Efficacy of thymosin α1 for sepsis: a systematic review and meta-analysis of randomized controlled trials.
This systematic review and meta-analysis evaluated the efficacy of thymosin α1 (Tα1), a synthetic immunomodulatory peptide, in treating sepsis. Researchers searched for prospective clinical studies measuring 28-day mortality in sepsis patients treated with Tα1 (excluding combination therapy studies), ultimately including 11 randomized controlled trials (RCTs) totaling 1,927 patients. The overall meta-analysis found a statistically significant reduction in 28-day mortality associated with Tα1 (OR 0.73, 95% CI: 0.59–0.90). However, when analysis was restricted to high-quality trials or multicenter trials — considered more rigorous subsets — the mortality benefit was no longer statistically significant (ORs 0.82 and 0.86, respectively). A heterogeneity of treatment effects analysis drawing on individual patient data from two large multicenter RCTs (representing ~75% of total patients) suggested potential benefits in subgroups with cancer (moderate credibility), diabetes, and coronary heart disease (both low credibility). Trial sequential analysis indicated the current evidence base is underpowered. The authors concluded that while Tα1 shows potential, its benefits appear to vary across patient subgroups, and personalized immunotherapy approaches warrant investigation in future, adequately powered trials.
Why this grade: Although based on human RCT data, the overall mortality benefit disappears in high-quality and multicenter subgroup analyses, and trial sequential analysis confirms the pooled sample size remains insufficient to draw definitive conclusions.
Background Despite advances in understanding sepsis pathophysiology and extensive research, few treatments effectively target its underlying immune dysfunction. Thymosin α1 (Tα1) shows promise as an immunomodulator, but its impact on sepsis remains unclear. Methods A search strategy was designed to include any prospective clinical studies using Tα1 for assessing 28-day mortality in patients with sepsis, excluding combination therapy studies. We conducted trial sequential analysis (TSA) to assess the robustness of meta-analyses findings. Heterogeneity of treatment effects (HTE) was conducted based on individual data from two multicenter randomized clinical trials (RCTs), with result credibility assessed through the instrument to assess the credibility of effect modification analyses (ICEMAN). Results Out of 3003 identified studies, 11 RCTs met the inclusion criteria (967 patients in Tα1 group and 960 patients in control group). The comprehensive meta-analysis demonstrated a significant reduction in 28-day mortality associated with Tα1 administration (OR 0.73, 95%CI: 0.59-0.90, P = 0.003). Nonetheless, analyses of high-quality (OR 0.82, 95%CI: 0.65-1.03, P = 0.09) and multi-center (OR 0.86, 95%CI: 0.68-1.08, P = 0.20) subgroups did not reveal a mortality benefit. The HTE analysis of multiple subgroups in two large RCTs (representing 75% of the total patients) showed heterogeneity. Potential benefits were noted in subgroups of cancer (moderate credibility), diabetes (low credibility), and coronary heart disease (low credibility). Furthermore, the trial sequential analysis (TSA) suggests that the current sample size is inadequate. Conclusion Tα1 has the potential to decrease 28-day mortality rates in patients with sepsis; however, it is crucial to recognize that its efficacy differs among various subgroups. These observations underscore the significance of personalized immunotherapy strategies in forthcoming clinical trials. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42024628937.
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