Study design
This clinical study is a multicentre, single-blind, double-dummy, randomised, active-controlled trial that compares the efficacy and safety of acupuncture versus itopride in improving upper abdominal discomfort in patients with PDS. The study protocol has been registered with the Chinese Clinical Trial Registry (ChiCTR2300068001). It adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 1) [19] as well as the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) checklist (Additional file 2) [20]. The study flowchart is shown in Figure 1.
Study setting and recruitment
This clinical trial will be conducted collaboratively by an academic center and three clinical institutions. Researchers from the Hunan University of Chinese Medicine will form an academic center group responsible for experimental design, data analysis and results dissemination. Recruitment, treatment and data collection will occur at the First Affiliated Hospital of Hunan University of Traditional Chinese Medicine, the Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, and Changsha Hospital of Traditional Chinese Medicine. Recruitment is scheduled to take place at inpatient and outpatient departments in three medical centers, and start in September 2024, with the follow-up assessments of all participants completed by December 2026. Recruitment information will be disseminated through various means such as paper flyers, posters, and social platform like Wechat. Participants interested in this trial will be informed about the purpose and process of the study as well as potential risks and benefits. If the patient decides to participate after understanding this information, they will undergo a clinical screening evaluation conducted by registered TCM practitioners with a minimum of 5 years of clinical experience. Eligible patients will sign an informed consent form, receive baseline assessment, and be randomly assigned.
Eligibility criteria
Inclusion criteria:
The study will involve individuals who meet the following criteria:
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Aged 18-60 years and long-term residents of Changsha.
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Diagnosed with FD-PDS according to the Rome IV criteria.
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No structural abnormalities were detected through upper gastrointestinal endoscopy surveillance.
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Non-refractory FD.
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Patients who are helicobacter pylori-negative or have persistent symptoms after helicobacter pylori eradication for one month.
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Good compliance.
Exclusion criteria:
The following individuals will be excluded from the study:
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Use drugs, such as prokinetics, acid suppression, mucosal protectants, or other FD-related agents, within 2 weeks.
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Do not tolerate acupuncture.
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Receive acupuncture treatment within 2 weeks.
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Have gastrointestinal diseases other than PDS.
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Pregnant or lactating women and those attempting conception.
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Patients who are participating in other clinical trials.
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Diagnosed with malignancy or other serious conditions, such as severe heart, liver, lung, or kidney dysfunction, severe autoimmune disease, or endocrine diseases.
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Unable to effectively communicate for any reason, such as severe mental illness, cognitive impairment, or impaired language comprehension.
Dropout exclusion criteria:
Patients who discontinue treatment due to any of the following reasons (including but not limited to) will be a dropout case:
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Voluntary withdrawal by participants for any personal reasons.
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The patient’s symptoms don’t improve and gradually worsened after treatment.
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Patients are unreachable due to relocated or changed contact information.
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Patients undergo changes in health status that need a timely manner.
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Patients experience intolerable side effects and are unwilling to continue treatment.
Exit/termination criteria:
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Patients do not meet the inclusion criteria and are enrolled mistakenly.
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Patients receive other or additional FD treatments during the study period.
Strategies to improve adherence to interventions
In order to mitigate the impact of dropout rates on research quality, we will enhance participant compliance through several strategies:
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Researchers will regularly contact with participants via WeChat or phone calls to understand their condition and remind them about the schedule of their next visit.
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We will schedule treatment and evaluation sessions at convenient times to minimize disrupting participants' work and daily lives.
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The evaluation process will be simplified to enhance patient engagement.
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Participants will be reimbursed for treatment expenses and transportation costs to and from the hospital.
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Dedicated staff will be available to address any study-related inquiries raised by participants.
Randomization, allocation, and concealment
A research assistant at each clinical center will conduct random assignments independently from other study activities. Eligible patients will be randomly assigned into the acupuncture plus placebo group, itopride plus sham acupuncture group, and sham acupuncture plus placebo group in a 1:1:1 ratio. A professional statistician will utilize SAS software (v9.3) to produce a list of random numbers stratified by clinical institution using block sizes of 6 or 9. The randomization process will be carried out through an online central randomization system. The randomization number and group assignment provided to each patient by the randomization system will be unique and unchangeable, ensuring fairness in treatment allocation.
