Efficacy and Mechanistic Evaluation of Hewei Anchang Formula for Overlapping Gastrointestinal Symptoms in Patients With Coexisting Functional Dyspepsia and Diarrhea-Predominant Irritable Bowel Syndrome

N/ANot Yet RecruitingNCT07715760

Xiyuan Hospital of China Academy of Chinese Medical Sciences120 enrolled

Overview

1. To conduct a multicenter, randomized controlled trial across four hospitals to evaluate the efficacy of Hewei Anchang Formula in patients with overlapping gastrointestinal symptoms of functional dyspepsia (FD) and diarrhea-predominant irritable bowel syndrome (IBS-D), characterized by liver-stomach disharmony syndrome and liver stagnation-spleen deficiency syndrome, respectively. By leveraging the holistic regulatory effects of Chinese herbal formulas and the traditional Chinese medicine principle of "treating different diseases with the same therapeutic approach," this study aims to generate high-level evidence for the management of overlapping gastrointestinal symptoms in functional gastrointestinal disorders (FGIDs) and to establish a standardized and scalable therapeutic strategy. 2. To elucidate the potential mechanisms underlying the therapeutic effects of Hewei Anchang Formula on overlapping gastrointestinal symptoms of FD and IBS-D through multiple targets and pathways, with particular emphasis on modulation of the gut microbiota and the neuroendocrine-immune network.

Functional gastrointestinal disorders (FGIDs) comprise a group of gastrointestinal conditions characterized predominantly by gastrointestinal symptom complexes in the absence of identifiable structural abnormalities or clearly defined pathophysiological mechanisms. Individual FGIDs are diagnosed primarily on the basis of symptom profiles and commonly present with manifestations such as reflux, heartburn, dyspepsia, abdominal pain, bloating, diarrhea, and constipation. The boundaries between different FGIDs are not distinct, and symptom overlap is common. Such overlap not only increases disease complexity and substantially complicates clinical diagnosis and management, but also increases healthcare utilization and imposes a considerable adverse impact on patients' quality of life. According to the Rome IV criteria, each patient with an FGID receives, on average, 1.5 FGID diagnoses, and approximately 36% of patients have FGIDs involving two or more gastrointestinal regions, representing a typical pattern of symptom overlap. Among the various overlapping phenotypes of FGIDs, the coexistence of functional dyspepsia (FD) and diarrhea-predominant irritable bowel syndrome (IBS-D) is one of the most common. These patients experience both typical upper gastrointestinal symptoms of FD, including postprandial fullness, early satiety, and epigastric pain, and core lower gastrointestinal manifestations of IBS-D, such as abdominal pain, diarrhea, and altered stool form, making this overlap phenotype a major challenge in gastroenterological practice. Compared with patients with FD or IBS-D alone, those with coexisting FD and IBS-D tend to experience more persistent, frequent, and severe symptoms. These symptoms can substantially affect eating habits, daily routines, social activities, and other aspects of everyday life, thereby markedly impairing quality of life. Repeated healthcare-seeking behavior also increases both individual medical expenditures and the consumption of healthcare resources, making this condition an important clinical and public health concern requiring effective intervention. The clinical management of overlapping gastrointestinal symptoms in FGIDs remains challenging. Conventional pharmacological treatments often act on limited therapeutic targets and may therefore provide suboptimal efficacy in patients with overlapping symptom profiles, while also contributing to a substantial socioeconomic burden. Commonly used medications, including prokinetic agents, proton pump inhibitors, antidiarrheal agents, and anticholinergic antispasmodics, generally target symptoms arising from a single gastrointestinal region. Consequently, treatment outcomes may be unsatisfactory when upper and lower gastrointestinal symptoms coexist. Although combination pharmacotherapy may address multiple symptoms, it may also increase the risk of adverse drug reactions, and some patients discontinue treatment because of poor tolerability or adverse effects, resulting in limited overall clinical benefit. In addition, the pathophysiology of coexisting FD and IBS-D is complex and has been associated with multiple interacting mechanisms, including gastrointestinal dysmotility, gut microbial dysbiosis, and dysregulation of the neuroendocrine-immune network. Thus, single-target pharmacotherapy may be poorly suited to the multifactorial pathophysiological features of this overlap phenotype, which may partly explain its limited therapeutic effectiveness. Patients with FD and IBS-D frequently experience psychological disturbances, including anxiety and depression. From the perspective of traditional Chinese medicine (TCM), liver qi stagnation is considered a key underlying pathogenesis, while spleen-stomach deficiency and liver stagnation with spleen deficiency are among the most common syndrome patterns in patients with overlapping FD and IBS-D. Accordingly, strengthening the spleen and regulating qi, as well as soothing the liver and strengthening the spleen, are regarded as core therapeutic principles. Owing to its holistic regulatory effects and individualized treatment based on syndrome differentiation, TCM may be particularly well suited to the multifactorial pathophysiology of overlapping FGIDs. Guided by the TCM principle of "treating different diseases with the same therapeutic approach," TCM interventions may target the shared pathogenesis of liver stagnation with spleen deficiency through multicomponent, multitarget, and multipathway mechanisms, thereby exerting integrated effects on gastrointestinal function, emotional well-being, and internal homeostasis. This therapeutic model may offer advantages over conventional single-target symptomatic treatment. Chaihu Shugan San has the traditional actions of regulating qi, relieving stagnation, harmonizing the stomach, and redirecting rebellious qi downward, and has been strongly recommended in several expert consensuses and clinical guidelines for the treatment of FD with liver-stomach disharmony syndrome. Based on more than four decades of clinical experience, Professor Xudong Tang of Xiyuan Hospital, China Academy of Chinese Medical Sciences, proposed the theory of "regulating the middle and restoring balance." Under the guidance of this theory, Chang'an I Formula was developed according to the core pathogenesis of IBS-D. Hewei Anchang Formula is an optimized herbal formula derived from Chang'an I Formula and modified Chaihu Shugan San, with modifications tailored to the pathophysiological characteristics of liver-stomach disharmony syndrome in FD and liver stagnation with spleen deficiency syndrome in IBS-D. The formula has demonstrated promising clinical effects. Based on the theory of "regulating the middle and restoring balance," Hewei Anchang Formula is designed to address the core pathogenesis of overlapping gastrointestinal symptoms in FD and IBS-D, with therapeutic actions aimed at strengthening the spleen, soothing the liver, regulating qi, and alleviating diarrhea. Its composition is therefore closely aligned with the principles of TCM syndrome differentiation and provides a suitable intervention for investigating TCM-based treatment of this overlap phenotype. This study is designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial and will enroll 120 patients with overlapping gastrointestinal symptoms of FD with liver-stomach disharmony syndrome and IBS-D with liver stagnation-spleen deficiency syndrome. The study aims to evaluate the clinical efficacy and potential therapeutic advantages of Hewei Anchang Formula in the treatment of coexisting FD and IBS-D. Metagenomic and metabolomic approaches will also be used to investigate its potential mechanisms of action, with particular emphasis on the gut microbial ecosystem and the neuroendocrine-immune network. The findings are expected to provide a practical TCM-based therapeutic strategy for improving the overall management of overlapping gastrointestinal symptoms in FGIDs and reducing the associated medical and socioeconomic burden.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Meet the Rome IV diagnostic criteria for both functional dyspepsia (FD) and diarrhea-predominant irritable bowel syndrome (IBS-D). 2. Meet the diagnostic criteria for liver-stomach disharmony syndrome in FD and liver qi stagnation with spleen deficiency syndrome in IBS-D. 3. Aged 18-65 years, with no restriction on sex. 4. Fully informed about the study and voluntarily provide written informed consent. - Exclusion Criteria: 1. Severe primary diseases of the cardiovascular, hepatic, renal, hematologic, or respiratory systems, or malignant tumors. 2. Other organic gastrointestinal diseases, such as peptic ulcer or ulcerative colitis, or systemic diseases that may affect gastrointestinal motility, such as hyperthyroidism or diabetes mellitus. 3. Current or anticipated continuous use of medications that may affect gastrointestinal function, including prokinetic agents, antidiarrheal agents, antidepressants, anxiolytics, gut microbiota-modulating agents, and antibiotics. 4. A history of allergy to any study-related medication or a history of severe food allergy. 5. Psychiatric disorders, intellectual impairment, or language impairment. 6. Women who are planning pregnancy, pregnant, or breastfeeding. 7. Current participation in another drug clinical trial or participation in another drug clinical trial within the previous 4 weeks. 8. Severe anxiety or depression, as assessed using the Hospital Anxiety and Depression Scale (HADS). An anxiety subscale score of ≥15 is defined as severe anxiety, and a depression subscale score of ≥15 is defined as severe depression. Participants meeting the criterion for severe anxiety or severe depression on either subscale will be excluded. 9. A suspected or confirmed history of alcohol or drug abuse, or other circumstances that, in the investigator's judgment, may reduce the likelihood of enrollment or complicate study participation, such as frequent changes in the work environment that may increase the risk of loss to follow-up. -

