TEA for Study Participants With IBS-C Optimization of TEA Modalities for Treatment of IBS-C: A Phase 1 25 Study Participant Clinical Trial of Transcutaneous Electrical Acustimulation (TEA) in Study Participants With IBS-C
Phase: NA
Conditions: IBS, Constipation
Sponsor: University of Michigan

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Version 1        2-10-21 
 
 
 
Optimization of TEA Modalities for Treatment of IBS-C 
A Phase 1 25 Study participant Clinical Trial of Transcutaneous 
Electrical Acustimulation (TEA) in Study participants with IBS-C 
 
 
 
 
 
 
 
 
 
NCT04953728 
 
Actual Date of IRB Approval: May 18, 2022 
 
 
 

 ____________________________________________________________________________________________ 
 
 
Version 1        2-10-21 
Optimization of TEA Modalities for Treatment of IBS-C 
A Phase 1 25 Study participant Clinical Trial of Transcutaneous Electrical 
Acustimulation (TEA) in Study participants with IBS-C 
 
HUM00189911 
Principal Investigator: 
Primary Investigator: Dr. Jiande Chen 
Co-Investigators: Dr. William Chey, Dr. Borko Nojkov, Dr. Chung Owyang 
Statistician: Jonathan Troost 
Supported by: The National Institute of Health: HEAL Transfer Home-based for 
abdominal pain 
Study Intervention Device Provided by: Transtimulation Inc. 
 
Version Number: 1 
 
Date: 2/10/2021 
 

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3 
 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as 
required by the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• NIH Clinical Terms of Award 
• The University of Michigan 
All key personnel (all individuals responsible for the design and conduct of this study) 
have completed Human Study participants Protection Training. 
 
 
 
 
 
 

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SIGNATURE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations. 
Primary Investigator:* 
 
Signed: 
 
Date: 
1/5/2021 
 
Name: Jiande Chen 
Title: Professor of Medicine 
 
 
 

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5 
TABLE OF CONTENTS 
 
Page 
Statement of Compliance ............................................................................................................ 2 
Signature Page ........................................................................................................................... 3 
Table of Contents ........................................................................................................................ 4 
List of Abbreviations .................................................................................................................... 6 
Protocol Summary ...................................................................................................................... 7 
1 
Key Roles ........................................................................................................................... 9 
2 
Introduction: Background Information and Scientific Rationale ......................................... 10 
2.1 
Background Information ........................................................................................ 10 
2.2 
Rationale .............................................................................................................. 10 
2.3 
Potential Risks and Benefits ................................................................................. 11 
2.3.1 Potential Risks .......................................................................................... 11 
2.3.2 Known Potential Benefits........................................................................... 12 
3 
Objectives ........................................................................................................................ 12 
3.1 
Study Objectives ................................................................................................... 12 
3.2 
Study Outcome Measures .................................................................................... 12 
3.2.1 Primary Outcome Measures ...................................................................... 12 
3.2.2 Secondary Outcome Measures ................................................................. 12 
4 
Study Design .................................................................................................................... 12 
4.1 
Schedule of events ............................................................................................... 13 
5 
Study Enrollment and Withdrawal ..................................................................................... 15 
5.1 
Study participant Inclusion Criteria ........................................................................ 15 
5.2 
Study participant Exclusion Criteria ....................................................................... 15 
5.3 
Strategies for Recruitment and Retention ............................................................. 15 
5.4 
Treatment Assignment Procedures ....................................................................... 16 
5.4.1 Randomization Procedures ....................................................................... 16 
5.4.2 Reasons for Withdrawal ............................................................................ 16 
5.4.3 Handling of Withdrawals ............................................................................ 16 
6 
Study Intervention/Investigational Product ........................................................................ 17 
6.1 
Study Device Description ...................................................................................... 17 
7 
Study Schedule ................................................................................................................ 17 
7.1 
Screening ............................................................................................................. 17 
7.2 
Visit schedule of events ........................................................................................ 17 
7.3 
Visit compensation ................................................................................................ 17 
8 
Study Procedures/Evaluations .......................................................................................... 17 
8.1 
Surveys................................................................................................................. 17 
9 
Assessment of Safety ....................................................................................................... 18 
9.1 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 18 
9.1.1 Adverse Events ......................................................................................... 18 
9.1.2 Expected Adverse Reactions .................................................................... 19 
9.1.3 Serious Adverse Events ............................................................................ 19 

