A Multicenter RCT and Metabolomics Exploration of TCM Pattern-Based Therapy for Stable COPD

Background: Traditional Chinese medicine (TCM) is widely used as a complementary therapy for stable chronic obstructive pulmonary disease (COPD). However, the effectiveness and mechanisms of comprehensive therapy based on TCM patterns in stable COPD remain unclear. Purpose: To assess the efficacy of TCM pattern-based comprehensive therapy and its impact on metabolic profiles in participants with stable COPD. Design: This multicenter trial enrolled participants from nine hospitals and randomly assigned them in a 2:1 ratio to a trial or control group. The trial group received a combination therapy of Tiotropium Bromide Powder for Inhalation (TBPI) with Shenqi Wenfei Formula (SQWF), Shenqi Buzhong Formula (SQBZ), or Shenqi Tiaoshen Formula (SQTS) granules, while the control group was only administered TBPI. This study comprised a 24-week treatment phase and a 52-week follow-up period. The primary outcome measure was acute COPD exacerbation frequency during follow-up. Secondary outcome measures included the acute COPD exacerbation rate, COPD Assessment Test (CAT) score, modified Medical Research Council (mMRC) dyspnea scale score, 6-minute walk test (6MWT) distance, and lung function results, assessed at weeks 0, 24, and 52. Additionally, serum samples for metabolomics analysis were collected from the trial group participants before (group A) and after (group B) treatment and from healthy participants (group C). Results: Of the 270 included patients, 175 completed the study. During the 52-week follow-up, the trial group exhibited fewer acute exacerbations than the control group (P < 0.05). At 24 weeks post-treatment, comprehensive therapy (trial group) led to improvements in the CAT score, mMRC dyspnea scale score, and 6MWT distance compared to only TBPI treatment (control group) (P < 0.05). At the follow-up on week 52, the mMRC dyspnea scale score and 6MWT distance in the trial group still showed enhancements compared to those in the control group (P < 0.05), with no such significant difference between the CAT scores of the two groups (P > 0.05). In contrast, no significant lung function differences were observed between the two groups (P > 0.05). A total of 484 metabolites were detected, among which 32 significantly differed between groups A and C. In the case of post-treatment findings, 17 metabolites in group B displayed opposite trends, indicating their role as potential therapeutic targets. Bioinformatics analysis revealed that compared to group C, group A demonstrated a significant upregulation of pathways such as pyruvate metabolism and citrate cycle and a significant downregulation of pathways including protein digestion and absorption, aminoacyl-tRNA biosynthesis, and D-amino acid metabolism. Conversely, significant reverse changes were found in these pathways after treatment (i.e., group B) compared to the results before treatment (i.e., group A). Conclusion: Comprehensive therapy based on TCM patterns reduces the risk of acute exacerbations and enhances the quality of life, respiratory symptoms, and exercise tolerance in patients with stable COPD. The therapeutic effects of this treatment approach may be attributed to the modulation of energy metabolism pathways as well as protein and amino acid metabolism pathways. Trial Registration: This study was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn; no. ChiCTR2200058463). Funding: This study was financially supported by the National Natural Science Foundation of China Joint Key Project (grant no. U20A20398) and the 2022 Anhui Provincial Natural Science Foundation, China (grant no. 2208085QH264). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: This study adhered to the Helsinki Declaration and received approval from the Ethics Committee of the First Affiliated Hospital of Anhui University of Chinese Medicine (Hefei, China; approval no.: 2021AH-31[X2]).