Evaluating the effectiveness and safety of Xiyanping injection for severe pneumonia: a target trial emulation...

Severe pneumonia remains a major public health challenge characterized by high mortality. Xiyanping Injection (XYP) is a Traditional Chinese Medicine injectable preparation whose core active constituent is andrographolide sulfonate, a sulfonated derivative of andrographolide extracted from Andrographis paniculata (Burm.f.) Wall. ex Nees [Acanthaceae; Andrographis paniculatae herba]. XYP exhibits anti-inflammatory, antiviral, antibacterial, antipyretic, and immunomodulatory activities. Although preliminary studies indicated the potential efficacy of XYP as an adjunctive therapy, its real-world effectiveness, safety, and optimal dosing in severe pneumonia remain uncertain. To bridge the gap between theoretical efficacy and real-world clinical benefit, and to overcome the methodological biases inherent in traditional observational studies, target trial emulation (TTE) is needed to generate high-quality real-world evidence.

We will emulate a pragmatic target trial using multicenter electronic health records. Time zero will be aligned with the date of confirmed severe pneumonia diagnosis, and a new-user design will be implemented to reduce immortal time bias and prevalent user bias. We will compare XYP combined with standard care versus standard care alone. The primary outcomes are 28-day all-cause mortality and in-hospital mortality. Missing data will be handled using machine-learning-based imputation tailored to variable types. The clone-censor-weight method will serve as the primary analytical strategy. The instrumental variable approach will be used as a secondary method to explore residual confounding. We will further apply causal forests to estimate conditional average treatment effects and to explore potential treatment-effect heterogeneity and high-benefit subgroups. A multistage dose-response analysis will examine the association between continuous XYP dosing and clinical outcomes to explore potential dosing patterns and therapeutic windows.

This protocol applies a rigorous causal inference framework to evaluate the real-world effectiveness and safety of XYP as adjunctive treatment for severe pneumonia. The study is expected to provide real-world evidence to inform future evaluation of XYP in real-world clinical practice and to provide a replicable TTE-based methodological template for real-world evaluation of other Traditional Chinese Medicine injections.

https://itmctr.ccebtcm.org.cn/, Identifier ITMCTR2026000820.