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9.1.4 Unanticipated Problems ............................................................................ 19 
9.2 
Reporting Procedures ........................................................................................... 20 
9.2.1 Serious Adverse Events ............................................................................ 20 
9.2.2 Regulatory Reporting ................................................................................ 20 
9.2.3 Other Unanticipated Problems .................................................................. 20 
9.2.4 Reporting of Pregnancy ............................................................................. 21 
9.3 
Type and Duration of Follow-up of Study participants after Adverse Events ......... 21 
9.4 
Safety Oversight (ISM plus SMC or DSMB) .......................................................... 21 
10 
Statistical Considerations ................................................................................................. 22 
10.1 
Study Hypotheses ................................................................................................. 22 
10.2 
Sample Size Considerations ................................................................................. 22 
10.2.1 Safety Review ........................................................................................... 22 
10.2.2 Efficacy Review ......................................................................................... 23 
10.3 
Final Analysis Plan ............................................................................................... 23 
11 
Source Documents and Access to Source Data/Documents ............................................ 23 
12 
Quality Control and Quality Assurance ............................................................................. 23 
13 
Ethics/Protection of Human Study participants ................................................................. 23 
13.1 
Ethical Standard ................................................................................................... 23 
13.2 
Institutional Review Board .................................................................................... 23 
13.3 
Informed Consent Process ................................................................................... 24 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 24 
13.5 
Study participant Confidentiality ............................................................................ 24 
13.6 
Study Discontinuation ........................................................................................... 25 
14 
Data Handling and Record Keeping ................................................................................. 25 
14.1 
Data Management Responsibilities ....................................................................... 25 
14.2 
Types of Data ....................................................................................................... 25 
14.3 
Timing/Reports ..................................................................................................... 25 
14.4 
Study Records Retention ...................................................................................... 25 
14.5 
Protocol Deviations ............................................................................................... 25 
15 
Publication Policy ............................................................................................................. 26 
Supplements/Appendices ......................................................................................................... 26 
Appendix A: Schedule of Events ............................................................................................... 27 
 
 
 
 

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Abbreviations  
TEA: Transcutaneous electrical acustimulation  
EA: Electrical acustimulation  
IBS-C: Irritable Bowel Syndrome with Constipation  
PC6: acupuncture point three finger widths below the wrist 
ST36: acupuncture point four finger widths below the knee  
EA: Electro acupuncture 
CRF: Case report form 
SOP: Standard of procedure   
 
 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
Title: 
Optimization of TEA Modalities for Treatment of IBS-C: 
A Phase I 25 Study participant Clinical Trial of Transcutaneous 
Electrical Acustimulation (TEA) in Study participants with IBS-C 
Précis: 
This study aims to discern whether Transcutaneous Electrical 
Acustimulation (TEA) at acupuncture points ST36 and/or PC6 will 
relieve the abdominal pain associated with IBS-C.  Each study 
participant will have 5 research visits at the Michigan Medicine GI 
physiology lab. During these visits, they will undergo a procedure 
similar to Anal Rectal Manometry performed by the GI physiology lab 
staff. TEA is similar to this procedure as it is uses the barostat device 
and is performed by the GI physiology lab staff.  This device has a 
rubber catheter that will be inserted 5-15 cm into the rectum of the 
study participant. Then the GI physiology staff will inflate the 
catheter. They will ask the study participant when they can sense the 
catheter. Then the GI physiology staff will continue to inflate the 
catheter and the study participants feel discomfort (described as the 
'urge to defecate'). Then the study participant will be asked to pass 
the balloon (like they would pass a bowel movement).  
The difference between ARM procedure and the study procedure is 
that there will be stimulation of acupuncture point ST36 which is 
below the knee cap or stimulation of acupuncture point PC6 which is 
just above the wrist. 
At each visit there will be stimulation of only one of the points at 
either 100Hz or 25Hz.   These are the potential combinations: ST36 
100Hz, ST36-25Hz, PC6-100Hz, PC6-25Hz, Sham-TEA.  
The frequency and position combination (or sham visit) is randomly 
assigned. The randomization determines the order in which the study 
participant moves through the study. Every study participant will, in 
the end, complete one visit at each frequency and a sham visit. The 
study participant will also complete surveys at the appointment. 
Study participants will be compensated for their participation and 
given a parking pass. 
Objectives: 
 
