Aurantii Fructus Immaturus Flavonoid tablets for functional dyspepsia: A multicenter, double-blind, dose-exploring IIb randomized controlled trial

Abstract

BACKGROUND

Functional dyspepsia (FD) is a prevalent chronic upper gastrointestinal disorder with limited safe long-term treatment options, highlighting the need to explore novel therapies such as Aurantii Fructus Immaturus Flavonoid (AFIF).

AIM

To evaluate the efficacy and safety of AFIF tablets as a potential long-term treatment option for patients with FD in this multicenter, randomized, double-blind, placebo-controlled phase IIb trial.

METHODS

This double-blind randomized controlled trial used central stratified block randomization and was designed to enroll 400 eligible participants aged 18-65 years who met the Rome III criteria. Participants were allocated in a 1:1:1:1 ratio to receive high-dose AFIF (4 tablets/tid), medium-dose AFIF (3 tablets/tid), low-dose AFIF (2 tablets/tid), or placebo for 4 weeks. The primary efficacy endpoints were the resolution rates for all 4 FD symptoms (postprandial fullness, early satiety, epigastric burning sensation, and abdominal pain) and the individual symptom resolution rates after 4 weeks of medication. Secondary endpoints included the resolution rates of all four FD symptoms and individual symptoms at other visit time points, the postprandial 2-hour gastric emptying rate, and gastric half-emptying time. Safety was assessed through adverse events (AEs) and laboratory tests.

RESULTS

Of the 399 enrolled participants, 267 were included in the Full Analysis Set. In the Full Analysis Set, the 4-week resolution rates of all four symptoms differed significantly across groups [22.39% (high), 27.27% (medium), 2.99% (low), and 5.97% (placebo); P < 0.0001]. The high- and medium-dose AFIF groups showed higher rates than the low-dose and placebo groups, with no significant differences between the high- and medium-dose groups or between the low-dose and placebo groups. Individual symptom resolution rates showed similar patterns. AFIF improved gastric emptying, although the improvement was not significant compared with placebo. AE incidence was comparable across groups [5.97% (high), 6.06% (medium), 0.00% (low), and 7.46% (placebo); P = 0.112], with no serious AEs reported in the AFIF groups.

CONCLUSION

Medium- and high-dose AFIF significantly improved FD symptoms with good safety. The medium dose (3 tablets/tid) is recommended for phase III trials and may be a safer alternative to proton pump inhibitors or prokinetics. Limitations include small follow-up samples and restricted gastric emptying testing; therefore, larger long-term studies are needed.

Keywords: Functional dyspepsia; Traditional Chinese medicine; Aurantii Fructus Immaturus Flavonoid; Optimal dosage; Zhi Shi

Core Tip: This placebo-controlled, randomized phase IIb trial identified, for the first time, the optimal clinical dose of Zhi Shi Flavonoids for functional dyspepsia. Both the medium- and high-dose Aurantii Fructus Immaturus Flavonoid groups showed significant improvement in functional dyspepsia symptoms after 4 weeks compared with the placebo group, with good tolerability and no serious adverse events. These findings inform optimal dosing for phase III trials and support the integration of personalized traditional Chinese medicine into the modern management of gastrointestinal disorders.