Effect of Transcranial Magnetic Stimulation vs Sham Stimulation Combined With Pinaverium Bromide vs Bifidobacteria in Diarrhea-Predominant Irritable Bowel Syndrome: A 2×2 Factorial Randomized Clinical Trial
Phase: NA
Conditions: IBS (Irritable Bowel Syndrome)
Sponsor: Rui Li

The First Affiliated Hospital of Soochow University
Form-MB-7-V4.0，2024.12.31
Study Protocol
(Version number: 2.0 Version date: 2025.08.21)
Project Title: Effect of Transcranial Magnetic Stimulation vs Sham Stimulation
Combined With Pinaverium Bromide vs Bifidobacteria in Diarrhea-Predominant
Irritable Bowel Syndrome: A 2×2 Factorial Randomized Clinical Trial
Sponsor: The First Affiliated Hospital of Soochow University
Responsible Department: Gastroenterology Department
Principal Investigator: Rui Li
Participating Centers: Xiangcheng People's Hospital of Suzhou, The People's
Hospital of Suzhou New District

The First Affiliated Hospital of Soochow University
Investigator Statement and Protocol Signature Page
As the principal investigator of this research project, I hereby commit to
adhering to the ethical principles outlined in the National Health Commission's
"Ethical Review Measures for Biomedical Research Involving Humans" (2016), the
WMA's "Declaration of Helsinki" (2013), the CIOMS's "International Ethical
Guidelines for Biomedical Research Involving Human Subjects" (2002), and Good
Clinical Practice (GCP). Under the guidance of the Quality Management Standards
for Drug Clinical Trials, I will implement the study protocol approved by the Ethics
Committee and conduct the research in strict accordance with the requirements of this
protocol, ensuring the scientific validity of the study and protecting the health and
rights of the subjects.
Name: Rui Li
Signature:
Date:2025.07.01

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Protocol Synopsis
Study objective
(1) To evaluate the alleviating effect of repetitive transcranial
magnetic stimulation (rTMS) on chronic visceral pain in patients
with diarrhea-predominant irritable bowel syndrome (IBS-D); (2) To
assess
the
interventional
effect
of
pinaverium
bromide
and
bifidobacterium used alone on chronic visceral pain in IBS-D; (3)
To analyze potential interactions between the two intervention
measures.
Sample size
140
Study population
Patients with diarrhea-predominant irritable bowel syndrome
Study design
Randomized, controlled factorial design study
Inclusion criteria
(1) Age range 18-75 years (either sex)
(2) Fulfilling the Rome IV criteria for irritable bowel
syndrome diagnosis
(3) Bristol stool type 6-7 in >25% and type 1-2 in <25% of
bowel movements
(4) Patients experienced Bristol stool type 6 or 7 on ≥4 days
with mean abdominal pain score ≥3 during the initial
2-week period
Exclusion criteria
(1)
Documented
organic
gastrointestinal
pathology;
endocrinologic
or
metabolic
diseases
with
known
gastrointestinal motility effects including diabetes mellitus
and
hyperthyroidism;
previous
surgical
interventions
involving abdominal cavity intestinal tract or anal region
(2) current use of any medication with documented effects
on
gastrointestinal
motility
or
secretory
function;
administration of concurrent therapies or pharmacologic
agents capable of confounding treatment efficacy or safety
evaluations
(3) pregnancy lactation or postpartum status within 12

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months
(4) noncompliance with randomized treatment allocation or
demonstrated poor adherence tendencies
Intervention
(1)IBS patients receiving rTMS stimulation + pinaverium
bromide treatment
rTMS stimulation: 1 Hz, 80% MT, 20 min/d, once daily for
2 weeks;
Pinaverium bromide: Oral, 3 times daily, 1 tablet/time, for 2
weeks;
(2)IBS
patients
receiving
rTMS
stimulation
+
bifidobacterium treatment
rTMS stimulation: 1 Hz, 80% MT, 20 min/d, once daily for
2 weeks;
Bifidobacterium: Oral, 2 times daily, 4 capsules/time, for 2
weeks;
(3)IBS
patients
receiving
sham
rTMS
+ pinaverium
bromide treatment
Sham rTMS treatment: 0 Hz, 0% MT, 20 min/d, once daily
for 2 weeks;
Pinaverium bromide: Oral, 3 times daily, 1 tablet/time, for 2
weeks;
(4)IBS patients receiving sham rTMS + bifidobacterium
treatment
Sham rTMS stimulation: 0 Hz, 0% MT, 20 min/d, once
daily for 2 weeks;
Bifidobacterium: Oral, 2 times daily, 4 capsules/time, for 2
weeks;
Primary endpoint
The primary outcome measure is the proportion of patients
achieving a composite response at the end of treatment