Primary: Determine the best stimulation point and frequency for 
relieving the abdominal pain in study participants with IBS-C. 
Secondary: Collect measurements of visceral hypersensitivity in 
study participants with IBS-C. 
Population: 
25 study participants, male and females, age ≥18 years, IBS-C 
satisfying Rome IV criteria 
Phase: 
1 

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Number of Sites: 
1, Michigan Medicine, University of Michigan 
Study Duration: 
24 Months 
Study participant 
Participation Duration: 
Each visit will be 120 minutes long. There will be 5 visits total. The 
maximum amount of time between visits is 3 weeks. The minimum 
amount of time between visits is 1 week 
Description of Intervention: 
The device being studied, the Transcutaneous Electrical 
Acustimulation (TEA) will give stimulation similar to electro 
acupuncture at two specific acupuncture points (ST-36 and PC-6) 
known to impact pain perception. The study team would like to 
access if TEA is safe for study participants and will impact the pain 
perception in study participants with IBS-C. 
Estimated Time to Complete 
Enrollment: 
12 Months 
 
Schematic of Study Design: 
Table 1: Arm of the study  
This study has 1 
cohort all study 
participants are in 1 
arm 
Sample size: 25 
study participants 
Intervention: 
Transcutaneous 
Electrical 
Acustimulation (TEA) 
Randomization: The 
order of TEA will be 
randomized for each 
study participant.  
 
See appendix A for the schedule of events table. 
 

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1 
KEY ROLES 
For questions regarding this protocol, contact Jiande Chen PhD. at 734-647-9252 
Individuals: 
Principal Investigator:  Jiande Chen PhD. responsible for 
conducting the study. 
 
Emergency Contact: William Chey M.D. will be responsible 
for evaluation and connecting the study participant to 
treatment options. 
Co-Investigators: Chung Owyang and Borko Nojkov serve 
will help the PI in recruiting study participants and clinical 
research study design. 
Lead Statistician: Jonathan Troost will be the lead 
statistician. 
 
Institutions: 
 
University of Michigan (Michigan Medicine) 
1500 E Medical Center Drive, 
Ann Arbor MI 48109 
Contact person: Jiande Chen 
734-647-9252 
cjiande@umich.edu 
 
 
 
 
 
 
 
 
 

