Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an important occurrence in the natural history of idiopathic pulmonary fibrosis (IPF), associated with high hospitalization rates, high mortality and poor prognosis. At present, there is no effective treatment for AE-IPF. Chinese herbal medicine has some advantages in treating IPF, but its utility in AE-IPF is unclear.

Objective: The treatment of AE-IPF with Kangxian Huanji Granule (KXHJ), a compound Chinese herbal medicine, lacks an evidence-based justification. This study explores the efficacy and safety of KXHJ in patients with AE-IPF.

Design, setting, participants and interventions: We designed a randomized, double-blind, placebo-controlled, exploratory clinical trial. A total of 80 participants diagnosed with AE-IPF were randomly assigned to receive KXHJ or a matching placebo; the treatment included a 10 g dose, administered twice daily for 4 weeks, in addition to conventional treatment. Participants were followed up for 12 weeks after the treatment.

Main outcome measures: The primary endpoints were treatment failure rate and all-cause mortality. Secondary endpoints included the length of hospitalization, overall survival, acute exacerbation rate, intubation rate, the modified British Medical Research Council (mMRC) score, and the St George’s Respiratory Questionnaire for IPF (SGRQ-I) score.

Results: The rate of treatment failure at 4 weeks was lower in the intervention group compared to the control group (risk ratio [RR]: 0.22; 95% confidence interval [CI]: 0.051 to 0.965, P = 0.023). There was no significant difference in all-cause mortality at 16 weeks (RR: 0.75; 95% CI: 0.179 to 3.138; P > 0.999) or in the acute exacerbation rate during the 12-week follow-up period (RR: 0.69; 95% CI: 0.334 to 1.434; P = 0.317). The intervention group had a shorter length of hospitalization than the control group (mean difference [MD]: –3.30 days; 95% CI, –6.300 to –0.300; P = 0.032). Significant differences in the mean change from baseline in the mMRC (between-group difference: –0.67; 95% CI: –0.89 to –0.44; P < 0.001) and SGRQ-I score (between-group difference: –10.36; 95% CI: –16.483 to –4.228; P = 0.001) were observed after 4 weeks, and also in the mMRC (between-group difference: –0.67; 95% CI: –0.91 to –0.43; P < 0.001) and SGRQ-I (between-group difference: –10.28; 95% CI, –15.838 to –4.718; P < 0.001) at 16 weeks. The difference in the adverse events was not significant.

Conclusion: KXHJ appears to be effective and safe for AE-IPF and can be considered a complementary treatment in patients with AE-IPF. As a preliminary exploratory study, our results provide a basis for further clinical research.

Trial registration: Chinese Clinical Trial Registry (ChiCTR1900026289).

Key words: Idiopathic pulmonary fibrosis, Acute exacerbation, Chinese herbal medicine, Integrative medicine, Randomized controlled trial