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(Week 2), defined as: a reduction of ≥30% from baseline
in the average daily worst abdominal pain score, and a
reduction of ≥50% in the number of days with at least one
stool consistency meeting BSFS type 6 or 7 criteria during
Week 2. Abdominal pain intensity is assessed using an
11-point NRS scale (0-10) for the last 24 hours daily. Stool
consistency is recorded daily by the patient selecting the
most representative category according to the BSFS.
Secondary endpoints
1) Anorectal
manometry:
Record
the
subject's
initial
sensation threshold, constant urge sensation threshold, and
maximum tolerable volume at baseline (before treatment)
and after the end of treatment.
2) IBS Symptom Severity Score (IBS-SSS): Evaluated at 1
week, 2 weeks, and 4 weeks after treatment.
3) IBS Quality of Life (IBS-QoL) score: Evaluated at 1
week, 2 weeks, and 4 weeks after treatment.
Study timeline
2025.07.1-2026.03.30:
Recruit
20-25
patients
with
diarrhea-predominant
IBS
meeting
Rome
IV
criteria
monthly
through
multiple
centers,
using
standardized
screening
procedures
(including
symptom
assessment,
exclusion checks, and baseline tests), aiming to complete
randomization of 140 cases within 12 months.
Statistical analysis
Use Shapiro-Wilk test to assess normality. Parametric t-test,
Wilcoxon rank-sum test, or Kruskal-Wallis test will be used
to evaluate continuous data between groups as appropriate.

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1.Background
Irritable bowel syndrome (IBS) is a clinically common functional gastrointestinal disorder,
affecting 10%-25% of the world's population. The prevalence of IBS in China ranges from 5% to
11%1. Among patients visiting the gastroenterology specialty outpatient clinic of our hospital, IBS
accounts for more than one-third of cases, with diarrhea-predominant IBS (IBS-D) being the most
common subtype. Current symptomatic treatments in both Western and traditional Chinese
medicine can temporarily alleviate symptoms of intestinal dysmotility. However, these therapies
may cause varying degrees of side effects and lack personalized treatment strategies. In Western
countries, over 50% of patients turn to complementary and alternative therapies due to insufficient
or unstable symptom relief following pharmacological treatment2.
A substantial body of literature reports that Transcranial Magnetic Stimulation (TMS) can
alleviate chronic visceral hypersensitivity. The specific mechanisms include TMS's ability to
modulate
cortical
excitability,
improve
cerebral
blood
flow
and
metabolism,
regulate
neurotransmitters and gene expression, as well as induce neural plasticity changes3. Our
preliminary basic research identified the claustrum–anterior cingulate cortex neural circuit as a
unique pathway regulating chronic visceral hypersensitivity in IBS animal models. Translating this
finding to clinical applications, TMS-based modulation of this circuit has been shown to alleviate
chronic visceral hypersensitivity in IBS patients4. Building on these initial results, the current
study aims to further expand the sample size and conduct a multicenter randomized controlled trial
to validate the long-term efficacy and safety of rTMS in IBS patients with chronic visceral pain,
thereby providing higher-level evidence for its clinical application. As a non-invasive stimulation
technique with a favorable safety profile, TMS demonstrates significant therapeutic advantages in
clinical practice5. Therefore, through this study, we aim to further investigate the clinical efficacy
of TMS in treating chronic visceral pain associated with irritable bowel syndrome.
2. Study Objectives
2.1 Primary Objectives
(1) To evaluate the alleviating effect of repetitive transcranial magnetic stimulation (rTMS) on
chronic visceral pain in patients with diarrhea-predominant irritable bowel syndrome (IBS-D); (2)
To assess the interventional effect of pinaverium bromide and bifidobacterium used alone on