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2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
• 
In this project, we will use a novel transcutaneous electrical acustimulation (TEA) device for 
treatment of chronic abdominal pain in study participants with Irritable Bowel Syndrome with 
Constipation (IBS-C).  This is a device that has stimulating electrodes. The electrodes are placed on 
acupuncture points that previous studies demonstrate relieve pain related to constipation.   
• 
This therapeutic strategy is called Neuromodulation. The process of preforming acupuncture via 
electrical stimulation in place of traditional acupuncture methods is called electroacupuncture, EA.  
The two acupuncture points, acupoints, that have been found to 
improve autonomic functions impaired in animal models of IBS are 
points ST-36 and PC6. 
• 
In the human PC6 is three finger widths above the wrist. In the 
human ST-36 is four finger widths below the knee. 
• 
The motivation behind this study is to access the impact of TEA on 
pain and motility in study participants with IBS-C.  If successful, 
TEA could serve as a non-opioid treatment for pain related to IBS-
C. 
• 
The barostat is a FDA approved device (K99 1288) used in 
clinical practice and research to study the function and activity 
of the motor and sensory functions of the gastrointestinal tract. 
This is a common method used to measure gastric motility (or   
the movement of food from the mouth through the pharynx 
(throat), esophagus, stomach, small and large intestines and 
out of the body). It can monitor volume changes while 
maintaining a set constant pressure and deliver controlled 
distensions of gastrointestinal organs. The controlled distension 
is completed by the device’s ability to inflate at the tip of the 
catheter. In this study, the device will be used in the rectum.  
This device does not use electricity to stimulate the rectum.  
• 
This device is not being studied. Rather it is used to collect 
measurements.  In this case, we will use the barostat device to 
monitor the activity in the rectum. The rectum of the GI track 
thought to be have abnormal activity in study participants with 
IBS-C, contributing to their symptoms.  
2.2 
Rationale 
 
• 
The aim of the study is to determine the best TEA stimulation 
point and parameters for treating the abdominal pain in study 
participants with IBS based on a well-established measurement of motility, the barostat and the study 
participant’s survey responses. 
Left: image of acupuncture 
point PC6. Right: image of 
acupuncture point ST-36. 
Top: Image of the rectal barostat 
balloon, partially inflated. Bottom: 
Image of the barostat device, control 
panel. 

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2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
The immediate risks involved with barostat inflation and subsequent rectal distension include: 
• 
Discomfort during the balloon insertion  
• 
Sensation (discomfort) with the balloon inflation which is a variable of the study. The likelihood of 
this risk is common, up to 100% of participants will experience discomfort. The study team will 
make the study participant aware of this before consenting to the procedure. The study 
participant has the right to stop the procedure at any time. 
• 
Bleeding at the site of balloon inflation (in the rectum). The likelihood of this risk is rare, 
approximate incidence of <1%. 
 However, the duration of rectal distention is brief and the distention can be immediately terminated upon 
intolerable pain or discomfort.  
 
The long range risk of barostat inflation is: 
• 
Perforation of the rectum into the peritoneal space, the likelihood of this risk is rare, approximate 
incidence of <1%. 
 
The risks of electrical stimulation via TEA are: 
• 
Possible allergic reaction to the stimulation electrodes and sensation of electrical stimulation. 
The likelihood of this risk is rare, approximate incidence of <1%. 
However, the stimulation output will be set at a level that is well tolerated by the participant. In very rare 
occasions, the participant might experience rash or minor infection at the stimulation point that can be  
treated locally if needed.  
 
The risk involved with the ECG recording: 
• 
Allergic reaction of ECG electrodes. The likelihood of this risk is rare, approximate incidence of 
<1% 
 
The researchers will try to minimize these risks by having an experienced investigators and lab personnel 
performing the barostat studies with particular care. The study investigators and our GI Physiology lab  
staff are well versed in doing these type of procedures. In addition, one of gastroenterologist-physician 
study investigators will be present/perform the studies or will be readily available on site for 
consultation/evaluation in case of any study complications or questions. 
 
