directed adjunctive therapies everolimus and CC-11050 are safe and reasonably well-tolerated in adults with pulmonary tuberculosis infection, according to results of a study published in the journal Lancet Respiratory Medicine. In addition, the 2 therapies may also improve lung function recovery.
A team of investigators conducted a prospective, open-label, phase 2, randomized controlled trial (ClinicalTrials.gov Identifier: NCT02968927) to determine the safety and preliminary efficacy of 4 host-directed therapies for pulmonary tuberculosis in adults aged 18 to 65 years.
At 3 clinical sites in South Africa, 200 patients (median age, 35 years; 88% men) with rifampicin-susceptible Mycobacterium tuberculosis infection were randomly assigned to one of the 4 oral host-directed treatments groups with standard tuberculosis treatment or standard treatment only (control). Patients in the host-directed treatment groups were treated with either CC-11050 (200 mg twice daily; days 1-112), everolimus (0.5 mg/d; days 1-112), auranofin (3 mg/d for 7 doses, then 6 mg/d; days 1-112), or ergocalciferol (5 mg on day 1 then 2.5 mg on days 28 and 56).
The primary endpoint was safety and tolerability of the 4 treatments up to 210 days. Secondary preliminary efficacy endpoints were the treatment effects on sputum microbiology and lung function measured by spirometry on days 56, 180, and 540.
Patients who were eligible for participation were HIV-1-negative, had an Xpert MTB/RIF sputum testing cycle threshold less than 20, and had moderately advanced or far advanced pulmonary tuberculosis confirmed upon chest radiography. Patients with a history of tuberculosis were excluded from the study.
Of the remaining 199 participants, cavitary disease was present in 167 patients (84%), and far advanced disease was present in 83 patients (42%). There were 11 treatment-emergent serious adverse events, 3 of which were considered to possibly be linked to host-directed therapy.
A patient treated with auranofin experienced life-threatening thrombocytopenia 53 days after study entry, which was resolved without consequence after discontinuing auranofin treatment. Another patient in the auranofin group died following intra-abdominal sepsis. No patients treated with CC-11050 or everolimus experienced serious adverse events related to treatment.
Compared with patients in the control group, patients who were treated with CC-11050 and everolimus had increased lung function recovery at day 180 (P =.048 and P =.044, respectively). Lung function recovery was not observed with auranofin or ergocalciferol therapies. None of the 4 treatments affected forced vital capacity during 180 days of follow-up or when measuring sputum culture status.
“The findings of this trial are best considered in the context of its experimental medicine design,” the study authors noted. “Further definitive studies of CC-11050 and everolimus in patients with pulmonary tuberculosis are warranted.”
Wallis RS, Ginindza S, Beattie T, et al. Adjunctive host-direction therapies for pulmonary tuberculosis: a prospective, open-label, phase 2, randomised controlled trial. Lancet Respir Med. Published March 16, 2021. doi:10.1016/S2213-2600(20)30448-3