Blinding
This study will maintain blinding among patients, observers, and statisticians. However, acupuncturists will not be blinded due to the nature of the acupuncture procedure. Patients will be informed that the study involves two types of acupuncture treatment and two types of drug, which theoretically can improve PDS symptoms. Regardless of their assigned group, patients will receive a combination treatment comprising one type of acupuncture treatment and one type of drug. Sham acupuncture will be performed by superficial needling on non-acupoints to mimic the verum acupuncture treatment successfully. Itopride placebo tablets will be indistinguishable from verum itopride tablets in taste and appearance. Each patient will undergo treatment in separate rooms to prevent communication between them. Acupuncturists, who will not be blinded, must refrain from discussing assignment information with participants. In the case the trial goes well, the research center will perform unblinding once the statistical analysis is complete. However, if any emergencies arise, such as life-threatening adverse events (AEs), the acupuncturists will perform urgent unblinding. The monitoring team and ethics committee will then analyze the relationship between patient intervention strategies and AEs.
Intervention
This trial consists of a screening phase (1 week), a treatment phase (4 weeks), and a post-treatment follow-up phase (12 weeks). During the treatment period, participants in the acupuncture plus placebo group will receive 12 sessions of verum acupuncture treatment and itopride placebo tablets for 20 days. Patients in the itopride plus sham acupuncture group will take itopride tablets for 20 days and receive 12 sessions of sham acupuncture treatment. Patients in the placebo plus sham acupuncture group will take itopride placebo tablets for 20 days and receive 12 sessions of sham acupuncture treatment. The detailed treatment procedures is as follows:
Verum or sham acupuncture
Participants in the acupuncture plus itopride group will receive verum acupuncture at 5 specific acupoints: SiBai (ST2), Liangmen (ST21), Zusanli (ST36), Neiguan (PC6), and Gongsun (SP4). This acupoint protocol is based on our prior clinical research on acupuncture for FD. The location of all acupoints is illustrated in Figure 2 and detailed in Table 1, following the Nomenclature and location of acupuncture points per the Chinese National Standard (GB/T22163-2008). Patients will be supine and maintain mental relaxation as per practitioner instruction. Acupuncturists will sterilize both the needle (Huatuo brand, Suzhou Medical Supplies Factory, China) and the skin at the acupoint locations before insertion. The depth of needle penetration will vary depending on the acupoints, refer to Table 1 for details. After the needles penetrate the skin, acupuncturists will manipulated them with lifting, inserting, or twisting movements until patients feel the Deqi sensation. The needles will be stay in place for 30 minutes, during which they will be manually stimulated by rotation every 10 minutes to elicit the needle sensation.
In the itopride plus sham acupuncture group and sham acupuncture plus placebo group, the patient’s position and disinfection methods will be the same as those in the acupuncture plus placebo group. Participants will receive a shallow puncture at non-acupoints. The selection of sham acupoints was based on published literature related to acupuncture for FD [11,21], and these points are illustrated in Figure 2 and detailed in Table 1. Needles will be inserted perpendicularly to a depth of 0.3~0.5 cm at sham acupoints without any manipulation to avoid the de-qi sensation.
The treatment frequency of verum acupuncture or sham acupuncture will be 3 times a week for 4 consecutive weeks, a total of 12 sessions.
Itopride or placebo
Patients assigned to the itopride plus sham acupuncture group will take 50 mg of itopride orally 3 times a day, 5 days per week, for 4 weeks. Participants in the acupuncture plus placebo group and sham acupuncture plus placebo group will receive an itopride placebo that is identical in taste and appearance to actual itopride tablet; they will follow the same frequency and dosage as the itopride plus sham acupuncture group. All patients are instructed to maintain a medication diary to document their usage and return unused medication.