The rationale behind these risks is that the risks are unlikely and the study participant would receive care 

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13 
immediately.  Moreover, the study team would not be able to collect this data without study participants 
enduring the risks.  Alternative procedures would not provide the same understanding of the influence 
of TEA for IBS-C study participants.  
2.3.2 
Known Potential Benefits 
A potential benefit for study participant is a reduction in pain related to their IBS-C. 
3 
Objectives 
3.1 
Study Objectives 
The objectives of this study are as follows:  
• 
To understand the impact of TEA on study participants with IBS-C (reduction of pain related to IBS-C) 
• 
Access the safety of TEA in study participants with IBS-C 
• 
Refine which (if any) TEA stimulation and location combination delivers the greatest reduction in pain 
associated with IBS-C 
3.2 
Study Outcome Measures 
The barostat device and study participant survey responses will measure the study outcomes. 
3.2.1 
Primary Outcome Measures 
The barostat device will measure the volume changes in the rectum during controlled distension of the 
gastrointestinal organs. If the TEA is successful, the study participant’s maximum tolerance should 
increase after TEA compared to their first maximum tolerance of the visit. This will be defined by 
comparing their maximum tolerance pre and post TEA. 
3.2.2 
Secondary Outcome Measures 
A secondary outcome of the study will be reviewing the volume and pressure measurements from the 
barostat device.  The surveys will also be reviewed to see if the study participants have a change in their 
symptoms. 
4 
Study Design 
This is a placebo-controlled trial.  The placebo is the sham-TEA visit. The study will recruit 25 study 
participants with IBS-C. These study participants will be recruited from the UM Health Research 
Recruiting Registry (UM HealthResearch.org), Michigan Bowel Control Program (MBCP), Functional 
Bowel Disease (FBD), and the study team will screen the gastroenterology clinic schedules via 
MiChart. 
This is a phase 1 trial. This is study will only occur at the University of Michigan. There is only one 
group/arm of study participants.  The study team plans to complete enrollment within 12 months of 
beginning to the study. Study participant participation will be at a minimum 5 weeks (1 week between 

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14 
visits) and at a maximum 15 weeks (3 weeks between each visit).  The test agent is the novel TEA 
device.  
4.1 Schedule of Events for Each Visit 
Every visit is the same and will follow the steps detailed below, with the exception of the first visit which 
will include the informed consent process. At visit one, the study team will randomly generate the 
stimulations schedule unique to each study participant; this is the order of locations and currents by using 
a random generator.  For example, ST36-100Hz, ST36-25Hz, PC6-100Hz, PC6-25Hz and Sham-TEA. 
 
48 Hours prior to the visit: The study participants will not take any medications known to affect the gut 
or pain perception. 
 
8:00 pm on the night before the visit: The study participants begin fasting for their visit the next day. 
Study participants can still drink water. Study participants cannot drink coffee, tea, juices or eat any food 
items. 
 
Day of the Visit:  
Study participants will come to the study location, the Gastrointestinal Physiology Lab in University of 
Michigan. The visit will take place in one of the private rooms within the lab.  If the study participant is a 
women of child bearing potential: She will complete a pregnancy test provided by the study team.  If 
her pregnancy test is positive, she will be excluded from further participation in the study and will not 
complete the visit. 
 
Rome IV Criteria for Irritable Bowel Syndrome: Upon arrival for every visit, the study participant will 
complete the Rome IV Criteria for Irritable Bowel Syndrome survey. 
 
Enema: The study participant will be given a rectal enema to clean the rectum. Then the study 
participant will undress from the bottom down and be given a gown and sheets for comfort and privacy. 
 
Position the study participant: The study participant will be asked to lie down on the medical 
examination table on one side and bring his or her knees up to the chest, similar to the fetal position. 
The table has rails that will protect the study participant from falling.  The staff may use pillows to adjust 
and secure the study participant as well as for comfort.  
 
Electrode Placement: The GI physiology laboratory staff will place two electrocardiogram (ECG) 
electrodes from of the TEA device on the subject’s skin, one on the wrists at location PC6 and the other 
on upper leg below the knee at location ST36.  These two electrodes 
will be used for delivering weak electrical current stimulation.  The 
electric current and stimulating electrode location is determined by 
that study participant’s randomized stimulation schedule.  Electrodes 
will be placed at both locations at each visit. 
Fig.1: Locations of PC6 and 
ST36. 