Outcomes

Primary Outcomes

Functional Dyspepsia Symptom Severity Scale Scores

The scale assesses the frequency and severity of four functional dyspepsia symptoms: postprandial fullness, early satiation, epigastric pain, and epigastric burning. For each symptom, frequency is rated on a 5-point scale ranging from 1 (never) to 5 (present throughout the day), and severity is rated on a 4-point scale ranging from 1 (none) to 4 (severe).

Time frame: Baseline (Day 0), Week 2, Week 4, and Week 8

Global Impression Scale for Dyspepsia Symptom Relief

Participants will evaluate the overall relief of dyspepsia-related symptoms during the previous 2 weeks using a 7-point scale: 1 = markedly worse, 2 = worse, 3 = slightly worse, 4 = no relief, 5 = slight relief, 6 = marked relief, and 7 = complete relief. Higher scores indicate greater overall symptom relief.

Time frame: Baseline (Day 0), Week 2, Week 4, and Week 8

Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) Score

The IBS-SSS assesses abdominal pain severity, the number of days with abdominal pain during a 14-day period, abdominal distension severity, satisfaction with bowel habits, and the extent to which irritable bowel syndrome interferes with daily life. Higher scores indicate greater symptom severity.

Time frame: Baseline (Day 0), Week 2, Week 4, and Week 8

Secondary Outcomes

Traditional Chinese Medicine Syndrome Score

The Traditional Chinese Medicine syndrome score assesses 15 symptoms: epigastric fullness, epigastric pain, reduced appetite, heartburn or a burning sensation, belching or acid regurgitation, excessive clear salivation, a sensation of obstruction in the throat, thirst without a desire to drink, lower abdominal distension or pain, limb weakness, shortness of breath, disinclination to speak, heaviness of the body and limbs, aversion to cold, and loose stools. Each item is rated from 0 (none) to 3 (severe). The item scores are summed to obtain a total score ranging from 0 to 45, with higher scores indicating greater symptom severity.