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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
60
The acupuncture needles and related equipment will have already received approval for routine Traditional Chinese Medicine (TCM) clinical practice in Singapore.
Nanyang Technological University, School of Biological Sciences
Singapore, Singapore, Singapore
Responders have a decrease in the weekly average of worst abdominal pain scores of ≥30% compared with baseline and a weekly increase of ≥1 CSBM
Proportion of patients with a decrease in the weekly average of worst abdominal pain scores of ≥30% and a weekly increase of ≥1 CSBM as compared with the baseline.
Time frame: Baseline (week 2), after treatment period (week 8), end of follow-up (week 14)
Proportion of patients with an improvement of ≥30% in abdominal pain scores
Proportion of patients with an improvement of ≥30% in abdominal pain scores from baseline.
Time frame: Baseline, week 8, week 14
Proportion of patients with an average increase of 1 or more spontaneous, complete bowel movements per week
Proportion of patients with an average increase of 1 or more spontaneous, complete bowel movements per week as compared with the baseline.
Time frame: Baseline, week 8, week 14
Average number of spontaneous bowel movements, complete spontaneous bowel movements per week
Average number of spontaneous bowel movements, complete spontaneous bowel movements per week as compared with the baseline.
Time frame: Baseline, week 8, week 14
Percentage of bowel movements with normal consistency
Percentage of bowel movements with normal consistency as compared with the baseline.
Time frame: Baseline, week 8, week 14
Percentage of bowel movements with severe or very severe straining during defecation
Percentage of bowel movements with severe or very severe straining during defecation as compared with the baseline.
Time frame: Baseline, week 8, week 14
Median time to the first spontaneous bowel movements, complete spontaneous bowel movements after electro-acupuncture
Median time to the first spontaneous bowel movements, complete spontaneous bowel movements after intake of the first session of electro-acupuncture.
Time frame: From first session of electro-acupuncture up to the end of follow-up, approximately 12 weeks
Average number of bisacodyl tablets or enemas used per week
Average number of bisacodyl tablets or enemas used per week as compared with the baseline number.
Time frame: Baseline, week 8, week 14
Global assessment of efficacy of treatment with Likert scale
Global assessment of efficacy of treatment with Likert scale (range: 1-5) at weeks 5, 8, and 14.
Time frame: Week 5, week 8, week 14
Change from baseline in the IBS-C symtoms using IBS Symptom Severity Scale (IBS-SSS)
IBS-SSS (range: 0-500) is a questionnaire used to assess the severity of symptoms in individuals with Irritable Bowel Syndrome (IBS). It typically includes questions related to abdominal pain, bloating, stool consistency, and the impact of IBS symptoms on daily life. Higher scores on this scale indicate more severe symptoms.
Time frame: Baseline, week 5, week 8, week 14
Change from baseline in the IBS-C symtoms using IBS Quality of Life (IBS-QOL)
IBS-QOL (range: 0-100) is a measure designed to assess the impact of IBS on a person's quality of life. It includes questions related to how IBS symptoms affect various aspects of daily functioning, such as physical health, emotional well-being, and social activities. Lower scores on this scale indicate a lower quality of life due to IBS.
Time frame: Baseline, week 5, week 8, week 14
Change from baseline in the IBS-C symtoms using Patient Assessment of Constipation Symptoms (PAC-SYM)
PAC-SYM (range for each item: 0-4) is a questionnaire used to evaluate the severity and frequency of constipation-related symptoms in patients. It typically covers symptoms like abdominal discomfort, straining during bowel movements, and incomplete evacuation. Higher scores suggest more severe constipation symptoms.
Time frame: Baseline, week 5, week 8, week 14
Change from baseline in the IBS-C symtoms using Constipation Quality of Life (PAC-QOL)
PAC-QOL (range for each item: 0-4) is a measure that assesses the impact of constipation on a person's quality of life. It includes questions about how constipation symptoms affect daily activities, emotional well-being, and overall satisfaction with life. Lower scores indicate a poorer quality of life related to constipation.
