Study design

This study is a single-center, randomized, double-blind, double-dummy, parallel-design clinical trial to evaluate the safety and efficacy of co-administered YGJ and PPI for rGERD. Patient recruitment has already commenced in August 2023 and will continue until February 2025 at the Kyung Hee University Korean Medicine Hospital (Seoul, Republic of Korea).

A total of 86 participants who fulfill the study criteria and consent to participate will be randomized in a 1:1 ratio for the test (43 participants; YGJ and RPZ 10 mg/d) and control (43 participants; RPZ 20 mg/d) groups. The study will consist of a screening visit and 4 weeks of treatment (weeks 0–4), followed by 4 weeks of follow-up (weeks 4–8).

In this study, the principal investigator (PI) and researchers will follow lawful procedures based on ethical principles, including the principles of the Declaration of Helsinki, to provide participants with detailed study information and obtain informed consent for participation. Participants are free to withdraw from the study at any time for any reason.

This study will be conducted according to an approved protocol by the Institutional Review Board (IRB) of Kyung Hee University Korean Medicine Hospital and will adhere to the Good Clinical Practice standards established by the Korean Food and Drug Administration. The study will also follow the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and the Consolidated Standards of Reporting Trials (CONSORT) statement [33, 34]. The flowchart and outcome evaluation points for this trial are shown in Fig. 1 and Table 1.

Fig. 1

Flow diagram of the trial. B.i.d: Bis in die; RPZ: Rabeprazole; Sac: Sachet; Tab: Tablet; T.i.d: Ter in die; Q.d: Quaque die; YGJ: Yukgunja-tang

Table 1 Study procedure of enrolment, allocation, and outcome assessmentsParticipantsRecruitment

Participants will be recruited through notices posted on clinical bulletin boards, online platforms, and public transportation bulletin boards.

Inclusion criteria 1.

Participants aged between 19 and 75 years.

2.

Participants diagnosed with GERD, including EE or NERD.

3.

Participants who have received PPI therapy for at least 4 weeks but still experience typical GERD symptoms (heartburn and acid regurgitation).

4.

Participants with dyspeptic symptoms, measured on a 0–100 mm visual analogue scale (VAS), of 40 points or higher.

5.

Participants who voluntarily agree to participate in this clinical trial and have signed the consent form.

Exclusion criteria 1.

History of hypersensitivity reactions (e.g., rash, urticaria, and itching) to components of the investigational product (IP) or benzimidazole.

2.

Participants with the following conditions detected by upper endoscopy: gastric ulcers (excluding scars), ulcer stenosis, esophageal varices, eosinophilic esophagitis, gastrointestinal bleeding, Zollinger-Ellison syndrome, Barrett's esophagus, esophageal stricture, or malignant tumors of the gastrointestinal tract.

3.

Participants diagnosed with FD, esophageal motility disorders, irritable bowel syndrome, or inflammatory bowel disease for the primary symptom.

4.

Participants presenting warning symptoms suggestive of malignancy (e.g., unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, and melena).

5.

Participants who have undergone surgeries affecting gastric acid secretion, such as esophageal surgery, anti-reflux surgery, and gastrectomy.

6.

Participants with a history of malignancy within 5 years before the screening date, except for cases other than gastrointestinal malignancies that had been cured without recurrence for at least 5 years from the date of screening.

7.

Participants diagnosed with severe liver disease, chronic kidney disease, or any severe renal dysfunction.

8.

Participants who have taken specific medications within 2 weeks of receiving IP or need continuous administration of these medications for the treatment of other diseases (including antipsychotics, non-steroidal anti-inflammatory drugs, corticosteroids, etc.).

9.

Pregnant or lactating participants.

10.

Female participants of reproductive age expected to become pregnant during the clinical trial period.

11.

Participants with a history of alcohol addiction or drug abuse.

12.

Participants with specific genetic disorders (e.g., galactose intolerance, Lapp lactase deficiency, and glucose-galactose malabsorption).

13.

Participants currently receiving Atazanavir or Rilpivirine.

14.

Chronic conditions poorly controlled despite appropriate treatment (e.g., hypertension, diabetes, and edema), posing a threat to life, requiring hospitalization, leading to significant physical disabilities, or interfering with daily activities.

15.

Participants who have participated in another clinical trial within 30 days prior to the date of written consent.

16.

Participants who have taken herbal/traditional medicine products or received traditional medicine treatments (e.g., acupuncture and moxibustion) affecting gastric acid secretion or the gastrointestinal system within 2 weeks prior to IP administration.

