Immunotherapies for sepsis and the impact of study design

Sepsis is a life threatening syndrome initiated by microorganisms.1 Severe and often lethal injuries (eg, shock, multiorgan failure, and metabolic derangements) are the manifestation of the syndrome, with systemic inflammatory cascade activation and circulating mediators thought to cause host injury.

Scores of trials evaluating host-immune modifiers, many of which were the initial ventures of a new biotech industry 30 years ago, did not improve patient outcomes in sepsis.2 Undaunted by this history, investigators in the linked trial(doi:10.1136/bmj-2024-082583) evaluated another immune therapy, thymosin-α-1, in patients with sepsis, enrolling 1106 participants at 22 sites in China.3 The trial compared thymosin-α-1 with placebo plus usual care in a blinded randomised trial evaluating all cause mortality at 28 days. The results showed 24% mortality with thymosin versus 23% in the control group (hazard ratio 0.99, 95% confidence interval 0.77 to 1.77), which indicate no improvement with thymosin. Several positive aspects of the trial’s design include a superiority hypothesis with direct patient-outcomes of all cause mortality using inferential statistics, rather than non-inferiority hypotheses on surrogate endpoints using descriptive statistics commonly used in infection …