Time frame: Baseline, week 5, week 8, week 14
Change from baseline in the IBS-C symtoms using Patient Health Questionnaire-15 (PHQ-15)
PHQ-15 (range: 0-30) is a self-report questionnaire that assesses somatic symptom severity in individuals. It includes questions related to various physical symptoms, such as headaches, back pain, and stomach discomfort. It is often used as a screening tool to assess somatic symptom burden, and higher scores indicate a greater presence of somatic symptoms.
Time frame: Baseline, week 5, week 8, week 14
Change from baseline in the psychological conditions using Hamilton Depression Scale (HAMD)
HAMD (range: 0-52 for HAMD-17) is a clinician-administered questionnaire used to assess the severity of depressive symptoms in individuals with depression. It includes items related to mood, feelings of guilt, sleep disturbances, and physical symptoms. Higher scores indicate more severe depression.
Time frame: Baseline, week 8, week 14
Change from baseline in the psychological conditions using Self-rating Depression Scale (SDS)
SDS (range: 20-80) is a self-report questionnaire designed to assess the presence and severity of depressive symptoms from the perspective of the individual. It includes questions about mood, feelings of sadness, and physical symptoms associated with depression. Higher scores suggest greater self-reported depression.
Time frame: Baseline, week 8, week 14
Change from baseline in the psychological conditions using Patient Health Questionnaire (PHQ-9)
PHQ-9 (range: 0-27) is a widely used self-report tool for assessing depression. It consists of nine questions that correspond to the criteria for major depressive disorder. Individuals rate the frequency of their symptoms over the past two weeks. Higher scores indicate more severe depression.
Time frame: Baseline, week 8, week 14
Change from baseline in the psychological conditions using General Anxiety Disorder (GAD-7)
GAD-7 (range: 0-21) is a self-report questionnaire used to assess the presence and severity of generalized anxiety disorder symptoms. It includes questions related to excessive worry, restlessness, and physical symptoms associated with anxiety. Higher scores indicate greater anxiety.
Time frame: Baseline, week 8, week 14
Change from baseline in the psychological conditions using Hospital Anxiety and Depression Scale (HADS)
HADS (range for each subscale: 0-21) is a self-report questionnaire that assesses both anxiety and depression symptoms in individuals, often used in healthcare settings. It includes items related to mood, anxiety, and physical symptoms. It provides separate scores for anxiety and depression.
Time frame: Baseline, week 8, week 14
Change from baseline in the psychological conditions using Visceral Sensitivity Index (VSI)
VSI (range: 0-75) is a self-report questionnaire used to assess the degree of visceral hypersensitivity in individuals with conditions like irritable bowel syndrome. It includes questions about gastrointestinal symptoms and discomfort, helping to measure sensitivity to visceral sensations.
Time frame: Baseline, week 8, week 14
Change from baseline in the psychological conditions using Perceived Stress Scale (PSS)
PSS (range: 0-40) is a self-report questionnaire that measures an individual's perception of stress in their life. It includes questions about how often one perceives situations as stressful and their ability to cope with stress. Higher scores indicate greater perceived stress.
Time frame: Baseline, week 8, week 14
Patient expectancy and trust in treatment with Likert scale
Assessment of patient expectancy and trust in treatment with Likert scale (range: 1-5) at weeks 2, 8, and 14. Higher scores suggest greater confidence, satisfaction, trust, and positive perception of the treatment.
Time frame: Week 2, week8, week 14
Recruitment rate
Number of eligible participants who consent and are enrolled in the study divided by the total number of participants screened for eligibility, reported as a percentage.
Time frame: Baseline
Retention rate
Number of enrolled participants who complete the final study visit divided by the total number of enrolled participants, reported as a percentage.
Time frame: Baseline to week 14
Adherence to treatment protocols
Proportion of prescribed treatments completed per participant, calculated as the number of treatment sessions received divided by the number of sessions planned, reported as a percentage.
Time frame: Baseline to week 14
Completeness and quality of symptom diaries and questionnaire responses
Percentage of symptom diaries and questionnaires that are fully completed with no missing or invalid entries, calculated as the number of complete and valid responses divided by the total number of expected responses.
Time frame: Baseline, week 5, week 8, week 14
Number and type of adverse events documented
Total number and types of adverse events recorded throughout the study, categorized by severity and relatedness to the intervention.
Time frame: Baseline to week 14
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