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.

Macronutrient intake and body composition changes during anti-tuberculosis therapy in adults.

BACKGROUND: Malnutrition is common in patients with active tuberculosis (TB), yet little information is available on serial dietary intake or body composition in TB disease. OBJECTIVE: To evaluate macronutrient intake and body composition in individuals with newly diagnosed TB over time. DESIGN: Adults with active pulmonary TB (n = 191; 23 with multidrug resistant TB (MDR-TB) and 36 culture-negative household contacts (controls) enrolled in a clinical trial of high-dose cholecalciferol (vitamin D3) were studied. Macronutrient intake was determined at baseline, 8 and 16 weeks. Serial body composition was assessed by body mass index (BMI; kg/m(2)) and bioelectrical impedance analysis (BIA) to estimate fat mass and fat-free mass. Descriptive statistics, repeated measures ANOVA for changes over time and linear regression were used. RESULTS: At baseline, mean daily energy, protein, fat and carbohydrate (CHO) intakes were significantly higher, and body weight, BMI, fat-free mass and fat mass were significantly lower, between TB subjects and controls. These remained significant after adjusting for age, gender, employment status and smoking. In all TB subjects, baseline mean daily intakes of energy, fat and protein were adequate when compared to the US Dietary Reference Intakes and protein significantly increased over time (p < 0.0001). Body weight, BMI, and fat and fat-free mass increased over time. MDR-TB patients exhibited lower body weight and fat-free mass over time, despite similar daily intake of kcal, protein, and fat. CONCLUSIONS: Macronutrient intake was higher in TB patients than controls, but TB-induced wasting was evident. As macronutrient intake of TB subjects increased over time, there was a parallel increase in BMI, while body composition proportions were maintained. However, individuals with MDR-TB demonstrated concomitantly decreased body weight and fat-free mass over time versus drug-sensitive TB patients, despite increased macronutrient intake. Thus, MDR-TB appears to blunt anabolism to macronutrient intake, likely reflecting the catabolic effects of TB.