Outcome
Primary outcomes in this study include the proportion of responders (PR) and the elimination rate of the main symptom. The secondary outcomes include changes in symptom score, QOL, and mood during the treatment and follow-up, as well as the participants’ expectancy for acupuncture before treatment. Table 2 display a summary of all measurements. Participants will keep an FD diary to record symptom severity, frequency, QOL, drug usage, and adverse events. Participants will complete the self-reported questionnaires based on the diary. Participants can seek assistance from research staff for any difficulties. The research staff should provide an unbiased explanation when responding to patient inquiries and should avoid influencing their judgment. Follow-up for all participants can be completed via social media (WeChat) or phone.
Primary outcome
The proportion of responders (PR): Positive responders are patients who had adequate relief of stomach discomfort (22). After receiving the weekly treatment, participants will be asked to measure changes in their symptom relief over the past 7 days using a 7-point Likert scale. This scale includes options of “extremely aggravated,” “aggravated,” “slightly aggravated,” “not changed,” “slightly improved,” “improved,” or “extremely improved,” corresponding to 0 to 6 points. Participants reporting a relief score of 5 or 6 points will be classified as positive responders. PR will be measured at week 2, week 3, week 4, week 5, week 9, week 13, and week 17.
The elimination rate (ER): ER refers to the proportion of patients whose main symptoms have disappeared. According to Rome Ⅳ criteria, we define postprandial fullness and bloating as the main symptoms. Included patients should have at least one of these symptoms. Using a 7-point Likert scale, the main symptoms are considered to have disappeared if the rating drops to 0 after treatment. ER will be measured at week 2, week 3, week 4, week 5, week 9, week 13, and week 17.
Secondary outcome
The Chinese version of the Nepean Dyspepsia Symptom Index (NDSI) The NDSI is a validated, dyspepsia-specific questionnaire used to quantify the severity of 15 upper gastrointestinal symptoms in patients with FD over the prior 14 days [22]. Each symptom is evaluated on three dimensions, including frequency, scored on a 5-point Likert scale from absence (0 points) to continuous symptoms (4 points); intensity, scored on a 6-point Likert scale from absence (0 points) to very severe symptoms (5 points); and level of interference with activities of daily living, scored on a 5-point Likert scale from no interference (0 points) to severe interference (4 points). A higher total score on the NDSI indicates more severe dyspeptic symptoms. During the study, the NDSI scores will be measured at week 1, week 5, week 9, week 13, and week 17.
The Chinese version of Short Form-Nepean Dyspepsia Life Quality Index (SF-NDLQI) TheSF-NDLQI instrument is an FD-specific 10-item questionnaire used to evaluate the impact of upper gastrointestinal symptoms on QOL across 5 domains: tension, interference with daily activities, eating/drinking, knowledge/control, and work/study [23]. Each domain has two items, and each item is scored from 1 to 5, with lower scores indicating higher quality of life. In this study, the SF-NDLQI will be administered at week 1, week 5, week 9, week 13, and week 17.
The Chinese version of the Hospital Anxiety and Depression Scale (HADS) The HADS, a 14-item self-report questionnaire, will be utilized to assess the anxiety and depressive symptoms of patients. The HADS contains 7 items for anxiety (HADS-A) and 7 for depression (HADS-D), each scored from 0 to 3 with a total subscale score range of 0 to 21 [24]. Based on recommended cutoffs, anxiety and depression severity will be categorized as normal (0-7), mild (8-10), moderate (11-14), or severe (15-21) [25]. The HADS has demonstrated good reliability and validity in screening for anxiety and depression in general medical patients [26]. HADS will be measured at week 1, week 5, week 9, week 13, and week 17.
Acupuncture expectation The Expectation for Treatment Scale (ETS), developed by Jürgen Barth and his colleagues, will be utilized to evaluate patients’ acupuncture expectations before treatment [27]. This scale comprises 5 items, such as “I anticipate that the treatment (acupuncture) will alleviate my complaints.” Each item is rated on a scale from 1 to 4, representing partial disagreement, partial agreement, agreement, and definite agreement, respectively. The total score ranges from 5 to 20. A higher total scale score indicates a greater expectation of achieving positive clinical outcomes. The ETS will be measured at week 1.
