Electro-acupuncture for Irritable Bowel Syndrome With Constipation

Electro-acupuncture for Irritable Bowel Syndrome With Constipation: a Pilot, Randomized, Double-blinded, Sham-controlled Trial

The aim of the clinical trial is to evaluate the efficacy and safety of electro-acupuncture for irritable bowel syndrome with constipation (IBS-C) patients. 60 IBS-C patients will be randomized and allocated to either the electro-acupuncture arm or the sham acupuncture arm. We hypothesize that electro-acupuncture would result in superior symptom improvement compared to sham acupuncture. In addition, biological samples (blood, urine, and stool) will be collected during the trial for future exploratory studies. These samples will be used to investigate changes in gut microbiota composition and related metabolites. These analyses aim to explore potential mechanistic links between electro-acupuncture interventions and clinical outcomes in subsequent research. Apart from the IBS-C participants, 30 healthy volunteers aged 21 to 65 years (inclusive) will be recruited to provide blood, urine, and stool samples. These samples will serve as a reference for comparative analyses with those from IBS-C patients before and after electro-acupuncture treatment. The healthy controls will not receive any interventions.

I) Study period:

14 weeks, including 2 weeks of run-in (wash-out), 6 weeks of treatment, and 6 weeks of follow-up. 15 visits will be scheduled for each participant, comprising 2 visits during recruitment and the wash-out period, 12 visits during the treatment period, and 1 visit at the end of the follow-up period.

II) Coding of data:

The trial uses patient-blind technique, which means needles for acupuncture and sham acupuncture will be of identical looking and use same package, conduct blinding according to randomization codes. The study will only be unblinded at final statistical analysis and in final report. In case of emergency code breaking, before code breaking, the investigator should well inform the principal investigator of the corresponding participating site. Investigators who break the codes need to explain the reasons and document on patients' notes. The following circumstances can be considered for an emergency breaking, including, but not limited to: (1) When a SAE happens and is considered to be relevant to experimental medication or placebo; (2) When a serious complication happens.

III) AE/SAE reporting:

All AEs that not meeting the criteria for SAEs will be captured on the case report form (CRF). The details include, but not be limited to: (1) date, (2) event description, (3) time of onset, (4) assessment of severity, (5) relationship to study intervention, and (6) time of resolution/stabilization of the event. All AEs occurring while on study will be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution or stabilization. Any medical condition that is present at the time that the participant is screened will be considered as baseline and not reported as an AE. However, if the study participant's condition deteriorates at any time during the study, it will be recorded as an AE. Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration of each episode. Regarding SAEs, the study investigator will immediately report to the principal investigator for any SAE. SAEs will be followed until satisfactory resolution or until the investigator deems the event to be chronic or the participant is stable. Other supporting documentation of the event may be requested by the Research Ethics Committee (REC) and should be provided as soon as possible. All SAE must be evaluated by the principal investigator and investigators. Once it happened, principal investigator must submit a SAE report to REC within 24 hours and follow up within 7 days. All AEs and SAEs will be reported to REC in the annual progress report and in the final study report.

IV) Compliance and dropout:

For maximizing participants' compliances, first, the investigators have a thorough consent process for all participants by explaining the details of the study schedule, potential side effects of treatment, the responsibilities the participants needed to take and together with the support and reassurance during the whole study. Second, the investigators have a careful scrutiny (2-week run-in period) to exclude ineligible and low compliance participants before randomization. Third, a special e-mail account and a direct telephone hotline equipping with this clinical trial are ways for the study team to actively communicate with participants and reply enquiries. Moreover, extra-visits will be arranged for participants to see WM doctor or TCM practitioner if participants develop adverse events before the next scheduled visit. If any patient has thoughts of withdrawing or dropping out, he/she will try to determine the reason. The investigators would try to find solution in order to keep the patient in the study.