17.

Participants unable to participate or receive treatment in the clinical trial due to severe mental disorders.

18.

Participants with clinical abnormalities identified through screening tests (vital signs, blood and urine tests, and electrocardiogram).

19.

Participants deemed unsuitable for participation in the study by the investigator.

Randomization and allocation concealment

Randomization will be assigned to each arm by a statistician blinded to the conduct and evaluation of the study. This will be based on a pre-generated 86-person (1:1) random number table using the statistical programs such as SAS® Version 9.4 (SAS Institute Inc., Cary, NC, USA) or IBM SPSS Version 25.0 (IBM Corp., Armonk, NY, USA). Each patient's allocation, according to the randomization table, will be placed in an opaque envelope, sealed in a double envelope, and stored until the end of the study. The random number will be communicated to the IP manufacturer's representative, who will mark the IP on the label without differentiation by group. Participants providing written consent and meeting all inclusion criteria will be enrolled and assigned a random number by the clinical research coordinator in the order of their visit.

Blinding

The trial will be double-blinded by producing placebos that are externally indistinguishable for both YGJ and RPZ. The manufacturer will package the IP identically to conceal the intervention allocation and affix the randomization number to the IP container and its placebo according to the pre-designed randomization table to ensure double-blinding. Participants, investigators, pharmacists, and outcome assessors will not know which container contains the study drug or placebo, nor will they know the patient's arm assignment.

Interventions

Participants will be randomized to receive the investigational drugs as prescribed for 4 weeks. The botanical drug preparation of YGJ and its placebo were manufactured by the National Institute for Korean Medicine Development (Gyeongsan, Republic of Korea), and RPZ and its placebo by KMEDIhub (Daegu, Republic of Korea). Each was manufactured in accordance with Korean Good Manufacturing Practice guidelines.

Botanical drug and placebo production YGJ

The raw materials of YGJ extract granules per sachet included 1.33 g each of Ginseng Radix (Korean Pharmacopoeia, KP), Atractylodis Rhizoma Alba (KP), Poria Sclerotium (KP), Pinelliae Tuber (KP), and Citri Unshius Pericarpium (KP), 0.67 g each of Zizyphi Fructus (KP) and Zingiberis Rhizoma (Korean Herbal Pharmacopoeia, KHP), and 0.50 g of Glycyrrhizae Radix et Rhizoma (KP). The dry YGJ extract (1.06 g) was mixed with 0.50 g of lactose hydrate (KP) and 1.44 g of corn starch (KP), which was dried to a granular form to obtain 3.0 g of brown YGJ extract.

YGJ placebo

The YGJ placebo was formulated considering the color, odor, and taste to minimize external differences from the actual drug for participant and investigator blinding. The optimal prescription was determined by conducting disintegration tests to establish stability during storage and checking the properties of the granules. The placebo (3.0 g/sachet) does not contain the main ingredient effective for the treatment of GERD and consists of lactose hydrate (KP), corn starch (KP), cacao color, caramel color, gardenia yellow color, and ginseng flavor powder.

Both the YGJ and placebo were hermetically packaged in opaque containers and labeled identically. Patients assigned to either treatment or comparison arm will consume one sachet (3.0 g) of YGJ extract granules or a placebo three times a day before or between meals for 4 weeks.

PPI and placebo production RPZ

RPZ is a pale yellow-pink, round, enteric-coated tablet containing 10.0 mg of rabeprazole sodium, administered orally as a single tablet.

RPZ placebo

The RPZ placebo contains no active ingredients and was produced with RPZ tablet-like appearance, containing only excipients, glossing and coating agents, and purified water.

The test group will take one RPZ tablet (30 min before breakfast) and one placebo tablet (30 min before dinner) per day, whereas the control group will take one RPZ tablet orally twice daily (30 min before breakfast and dinner).

The interval between the dosing of YGJ, RPZ and their corresponding placebos was set to at least 30 min to minimize drug interactions.

Medication compliance assessment

Participants in each group will receive IP at visits 1 (week 0) and 2 (week 2). The investigator will check the number of remaining medications to ensure that the participant had taken the medication as directed (visits 2 and 3). The medication compliance rate (%) will be calculated every 2 weeks by dividing the number of medications actually taken by those that should have been taken, with a threshold of 80% for efficacy analysis.

