Traditional Chinese Medicine FYTF-919 (Zhongfeng Xingnao Oral Prescription) for the Treatment of Acute Intracerebral Hemorrhage: A Methodological Appraisal of the CHAIN Trial.

Context: The Lancet report of the CHAIN trial evaluating FYTF-919, a traditional Chinese medicine (TCM) for moderate to severe acute intracerebral hemorrhage, concluded "no effect" on functional recovery, survival, and health-related quality of life compared to placebo. Objective: The current study intended to re-examine its methodology and conclusions about the efficacy of FYTF-919. Design: Reanalysis of data from the Lancet report. Intervention: Adopting the PICO framework and the CONSORT Extension, a critical appraisal of the trial's report and supplementary materials was conducted. Definition of TCM-specific patterns, sample size calculation, use of multiple concomitant therapies, timing of primary outcome assessment, and interpretation of results have been examined. Results: There was a risk of performance bias in the trial as it did not report TCM-specific patterns, despite FYTF-919 being formulated for qi deficiency, potentially including patients unsuitable for this intervention. The sample size calculation was flawed and inconsistently applied, altering the mean difference and potentially underestimating FYTF-919's effect. Both the FYTF-919 and placebo groups had 19 concomitant therapies applied as needed, making it difficult to isolate FYTF-919's benefits. The study mistakenly hypothesized that there was no difference between the two groups due to the use of the 19 concomitant therapies, referred to as "routine treatment". The main report ignored multiple significant differences in subgroups and at earlier timepoints. These potentially positive findings were not highlighted, raising concerns of a substantial risk of selective reporting bias. Conclusions: The trial's conclusion of "no effect" is questionable due to methodological flaws, trial design, and reporting errors. Proper assessment of complex interventions, clearer adherence to TCM-specific guidelines, rigorous sample size calculation, and balanced consideration of early recovery data and subgroups are essential. The current analysis of the appraisal found that the effect of the FYTF-919 was superior to that of the placebo. Keywords: Intracerebral hemorrhage, Traditional Chinese Medicine, FYTF-919, multiple interventions, CHAIN trial, selective report bias, critical appraisal, Zhongfeng Xingnao.