SMA-TB: study protocol for the phase 2b randomized double-blind, placebo-controlled trial to estimate the potential efficacy and safety of two repurposed drugs, acetylsalicylic acid and ibuprofen, for use as adjunct therapy added to, and compared with, the standard WHO recommended TB regimen.

BACKGROUND: The duration and regimen of tuberculosis (TB) treatment is currently based predominantly on whether the M. tuberculosis (Mtb) strain is drug-sensitive (DS) or multidrug-resistant (MDR) with doses adjusted by patients' weight only. The systematic stratification of patients for personalized treatment does not exist for TB. As each TB case is different, individualized treatment regimens should be applied to obtain better outcomes. In this scenario, novel therapeutic approaches are urgently needed to (1) improve outcomes and (2) shorten treatment duration, and host-directed therapies (HDT) might be the best solution. Within HDT, repurposed drugs represent a shortcut in drug development and can be implemented at the short term. As hyperinflammation is associated with worse outcomes, HDT with an anti-inflammatory effect might improve outcomes by reducing tissue damage and thus the risk of permanent sequelae. METHODS: SMA-TB is a multicentre randomized, phase IIB, placebo-controlled, three-arm, double-blinded clinical trial (CT) that has been designed in the context of the EC-funded SMA-TB Project ( www.smatb.eu ) in which we propose to use 2 common non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA) and ibuprofen (Ibu), as an HDT for use as adjunct therapy added to, and compared with, the standard of care (SoC) World Health Organization (WHO)-recommended TB regimen in TB patients. A total of 354 South African and Georgian adults diagnosed with confirmed pulmonary TB will be randomized into SoC TB treatment + placebo, SoC + acetylsalicylic acid or SoC + ibuprofen. DISCUSSION: SMA-TB will provide proof of concept of the HDT as a co-adjuvant treatment and identify the suitability of the intervention for different population groups (different epidemiological settings and drug susceptibility) in the reduction of tissue damage and risk of bad outcomes for TB patients. This regimen potentially will be more effective and targeted: organ saving, reducing tissue damage and thereby decreasing the length of treatment and sequelae, increasing cure rates and pathogen clearance and decreasing transmission rates. It will result in better clinical practice, care management and increased well-being of TB patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT04575519. Registered on October 5, 2020.

Timing of Pulmonary Rehabilitation in Readmitted Patients with Severe Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

Early pulmonary rehabilitation (PR), started during hospitalization or within the first month after discharge, has been shown to reduce exacerbations and improve health-related-quality of life (HRQoL) and exercise capacity. However, no randomized clinical trials (RCT) have compared the efficacy of PR started during hospitalization (DHPR) to PR initiated one month post-hospitalization (PHPR). We conducted an RCT to compare DHPR to PHPR in severe patients with COPD readmitted for exacerbations in a tertiary hospital setting. Patients were randomized to receive three months of DHPR or PHPR. Outcomes were assessed at completion of the PR programme and at months 3 and 9. A total of 53 patients (26 DHPR and 27 PHPR) were included. There were no between-group differences in the number of exacerbations (mean, 3.62 vs. 3.04 in the DHPR and PHPR groups, respectively; p = 0.403). Dyspnea in activities of daily living, exercise capacity, and all HRQoL parameters improved in the PHPR group. In the DHPR group, improvement was observed only for some HRQoL parameters. All gains in both groups were lost during follow-up. More adverse events were observed in the DHPR group (20 vs 5, p = 0.023), although none of these were clinically significant. In this sample of patients with severe COPD readmitted to the hospital for exacerbations, both approaches to PR were safe, but PHPR yielded better outcomes overall. These findings suggest that, PR should be initiated in patients with severe COPD only after hospital discharge when the patients' clinical condition has stabilized.