Concomitant drug investigation

During the study period, the participants are prohibited from taking medications that may affect gastric acid secretion and the digestive system, as determined by the investigator, including those mentioned in point 8 of the exclusion criteria. Patients will be able to participate in this study after discontinuing these treatments prior to study entry, following a 2-week washout period. Additionally, patients are prohibited from receiving other treatments stated in point 16 of the exclusion criteria to relieve the symptoms of GERD during the study. At each visit during the observation period, participants will be instructed to report concomitant medications and contraindications. All concomitant medications and treatments will be recorded in the Case Report Form (CRF).

Eating habits assessment

During the study period, all participants will be monitored for changes in dietary habits using a food recorder to determine the appropriateness of eating habits concerning dietary factors and foods at risk for GERD (e.g., coffee, alcohol, and fried foods).

Outcome measuresDemographic and baseline information

Demographic information, medical history including medications and surgery, and alcohol consumption will be examined in detail. The GERD-related information will be investigated to determine the timing of symptom onset and diagnosis, upper endoscopy findings, symptom severity, and treatment history. Participants will also be categorized into five subtypes using a 32-item questionnaire of standard tools for the pattern identification of GERD based on their GERD-related symptoms and health conditions: liver-stomach disharmony, middle qi deficiency counterflow, qi depression phlegm obstructing, stomach yin insufficiency, and spleen-stomach dampness-heat patterns [35].

Primary outcome Frequency Scale for the Symptoms of GERD (FSSG)

In addition to the typical symptoms of GERD, the FSSG includes an assessment of dyspeptic symptoms, such as bloating and postprandial fullness. Participants will be required to rate how often they experience each of the 12 symptoms on a scale of 0 (never) to 4 (always), with a total of 48 points, which will be summed by dividing the symptoms into two categories: acid reflux and dysmotility [36]. The FSSG will be measured at all visits except the screening visit, and the change in the FSSG score from baseline to 4 weeks will be calculated. The improvement between the baseline and follow-up period will be compared between the groups to determine the persistence of the treatment effect. In addition, the proportion of participants with no GERD symptoms at one-week recall, referred to as a treatment responder, will be compared between the groups.

Secondary outcomes Reflux Disease Questionnaire (RDQ)

Gastrointestinal symptoms associated with GERD will be assessed for both frequency and severity of discomfort. Scores will be summed on a Likert-type scale ranging from 0 to 5 with three subscales: heartburn, regurgitation, and dyspepsia [37]. Patients will provide their completed RDQ at visit 1 (week 0), 2 (week 2), and 3 (week 4).

Reflux Symptom Score (RSS)

For extra-esophageal throat symptoms and abdominal, chest, and respiratory symptoms caused by acid reflux, the overall severity of symptoms, frequency of occurrence, and impact on daily life are summed using a Likert-type score ranging from 0 to 5 [38]. The RSS will be obtained at visits 1 (week 0) and 3 (week 4).

GERD-Health Related Quality of Life (GERD-HRQL)

The impact of GERD symptoms on quality of life, including sleep and eating habits, will be assessed using a Likert-type scale ranging from 0 to 5 [39]. The GERD-HRQL assessment will be conducted at visits 1 (week 0), 2 (week 2), and 3 (week 4).

Overall Treatment Evaluation (OTE)

The OTE indicates the patients’ impressions of their treatment, including changes in their overall life and their GERD symptoms during the treatment period. Patients will rate their OTE on a 15-point scale ranging from ‘exacerbated symptoms (-7)’ to ‘no change (0)’ or ‘no symptoms (+ 7)’ [37]. The OTE will be performed at visits 2 (week 2) and 3 (week 4) and the follow-up phone visit (week 8).

Spleen Qi Deficiency Questionnaire (SQDQ)

The SQDQ is a 5-point questionnaire that assesses 11 items, including symptoms such as dyspepsia, lethargy, and loss of appetite, to determine dysfunction in the immune and digestive systems [40]. The SQDQ will be administered before and after taking the IP [visits 1 (week 0) and 3 (week 4)], with a cut-off value of 43.18.

Damum Questionnaire (DQ)

The DQ consists of 14 items, including dyspepsia, dizziness, and foreign body sensation in the throat, to diagnose phlegm-fluid retention (Damum in Korean), a sticky and murky pathological product of the body [41]. The DQ will be administered before and after taking the IP [visits 1 (week 0) and 3 (week 4)]. Each item is rated on a 7-point scale according to severity, with higher scores indicating the presence of Damum.

