The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial

Abstract

Objective: To evaluate whether the immunomodulatory drug thymosin α1 reduces mortality in adults with sepsis.

Design: Multicentre, double blinded, placebo controlled phase 3 trial.

Setting: 22 centres in China, September 2016 to December 2020.

Participants: 1106 adults aged 18-85 years with a diagnosis of sepsis according to sepsis-3 criteria and randomly assigned in a 1:1 ratio to receive thymosin α1 (n=552) or placebo (n=554). A stratified block method was used for randomisation, and participants were stratified by age (<60 and ≥60 years) and centre.

Interventions: Subcutaneous injection of thymosin α1 or placebo every 12 hours for seven days unless discontinued owing to discharge from the intensive care unit, death, or withdrawal of consent.

Main outcome measure: The primary outcome was 28 day all cause mortality after randomisation. All analyses were based on a modified intention-to-treat set, including participants who received at least one dose of study drug.

Results: Of 1106 adults with sepsis enrolled in the study, 1089 were included in the modified intention-to-treat analyses (thymosin α1 group n=542, placebo group n=547). 28 day all cause mortality occurred in 127 participants (23.4%) in the thymosin α1 group and 132 (24.1%) in the placebo group (hazard ratio 0.99, 95% confidence interval 0.77 to 1.27; P=0.93 with log-rank test). No secondary or safety outcome differed statistically significantly between the two groups. The prespecified subgroup analysis showed a potential differential effect of thymosin α1 on the primary outcome based on age (<60 years: hazard ratio 1.67, 1.04 to 2.67; ≥60 years: 0.81, 0.61 to 1.09; P for interaction=0.01) and diabetes (diabetes: 0.58, 0.35 to 0.99; no diabetes: 1.16, 0.87 to 1.53; P for interaction=0.04).

Conclusions: This trial found no clear evidence to suggest that thymosin α1 decreases 28 day all cause mortality in adults with sepsis.

Trial registration: ClinicalTrials.gov NCT02867267.

Fig 1

Flow of participants through study

Fig 2

Kaplan-Meier estimates of time-to-event for death at 28 days (primary outcome) and 90 days from randomisation. Log-rank tests were used for comparisons and the hazard ratios for relative risks of the primary outcome between the two groups, along with corresponding 95% CIs, were calculated using a Cox regression model adjusted for centre and age. The model assumption was assessed using Schoenfeld residuals. CI=confidence interval

Fig 3

Subgroup analyses. A Bonferroni threshold for significance for overall type I error of 0.05 was P=0.006. The HRs for relative risk of primary outcome of the two groups and associated 95% CIs were calculated with a Cox regression model adjusting for centre and age. An interaction term was added between treatment and subgroup in the Cox regression model. CI=confidence interval; COPD=chronic obstructive pulmonary disease

Fig 4

Dynamic change of immune markers in participants with sepsis. Mixed effects model for repeated measures was used to analyse the absolute changes in immune markers: mHLA-DR, lymphocyte count, neutrophil to lymphocyte ratio, and regulatory T cells from screening period to 28 day follow-up. This model included measurements of immune markers on days 7, 14, and 28 as dependent variables (the proportion of regulatory T cells was only measured on day 7), whereas immune marker levels at screening, centre, and age group served as independent variables. mHLA-DR=monocyte human leucocyte antigen-DR