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15 
 
 An additional three ECG electrodes connected to the ECG 
machine will be placed on the study participant’s skin, one 
on the manubrium of sternum, one above the breastbone 
and one on the study participant’s right chest. These three 
electrodes will be used for recording the ECG. Before the 
placement of each of the 5 electrodes, the skin area where 
the electrodes to be placed will be carefully cleaned using 
skin-prep materials.   
 
 
Baseline data collection with the Barostat:  
The Barostat is an FDA-Approved device that measures pressure in the rectum. The device has a thin 
and flexible polyvinyl catheter (PVC) will be placed 5-15 cm into the study participant’s rectum. Once 
placed, this catheter will be in the rectum for the reminder of the visit. 
 
Rest - 15 Minutes 
While the study participant is at rest, baseline data will be collected for 15 minutes. 
 
Inflation with the Barostat: 
The GI physiology lab staff will inflate a small balloon at the tip of the catheter and ask the study 
participant to assess the sensation. During this period, the study participant will be asked to take a note 
of their first sensation, urge to defecate and maximum tolerance; meanwhile, the study participant will 
also be asked to report the scale of pain or discomfort during the process of the balloon distention. The 
study participant will complete the Visual analog Scale Pain Score during inflation. 
 
Maximum Tolerance: 
Once the maximum tolerance is reached, the inflation will stop and the air will be removed.  
 
TEA – 15 minutes 
One of the randomly assigned TEA methods (or sham-TEA) will be performed for 15 minutes.  
 
Inflation with the Barostat and TEA:  
Then the inflation process described above will be repeated while applying the TEA. The study 
participant may sense the weak electrical stimulation.  If the stimulation intensity is uncomfortable for 
the study participant, the stimulation will be set a level where the study participant feels comfortable. 
This will be noted in the visit summary. The study participant will complete the Visual Analog Scale Pain 
Score during inflation. 
During the entire period, the ECG signal will be recorded from the three chest ECG electrodes.  Once the 
inflation with barostat and TEA is completed, the study participant’s visit will end.  
 
Fig.2: Locations of ECG electrodes to 
read electrocardiogram. 

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5 
Study Enrollment and Withdrawal 
Eligibility Criteria: 
5.1 
Study participant Inclusion Criteria 
In order to be eligible to participate in this study, a study participant must meet all of the following criteria: 
• 
Male or female, aged 18 to 99 
• 
Willing to comply with all study procedures and be available for the duration of the study 
• 
Diagnosed with IBS-C satisfying Rome IV criteria  
• 
Have symptoms present for at least the last 3 months 
• 
Have abdominal pain that is not adequately relieved at the time of screening and the time of 
randomization 
• 
Has a VAS pain score of >3 (on 0-10 score) 
5.2 
Study participant Exclusion Criteria 
A potential study participant who meets any of the following exclusion criteria at baseline will be excluded 
from participation in this study if: 
• 
Have an unrelated active disorder which may involve abdominal pain, such as inflammatory bowel 
disease, diabetes, unstable thyroid disease 
• 
Have history of abdominal surgery other than cholecystectomy (gallbladder removal) or 
appendectomy 
• 
Are taking anticoagulants or antispasmodic, antidiarrheal, or opioids or other pain relief medications 
and cannot stop these medications for three consecutive days before each study visit 
• 
Are pregnant or breastfeeding; women of child bearing potential complete a pregnancy test at each 
visit 
• 
Have known allergic reactions to components of the ECG electrodes  
• 
Received treatment with an investigational drug or other intervention within 6 months of the date of 
consent 
• 
Anything that, in the opinion of the investigator, would place the study participant at increased risk or 
preclude the study participant’s full compliance with or completion of the study 
• 
Are unable to provide informed consent 
5.3 
Strategies for Recruitment and Retention 
Recruitment: Co-investigators, Drs. Chey, Owyang and Nojkov, and physician colleagues seeing 
study participants at Michigan Bowel Control Program (MBCP) and Functional Bowel Disease (FBD) 
will refer potential study participants to the study team. MiChart schedule screening may also be 
used for identifying possible study participants. 