Dyspepsia VAS

At all visits except the phone visit (week 8), the participants will rate the intensity (ranging from none to very severe) of their dyspepsia symptoms in the past week using a 100 mm horizontal line.

Safety outcomes

To assess safety, all patients will be monitored for clinical changes in vital signs (blood pressure, heart rate, and body temperature) at each visit. After receiving IP at visit 1 (week 0), patients will be monitored for any adverse events that occur during the study and the investigator will record their timing, severity, outcome, and causality. In the event of a serious adverse event, such as death, illness requiring hospitalization, or disability, the investigator must promptly take appropriate action based on the pre-arranged insurance process, after the PI has viewed the sealed randomization. Detailed information will be documented and reported to the IRB and the clinical research associate. Blood tests, urinalysis, and pregnancy tests (Urine HCG) will be performed at the screening visit and visit 3 (week 4): common blood count, differential count, aspartate transaminase, alanine aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, direct bilirubin, albumin, blood urea nitrogen, creatinine, total cholesterol, triglyceride, glucose, creatine kinase, sodium, potassium, chloride, magnesium, urinalysis (occult blood, bilirubin, urobilinogen, keton, protein, nitrite, glucose, pH, specific gravity, and leukocyte), and electrocardiogram.

Sample size calculation

The results of previous study were used to determine the non-inferiority margin required to calculate the sample size [42]. The upper limit of the 95% confidence interval for the mean difference in the degree of improvement of FSSG between the test and control groups after 4-week treatment was estimated to be -8.29. Assuming a significance level of 2.5%, a statistical power of 90%, and a 1:1 allocation ratio, 86 participants (43 per group) would be required to account for a dropout rate of 30%, considering the larger standard deviation of 9.8.

Statistical analysis

Statistical analyses will be performed by an independent statistician using the statistical software IBM SPSS Version 25.0 (IBM Corp.). The study will use per-protocol set (PPS) as the primary method of analysis, with full analysis set (FAS) analysis as secondary confirmation, if necessary. The PPS analysis will be applied to patients who are fully compliant with the protocol. In this study, data from patients who comply with IP (≥ 80%), assess the primary efficacy endpoint, and complete the study without major protocol violations will be included in the analysis. The FAS population will consist of data from patients who meet the inclusion criteria, have taken the IP at least once, and have at least one endpoint measurement. The safety analyses set will include all data from patients who received at least one dose of IP after randomization.

For the comparative evaluation of demographic or clinical characteristics between groups, two-sample t-tests will be performed for continuous data, and the chi-squared test or Fisher's exact test will be used for dichotomous data. If significant differences are found between the groups, one-way analysis of covariance will be conducted for continuous data, and logistic regression will be performed for dichotomous data to correct the imbalance.

The basic principle of statistical analysis for the efficacy endpoints is the comparison of data between the two groups after the 4-week treatment intervention. For the efficacy endpoint at week 4, a one-sided 97.5% confidence interval will be calculated to confirm non-inferiority (p < 0.025) by determining the difference in mean changes of the questionnaire score between the treatment and control groups. All measurements will be presented as mean ± standard deviation or as percentages (n %). Mean comparisons between groups will be conducted using a two-sample t-test as a parametric method or a Mann–Whitney test as a non-parametric method. Differences within each group between baseline and measurements after a specific period will be analyzed using either the paired t-test or the Wilcoxon signed-rank test. Repeated measures will be analyzed to compare the changes in the mean value of the same variable measured over time between the two groups. For safety assessments, the incidence of adverse and serious adverse events will be calculated and tested by group using the chi-square test or Fisher's exact test. Differences in effectiveness between subtypes, where applicable, will be determined by analysis of variance, considering participant characteristics (such as sex and age), GERD classification (including EE and NERD), previous PPI therapeutic dosage, GERD pattern identification, and other clinical characteristics.

Data collection and monitoring

To maintain the accuracy and quality of the study procedures, data monitoring will be done by HelpTrial Inc. (Seoul, Republic of Korea), a clinical research organization. Thoroughly trained clinical research associates will conduct thorough and regular monitoring to ensure patient consent, detection of adverse events, and adherence of the study in accordance with standard operating procedures.

To ensure accurate and transparent data collection, management, and quality assurance, this study will utilize the electronic data capture system to implement an electronic CRF. Access to the database will be restricted to trained and authorized investigators. Once all the data has been collected, it will be encrypted and delivered to an independent statistician.