BCG vaccination prevents severe childhood tuberculosis (TB) and was introduced in South Africa in the 1950s. It is hypothesised that BCG trains the innate immune system by inducing epigenetic and functional reprogramming, thus providing non-specific protection from respiratory tract infections. We evaluated BCG for reduction of morbidity and mortality due to COVID-19 in healthcare workers in South Africa. This randomised, double-blind, placebo-controlled trial recruited healthcare workers at three facilities in the Western Cape, South Africa, unless unwell, pregnant, breastfeeding, immunocompromised, hypersensitivity to BCG, or undergoing experimental COVID-19 treatment. Participants received BCG or saline intradermally (1:1) and were contacted once every 4 weeks for 1 year. COVID-19 testing was guided by symptoms. Hospitalisation, COVID-19, and respiratory tract infections were assessed with Cox proportional hazard modelling and time-to-event analyses, and event severity with post hoc Markovian analysis. This study is registered with ClinicalTrials.gov, NCT04379336. Between May 4 and Oct 23, 2020, we enrolled 1000 healthcare workers with a median age of 39 years (IQR 30–49), 70·4% were female, 16·5% nurses, 14·4% medical doctors, 48·5% had latent TB, and 15·3% had evidence of prior SARS-CoV-2 exposure. Hospitalisation due to COVID-19 occurred in 15 participants (1·5%); ten (66·7%) in the BCG group and five (33·3%) in the placebo group, hazard ratio (HR) 2·0 (95% CI 0·69–5·9, p = 0·20), indicating no statistically significant protection. Similarly, BCG had no statistically significant effect on COVID-19 (p = 0·63, HR = 1·08, 95% CI 0·82–1·42). Two participants (0·2%) died from COVID-19 and two (0·2%) from other reasons, all in the placebo group. BCG did not protect healthcare workers from SARS-CoV-2 infection or related severe COVID-19 disease and hospitalisation. Funding provided by EDCTP, grant number RIA2020EF-2968. Additional funding provided by private donors including: Mediclinic, Calavera Capital (Pty) Ltd, Thys Du Toit, Louis Stassen, The Ryan Foundation, and Dream World Investments 401 (Pty) Ltd. The computations were enabled by resources in project SNIC 2020–5–524 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement No. 2018–05,973.

New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281.

With current treatment options most patients with CNS TB develop severe disability or die. Drug-resistant tuberculous meningitis is nearly uniformly fatal. Novel treatment strategies are needed. Bedaquiline, a potent anti-TB drug, has been reported to be absent from CSF in a single report. To explore the pharmacokinetics of bedaquiline and its M2 metabolite in the CSF of patients with pulmonary TB. Individuals with rifampicin-resistant pulmonary TB established on a 24 week course of treatment with bedaquiline underwent a lumbar puncture along with multiple blood sample collections over 24 h for CSF and plasma pharmacokinetic assessment, respectively. To capture the expected low bedaquiline and M2 concentrations (due to high protein binding in plasma) we optimized CSF collection and storage methods in vitro before concentrations were quantified via liquid chromatography with tandem MS. Seven male participants were enrolled, two with HIV coinfection. Using LoBind^® tubes lined with a 5% BSA solution, bedaquiline and M2 could be accurately measured in CSF. Bedaquiline and M2 were present in all patients at all timepoints at concentrations similar to the estimated unbound fractions in plasma. Bedaquiline and M2 penetrate freely into the CSF of pulmonary TB patients with a presumably intact blood–brain barrier. Clinical studies are urgently needed to determine whether bedaquiline can contribute meaningfully to the treatment of CNS TB.

Background: Tuberculous meningitis (TBM) remains the deadliest form of tuberculosis. Inadequate penetration of rifampicin and ethambutol into the brain and cerebrospinal fluid (CSF) may contribute to mortality. Over the last decade, research has focused on “intensified” treatment (higher-dose first-line drugs or addition of second-line drugs with good CSF penetration). This systematic review and meta-analysis evaluates the impact of intensified TBM treatment on mortality, disability, and safety. Methods: A systematic literature search was conducted of clinical trials examining intensified TBM treatments compared with a rifampicin-based standard-of-care regimen in adults. Odds ratios (ORs) were calculated using a random-effects model with mortality as the primary outcome, with OR <1 indicating lower mortality. Disability and safety were examined as secondary outcomes. Subgroup analyses included (1) higher-dose rifampicin, (2) addition of fluoroquinolones, and (3) addition of linezolid. Results: Ten trials meeting eligibility criteria, involving 1369 participants, were included. Higher-dose rifampicin (n = 1050; OR, 0.86; 95% CI, 0.54–1.35; P = .50), adjunctive fluoroquinolones (n = 1115; OR, 0.85; 95% CI, 0.56–1.27; P = .42), and linezolid (n = 79; OR, 0.73; 95% CI, 0.22–2.43; P = .61) did not significantly reduce TBM mortality. Due to heterogeneity in disability and safety endpoints, secondary outcomes could not be meta-analyzed. Conclusions: Current clinical trial evidence does not support the use of intensified TBM treatment in adults. However, these analyses are limited by diverse TBM case definitions, absence of MRC grading at enrollment, variable rifampicin dosing, limited data on linezolid and higher-dose isoniazid, and heterogeneous disability and safety outcomes. Use of uniform case definitions and consistent endpoints is essential to standardize data.

Large clinical trials often generate complex and large datasets which need to be presented frequently throughout the trial for interim analysis or to inform a data safety monitory board (DSMB). In addition, reliable and traceability are required to ensure reproducibility in pharmacometric data analysis. A reproducible pharmacometric analysis workflow was developed during a large clinical trial involving 1000 participants over one year testing Bacillus Calmette-Guérin (BCG) (re)vaccination in coronavirus disease 2019 (COVID-19) morbidity and mortality in frontline health care workers. The workflow was designed to review data iteratively during the trial, compile frequent reports to the DSMB, and prepare for rapid pharmacometric analysis. Clinical trial datasets (n = 41) were transferred iteratively throughout the trial for review. An RMarkdown based pharmacometric processing script was written to automatically generate reports for evaluation by the DSMB. Reports were compiled, reviewed, and sent to the DSMB on average three days after the data cut-off, reflecting the trial progress in real-time. The script was also utilized to prepare for the trial pharmacometric analyses. The same source data was used to create analysis datasets in NONMEM format and to support model script development. The primary endpoint analysis was completed three days after data lock and unblinding, and the secondary endpoint analyses two weeks later. The constructive collaboration between clinical, data management, and pharmacometric teams enabled this efficient, timely, and reproducible pharmacometrics workflow.