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chronic visceral pain in IBS-D; (3) To analyze potential interactions between the two intervention
measures.
3. Rationale
3.1 Preclinical Animal Experiments and Literature Basis
The mechanisms underlying chronic visceral pain in IBS are complex. The ascending transmission
of nociceptive signals primarily involves peripheral noxious information being transmitted via
primary sensory neurons to the dorsal horn of the spinal cord, where it is integrated and relayed
further to the brain. Current mechanistic research on chronic visceral pain in IBS primarily
focuses on the peripheral primary sensory neurons and central brain levels6. Studies on the central
sensitization mechanism of visceral pain include alterations in neuronal excitability in pain-related
brain regions, changes in synaptic transmission, and abnormalities in neural circuit function. Our
previous collaborative research with Professor Xu Guangyin’s team at the Institute of
Neuroscience, Soochow University, demonstrated that adverse neonatal stimuli (such as maternal
deprivation) lead to increased neuronal excitability in the insular cortex and enhanced function of
the claustrum–anterior cingulate cortex (ACC) neural circuit, thereby inducing chronic visceral
pain7. These findings suggest that the central nervous system plays a critical role in the
pathophysiology of chronic visceral pain in IBS. In the first part of our foundational study, using
an animal model simulating chronic visceral pain in IBS, we found that the glutamatergic neural
circuit between the ACC and medial prefrontal cortex (mPFC) is involved in the development and
persistence of chronic visceral pain, indicating that this circuit may be a key mechanism regulating
chronic visceral pain in IBS. These results not only reveal the neural circuit mechanisms
underlying central sensitization in chronic visceral pain but also provide new evidence for the
regulatory role of the central nervous system in the pathophysiology of IBS. Based on this
research, the critical role of the central nervous system in IBS-related chronic visceral pain has
become increasingly clear, providing a important theoretical foundation for developing treatments
targeting the central nervous system.
However, current treatment strategies for chronic visceral pain in IBS predominantly focus on
peripheral interventions, such as pharmacological, psychological, and dietary modifications.

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Although these approaches can provide temporary symptomatic relief, they are limited by unstable
efficacy and significant side effects8. Therefore, there is an urgent need to explore treatments that
target the central nervous system, offering holistic regulation, greater safety and efficacy, and
fewer side effects. Central neuromodulation, as an emerging therapeutic strategy, holds promise
for breakthroughs in treating chronic visceral pain in IBS by directly modulating pain-related
neural circuits and brain functions. In particular, the rapid advancement of neuromodulation
technologies in recent years has attracted widespread attention in the field of chronic pain
management. Among these, repetitive transcranial magnetic stimulation (rTMS) has become a
research focus due to its non-invasive, painless, and safe profile9. rTMS delivers repeated
magnetic stimuli via an electromagnetic coil placed on the head, transferring energy to brain tissue
to generate electric currents that modulate neuronal excitability and cerebral metabolism, thereby
achieving therapeutic effects. Since its introduction, rTMS has been widely used to treat
neurological and psychiatric disorders. The 2014 rTMS treatment guidelines indicate10 that rTMS
can be used to treat various conditions, including pathological pain, movement disorders,
disorders of consciousness, tinnitus, depression, and anxiety disorders. Previous studies have
shown that rTMS can directly excite the thalamus via corticothalamic projections, inhibiting the
transmission of sensory information through the spinothalamic tract, thereby alleviating
abdominal pain in patients with chronic pancreatitis11. However, research on whether rTMS can
alleviate chronic visceral pain in IBS patients remains limited12,13, and the specific mechanisms of
rTMS intervention in IBS-related chronic visceral pain are not yet fully understood. Based on our
previous findings, the ACC-mPFC glutamatergic neural circuit may play a key role in the
development and persistence of chronic visceral pain in IBS14-17, leading us to a new research
question: Could rTMS, by modulating excitability in the mPFC and influencing the ACC-mPFC
glutamatergic circuit, become a novel intervention for chronic visceral pain in IBS patients? This
question warrants in-depth investigation.
Therefore, this study aims to explore the efficacy of rTMS intervention for chronic visceral pain in
IBS, seeking to elucidate the specific mechanisms by which rTMS alleviates chronic visceral pain
through modulation of pain-related neural activity (e.g., in the mPFC) and neural network
interactions (e.g., the ACC-mPFC circuit). This research will not only provide central evidence