V) Data collection and management:

Case report forms (CRFs) will be filled in by investigators. Collectable information includes patient identification and demographic data, clinical history, dietary history, personal history, family history, substance use, IBS medical history and clinical examination. Data processing will be conducted in accordance with the following protocol:

1. Verification of CRFs: Investigators need to verify CRFs before inputting.

2. Data verification needs to be conducted successively in the following two steps:

   1. Verify the consistency and logicality of data: Review contents of data range and logicality will be determined by the range of each index and the interrelation. Corresponding software formula will also be applied to assist the data input.
   2. Compare database and CRFs by manual testing. Selectively counter check 10% CRFs with participants' medical notes to check the quality of input and analyze.

3. Data inspection and closure of database: After verifying the validity of established database and statistical protocol, principal investigators will lock the data. The locked data are not allowed to change. Confirmed problems found after locking will be handled in the process of statistical analysis. All mistakes and modification should be recorded and kept properly.

Investigators should keep all trial materials, including acknowledgement of all participants, original informed consent forms with participant's signature, all CRFs and detailed record of medications distribution, which should be provided to ethics committee and drug supervision and administration department for reviewing. All files will be maintained in storage for a period of 7 years after the completion of the clinical trial. Data access during study will be restricted except investigators, ethics committee, and government authority. After the study, all the data will be deidentified and available for sharing upon reasonable request.

VI) Sample size calculation:

The study is the first sham-controlled acupuncture trial that uses the Food and Drug Administration (FDA) recommended end point for IBS-C. The sample size was determined based on the study's purpose, statistical precision, feasibility, and reported improvements in clinical symptoms (abdominal pain, bloating, feeling of incomplete defecation, stool frequency, stool shape) from previous acupuncture studies on IBS-C patients. With an alpha of 0.05, a power of 0.8, a 20% dropout rate, and the potential for missing data, a total sample size of 60 patients (30 in experimental arm and 30 in control arm) is required.

VII) Statistical analysis:

All efficacy and safety analyses will be conducted based on intention-to-treat (ITT) principle. Missing values will be imputed by the last-observation-carried-forward method. The statistical analysis will be performed using the Stata software. The statistical significance will be defined as two-sided P-value of <0.05. Baseline characteristics will be reported as mean (SD). Baseline differences between the groups will be evaluated with the application of Student's t-test for normally distributed continuous variables and non-parametric Mann-Whitney U test for non-normally distributed variables. For categorical variables, chi-squared test or Fisher's exact test will be applied. Comparisons between groups will be conducted by using unpaired t-test for normally distributed data and Mann-Whitney test for non-normally distributed data. Within group differences will be evaluated with paired t-test for normally distributed data and Wilcoxon signed-rank test for non-normally distributed data.

Inclusion Criteria:

1. Fulfilment of the Rome IV criteria for IBS-C;
2. Age of 21 to 65 years (inclusive);
3. Weekly average of worst daily abdominal pain score of ≥3 (0-10 scale) for at least 12 weeks before the first visit and during screening period;
4. <3 complete spontaneous bowel movements (CSBMs) per week for at least 12 weeks before the first visit and during screening period;
5. Written informed consent.

Exclusion Criteria:

1. Pregnancy or breast-feeding;
2. Medical history of inflammatory bowel diseases, carbohydrate malabsorption, hormonal disorder, known allergies to food additives, and/or any other serious diseases;
3. History of gastrointestinal tract segment removal or bariatric surgery for obesity;
4. Appendectomy or cholecystectomy within the past 2 months, or other abdominal surgeries within the past 6 months prior to trial enrollment;
5. Unstable medical conditions that could be associated with abdominal pain or discomfort and could potentially influence the assessments in this trial (e.g., chronic kidney disease, endometriosis, lactose intolerance);
6. Diagnosed with primary severe mental illness;
7. Patients who have received acupuncture treatment in last three months, or took concomitant medication with affect gastrointestinal motility or visceral sensation, such as antidiarrheal agent, antidepressant, narcotic analgesic, and anticholinergic;
8. Alcoholism or drug abuse in past 1 year;
9. Having needle phobia or allergy to acupuncture needle materials;
10. Antibiotics and probiotics/prebiotics usage in the previous month;
11. Participating in other clinical studies.