The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial

Abstract

IntroductionSevere sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Tα1) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Tα1 improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis.MethodsWe performed a multicenter randomized controlled trial in six tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010. Eligible patients admitted in ICU with severe sepsis were randomly allocated by a central randomization center to the control group or Tα1 group (1:1 ratio). The primary outcome was death from any cause and was assessed 28 days after enrollment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA) and monocyte human leukocyte antigen-DR (mHLA-DR) on day 0, 3, 7 in both groups. All analyses were done on an intention-to-treat basis.ResultsA total of 361 patients were allocated to either the control group (n = 180) or Tα1 (n = 181) group. The mortalities from any cause within 28 days in the Tα1 group and control group were 26.0% and 35.0% respectively with a marginal P value (nonstratified analysis, P = 0.062; log rank, P = 0.049); the relative risk of death in the Tα1 group as compared to the control group was 0.74 (95% CI 0.54 to 1.02). Greater improvement of mHLA-DR was observed in the Tα1 group on day 3 (mean difference in mHLA-DR changes between the two groups was 3.9%, 95% CI 0.2 to 7.6%, P = 0.037) and day 7 (mean difference in mHLA-DR changes between the two groups was 5.8%, 95% CI 1.0 to 10.5%, P = 0.017) than in the control group. No serious drug-related adverse event was recorded.ConclusionsThe use of Tα1 therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis.Trial registrationClinicalTrials.gov NCT00711620.

Is this critically ill patient immunocompromised?

“…A lower expression and especially failure of restoration of HLA-DR expression appear indicative of immunoparalysis, as it is related to the susceptibility to opportunistic infections and outcome in sepsis patients [15]. Several promising immuno-adjuvant agents are slated for testing in the near future, including GM-CSF (ClinicalTrials.gov identifier: NCT02361528), IL-7, anti-PD-L1 (ClinicalTrials.gov identifier: NCT02576457), and thymosin-alpha-1 [2,8,12,13,16,17]. Given the remarkable success of immunotherapy in cancer and the similarities in the immune defects in cancer and sepsis patients [18], it appears plausible that immunotherapy may represent a major advance in the treatment of this highly lethal disease.…”

Current epidemiology of sepsis in mainland China

“…However, due to the lack of early triage of sepsis system, limited ICU resources, and low-to-high level hospital medical visiting system, many septic patients might lose the precious period when they could receive the intensive care management (5,16). The efficacy of thymosin alpha 1 for severe sepsis (ETASS) study conducted in Guangdong province, an economically developed region in mainland China, reported that the median time when the patient developed first organ failure and enrollment was 28 and 42 h, respectively in the control and treatment groups (17). While the data from our sepsis database represents the economically less developed area, more than 60% of the severe sepsis patients developed organ failure after more than 48 h upon ICU admission.…”

Thymosin α1-Based Immunomodulatory Therapy for Sepsis: A Meta-Analysis with Trial Sequential Analysis of Randomized Controlled Trials

“…The duration of treatment ranges from 6 to 10 days and the total dose ranges from 9.6 to 22.4mg. Four trials reported thymosin α1 alone (17,(23)(24)(25), and the remaining six trials reported thymosin α1 combination with ulinastatin (18)(19)(20)(21)(22) (19,21), and three reported interleukin-6 (19,21,22).…”

“…Overall, six trials were categorized as at low risk of bias (17)(18)(19)(20)24), and four as at unclear risk of bias (21)(22)(23)25). Adequate randomized sequence generated in seven trials (17-20, 24, 25), and appropriate allocation concealment were reported in six trials (17)(18)(19)(20)24). Blinding of outcome assessments was unclear or seldom reported in these trials, but the primary outcome (i.e., 28-day mortality) was less prone to be influenced by lack of blinding.…”

“…After removing duplicates and screening titles and abstracts, 13 articles were potentially eligible. After checking the full text, nine articles with 10 RCTs were finally included (17)(18)(19)(20)(21)(22)(23)(24)(25).…”