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supporting the clinical effects of rTMS for chronic visceral pain in IBS but also establish an
experimental foundation for future clinical applications.
3.2 Subject Selection Rationale
This study selects patients who meet the Rome IV diagnostic criteria for irritable bowel syndrome,
with Bristol Stool Form Scale types 6-7 accounting for >25% of bowel movements, and
hard/lumpy stools (types 1-2) accounting for <25%. Age range is between 18-75 years. During the
2-week run-in period, the patient has at least 4 days with diarrheal stools (Bristol Stool Form Scale
type 6 or 7), and an average abdominal pain intensity ≥3 points (based on a 0 to 10 point
Numerical Rating Scale [NRS]).
3.3 Endpoint Selection Rationale
The primary outcome measure is the proportion of patients achieving a composite response at the
end of treatment (Week 2), defined as: a reduction of ≥30% from baseline in the average daily
worst abdominal pain score, AND a reduction of ≥50% in the number of days with at least one
stool consistency meeting BSFS type 6 or 7 criteria during Week 2. Abdominal pain intensity is
assessed using an 11-point NRS scale (0-10) for the last 24 hours daily. Stool consistency is
recorded daily by the patient selecting the most representative category according to the BSFS.
3.4 Risk and Benefit Rationale
This study adopts a strict risk-benefit assessment system. Potential risks mainly include three
aspects: rTMS-related risks (10-15% of subjects may experience transient headache or scalp
discomfort, seizure risk <0.1%); pinaverium bromide may cause dry mouth and constipation
(incidence about 12%); bifidobacterium may cause mild bloating (incidence 8-10%). Main
benefits are reflected in: 1) Clinical level: it is expected that 60% of patients in the combination
therapy group will achieve a reduction in abdominal pain VAS score of ≥50%, and an increase in
quality of life score (IBS-QOL) of ≥20 points; 2) Long-term benefit: the recurrence rate in the
combination group at the 3-month follow-up is significantly lower than in the single-drug groups.
4. Sample Size Calculation

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We tested the null hypothesis of no difference in composite response rates between groups. Based
on previous literature18-20and our preliminary trial, assuming a placebo response rate of 23.8%, we
expected to double the response rate, assuming a composite response rate for repetitive
transcranial magnetic stimulation of 47.61%. At a significance level of α = 0.05, 63 patients per
group are needed to detect a 23% difference with 80% statistical power. Considering a 10%
dropout rate, the final estimated sample size required is 140 patients. [This center will recruit 70
cases, Xiangcheng People's Hospital of Suzhou will recruit 40 cases, and Suzhou New District
People's Hospital will recruit 30 cases.

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5. Detailed Study Content
5.1 Overall Study Design:
Project Title: The Effect of Repetitive Transcranial Magnetic Stimulation Combined with
Pinaverium Bromide or Bifidobacterium versus Sham Stimulation on Chronic Visceral Pain in
Patients with Diarrhea-Predominant Irritable Bowel Syndrome: A Randomized, Controlled
Factorial Design Study
Study Type: Prospective 2*2 factorial designed randomized controlled study
This is a multicenter, prospective, 2*2 factorial designed randomized controlled study19 evaluating
the effectiveness of TMS for treating irritable bowel syndrome. This study will recruit and screen
subjects according to ethical review standards. Subjects will be randomly divided into an rTMS
stimulation + pinaverium bromide treatment group, an rTMS stimulation + bifidobacterium
treatment group, a pinaverium bromide + sham rTMS treatment group, and a bifidobacterium +
sham rTMS stimulation group for clinical trials. Pain and stool characteristics will be assessed
after 2 weeks of treatment, and data will be collected and analyzed finally. This study aims to
deeply explore the clinical efficacy of Transcranial Magnetic Stimulation (TMS) on chronic
visceral pain in patients with Irritable Bowel Syndrome (IBS), in order to provide more reliable
and effective therapeutic targets for clinical application.
5.2 Subject Grouping
Intervention measures (Including whether the investigational drugs are used off-label. If used

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off-label, the safety and necessity of the research must be justified, and the off-label use must be
detailed in the informed consent form.)
(1) IBS-D patients receiving rTMS stimulation + pinaverium bromide treatment
rTMS stimulation: 1 Hz, 80% MT, 20 min/d, once daily for 2 weeks;
Pinaverium bromide: Oral, 3 times daily, 1 tablet/time, for 2 weeks;
(2) IBS-D patients receiving rTMS stimulation + bifidobacterium treatment
rTMS stimulation: 1 Hz, 80% MT, 20 min/d, once daily for 2 weeks;
Probiotic: Oral, 2 times daily, 4 capsules/time, for 2 weeks;
(3) IBS-D patients receiving Sham rTMS stimulation + pinaverium bromide treatment
Sham rTMS treatment: 0 Hz, 0% MT, 20 min/d, once daily for 2 weeks;
Pinaverium bromide: Oral, 3 times daily, 1 tablet/time, for 2 weeks;
(4) IBS-D patients receiving Sham rTMS stimulation + bifidobacterium
Sham rTMS stimulation: 0 Hz, 0% MT, 20 min/d, once daily for 2 weeks;
Probiotic: Oral, 2 times daily, 4 capsules/time, for 2 weeks;
Dose Selection/Adjustment
rTMS stimulation: 1 Hz, 80% MT, 20 min/d, once daily for 2 weeks;
Pinaverium bromide: Oral, 3 times daily, 1 tablet/time, for 2 weeks;
Probiotic: Oral, 2 times daily, 4 capsules/time, for 2 weeks;
Administration Time
This study adopts a standardized administration time scheme to ensure treatment consistency:
Pinaverium bromide (50mg) is taken orally 30 minutes before meals three times daily,
Bifidobacterium (500mg) is taken after breakfast and before bedtime, both study drugs are
dispensed with electronic medication boxes (MediSafe system) for timed reminders and
medication recording.
Blinding/Unblinding
Blinding method: rTMS real/sham stimulation uses identical equipment and operating sounds,
administered by an independent technician through an encrypted control system; drugs
(pinaverium bromide/bifidobacterium) use matching placebos (identical capsules, boxes, labels),