Safety
AEs are pivotal in evaluating the safety of treatments. All AEs, whether linked to the study treatment (acupuncture or itopride), will be recorded in the case report form (CRF). Each AE will be comprehensively described, including start/stop dates and times, severity, relationship to treatment, actions taken, and the necessity for treatment discontinuation. Researchers will closely monitor all AEs until they are resolved. In the case of serious AEs (e.g., events leading to disability, impaired ability to work, or life-threatening situations), immediate reporting will be made to both the research center and ethics committee. If any severe AEs associated with acupuncture arise, the ethics committee has the authority to consider suspending the trial.
Data collection and management
Clinical observers will complete a CRF for each participant to record all relevant clinical information. A dedicated data manager will then convert the paper-based CRF data to electronic format, with a secondary check by another research assistant to ensure data accuracy. Participants’ personal information will be anonymized and replaced with code for confidentiality during data collection. All data will be kept confidential, with electronic data secured on a password-protected server and paper data stored in locked cabinets. Access to clinical data will be restricted to authorized researchers only. Raw data will be retained for 5 years. The clinical inspectors/monitors will supervise the data collection and control for data completeness and quality.
Quality control
Before the study begins, the research center will provide standardized training sessions for the entire research team to ensure they follow the study protocol and become familiar with the administration process. Moreover, researchers will receive printed brochures detailing the trial procedures. Clinical researchers are encouraged to contact the research center for assistance if any technical or other issues arise at the clinical site. The research center should promptly provide practical guidance to address these issues. Registered acupuncturists with a minimum of five years of experience will perform the acupuncture treatment. These acupuncturists will undergo training and testing before the trial to ensure consistency in their acupuncture operation. A two-level quality inspection system will be established to ensure the implementation and quality of program. Inspectors at each center will conduct monthly quality examinations, while an independent monitoring team will carry out quality monitoring every three months. After each quality inspection, quality control reports should be submitted to the research center. Furthermore, any modifications to the research protocol must receive approval from the ethics committee.
Sample size calculation
The sample size for this study was determined based on the responder proportion at the end of a 4-week treatment, with 70.69% for the acupuncture treatment and 55.46% for the itopride treatment, as reported in a previous study [21]. The sample size calculation was performed using PASS 15.0 software, with a 1:1 ratio between the acupuncture plus placebo group and itopride plus sham acupuncture group. A statistical power of 80% (β=0.2), a one-sided alpha of 0.025 (α=0.025), and a non-inferiority margin of -10% (Δ=-10%) were considered in the calculation. The resulting sample size was 57 for each group. Accounting for a 15% dropout rate, each group needed 67 cases, resulting in a total enrollment of 201 cases across three groups.
Statistical analysis
Efficacy analyses will be performed on all random patients based on intention-to-treat principle. Missing data on the primary outcome will be imputed using the multiple imputation method under the missing at-random assumption. If there are significant differences in baseline variables between the two groups, those unbalanced variables will be included as covariates in the analysis of the primary outcome.
We will establish confidence intervals at a 95% level, with a significance level set at 0.05. Continuous data will be reported as mean ± standard deviation (SD) if it is normally distributed. Otherwise, it will be reported as median (interquartile range). For longitudinal continuous data, we will compare groups using repeated-measures analysis of variance (ANOVA), taking into account both group and time-group interactions. Student’s t-test or Wilcoxon rank-sum test will be used for other continuous data. For categorical data, Χ2 test or Fisher’s exact test will be applied as appropriate. The strength of linear relationships between variables will be evaluated using linear correlation analysis, and sensitivity analysis will be performed if required. The occurrence of AEs between groups will be summarized using descriptive analysis.
Dissemination Policy
We intend to publish the final trial results in medical journals related to functional gastrointestinal disorder or complementary and alternative medicine (CAM) within 2 years of completing the final data collection.