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distributed uniformly by the central pharmacy according to random codes; 2) Statistical
unblinding: Unblinding is performed in two stages after database lock -- first, an independent
statistician performs inter-group comparisons (Group A vs. B vs. C vs. D), the final reveal of the
intervention corresponding to each group occurs after the main conclusions are formed; 3) Quality
control: Blinded assessment is conducted monthly, accidental unblinding events must be recorded
within 48 hours and the impact on the study assessed.
Rescue Medication and Supportive Therapy (Necessary treatment measures
when SAEs related to the study occur)
This study establishes strict norms for rescue medication and supportive therapy: 1) rTMS-related
SAE: Seizure - immediately stop stimulation and intravenous push diazepam (5-10mg), transfer
persistent convulsions to neurological ICU for monitoring; Severe headache/dizziness - administer
paracetamol (≤1g/dose) combined with vestibular inhibitors; 2) Drug-related SAE: Pinaverium
bromide allergic reaction - immediately discontinue drug and intramuscular injection of adrenaline
(0.3-0.5mg,
1:1000),
oral
loratadine
(10mg/day);
Bifidobacterium-induced
bacteremia
-
immediately stop administration and intravenous infusion of vancomycin (15mg/kg q12h)
combined
with
blood
culture-guided
treatment;
3)
Psychological
support:
Worsening
anxiety/depression (HADS score increase ≥8 points) - refer to psychological department for
intervention. All SAE treatments are executed by the research center's 24-hour emergency team,
using standardized (emergency kits) (containing the above drugs and rescue equipment), the
treatment process involves continuous ECG monitoring and recording of vital sign changes. Costs
of rescue medication are covered by research insurance, subsequent medical follow-up for
subjects continues until symptoms completely resolve + 2 weeks. After SAE resolution, the causal
relationship with the intervention measures is assessed by an independent medical committee,
major SAEs (e.g., anaphylactic shock) require re-evaluation of the individual's risk-benefit ratio
for continuing the study. All rescue measures are recorded in the source documents and
synchronized to the eCRF system, serving as key data for safety analysis.
6. Study Implementation Procedures
Subject Management

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Subject recruitment methods: Establish open and transparent channels, publish recruitment
information approved by the Ethics Committee, post recruitment advertisements, etc., so that
patients with potential enrollment opportunities can directly contact the researchers.
Informed consent process: Include privacy protection in the informed consent form, fully inform
the subjects, obtain their consent, so that subjects know their personal information and privacy are
protected by law and the research team will use it reasonably according to legal provisions and the
requirements of documents such as the informed consent form. Once it is found that the subject's
personal information or privacy is violated, the subject can raise questions or even resort to legal
means, and these actions will not affect normal clinical diagnosis and treatment.
Screening number allocation
Take confidentiality measures to ensure the confidentiality of research project materials, such as
using codes to mark subject identification information. The subject's name and other identifying
information should be replaced with a "subject identification code" to ensure that identity
information, disease information, biological sample information, and other data are provided to
other trial researchers after encoding processing; use subject identification codes on case report
forms;
Post-treatment visits (Safety follow-up visits, follow-up visits, survival follow-up)
This study designs a comprehensive post-treatment follow-up system to ensure long-term efficacy
and safety assessment: a 12-week follow-up period is conducted after the last treatment.
7. Research Data Management and Statistical Analysis.
This study adopts strict data management and statistical analysis methods to ensure the
scientificity and reliability of the randomized controlled factorial design study.
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