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17 
The study team will also post the study on the UM Health Research Portal. According to NIH 
guidelines, we will also post the study on clinicaltrials.gov. 
Retention: The study team hopes to retain study participants in the study by allowing a flexible time 
period between visits; as short as one week and as long as 3 weeks between visits.  
5.4 
Treatment Assignment Procedures 
5.4.1 
Randomization Procedures 
Prior to the first visit, the order of TEA stimulation at the visits will be randomly assigned to each study 
participant. Every study participant will undergo every TEA combination (For example, ST36-100Hz, 
ST36-25Hz, PC6-100Hz, PC6-25Hz and Sham-TEA). 
5.4.2 
Reasons for Withdrawal 
A study participant will be discontinued from participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, intercurrent illness, or other medical condition 
or situation occurs such that continued participation in the study would not be in the best interest of 
the study participant. 
• 
The study participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
Study participants are free to withdraw from participation in the study at any time upon request. 
5.4.3 
Handling of Withdrawals 
This study may be prematurely terminated if, in the opinion of the investigator or the sponsor, there is 
sufficient reasonable cause.  Written notification, documenting the reason for study termination, will be 
provided to the investigator or sponsor by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to study participants. 
• 
Insufficient adherence to protocol requirements. 
• 
Data that are not sufficiently complete and/or evaluable.  
• 
Plans to modify, suspend, or discontinue the development of the TEA device. 
If the study is prematurely terminated or suspended, the sponsor will promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the 
reason(s) for the termination or suspension.  The IRB/IEC will also be informed promptly and provided the 
reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified 
by the applicable regulatory requirement(s). 
 
 

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6 
Study Intervention/Investigational Device  
6.1 
Study Device Description 
The TEA device is about 4x3cm. It is similar to a TENS (transcutaneous electrical nerve stimulation) unit 
that is classified by FDA as a non-significant risk device. For this study, two regular ECG electrodes will 
be placed on the skin surface on the preferred location as shown in Fig.1 and connected to the TEA 
device.  This device will deliver a specified weak electrical signal. The device is powered by a small 
rechargeable battery and the charging will take place only when the device is not in use. The maximum 
current output is 10mA. 
7 
Study Schedule 
7.1 
Screening 
Once a candidate is identified, a member of the study team will speak with the study participant to explain 
the study. The study participant may be contacted via phone and the study team member will follow the 
phone script and go through the pre-screen questions if interested.  If the study participant is determined 
to be ineligible or not interesed via the pre-screening contact, he or she will be excluded in the study and 
logged as pre-screened and ineligible or not interested. 
If the study participant is eligible and interested the study team will set up the first study visit. The study 
participant will go through the informed consent process at the first study visit. 
7.2 
Visit Schedule of Events  
see section 4.1 Schedule of Events for Each Visit and Appendix A for a Table Describing the Schedule of 
Events  
7.3 
Visit Compensation 
 
Subjects in this study will receive $200.00 per visits 1-3 and $350.00 per visits 4 and 5.  
This totals to $1,300.00 once all study activity is completed. 
The compensation is set at such a high value based on the lengthy duration of the study visits (120 
minutes), the strong likelihood of discomfort due rectal dilation (the balloon inflation with the barostat 
procedure) and the sensitive nature of the study.  
The additional payment in visits 4 and 5 is to encourage study participants to complete all five visits.  It is 
crucial to the study design that the study participant completes all five visits.   
 
 

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8 
Study Procedures/Evaluations 
8.1 Surveys  
The study participant will complete the Rome IV criteria for Irritable Bowel Syndrome at the 
beginning of every visit.  The study participant will complete the Visual Analog Scale Pain Score 
twice, once during both inflations, at every visit. 
9 
Assessment of Safety 
9.1 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
9.1.1 
Adverse Events 
Adverse Event:  AE is defined as any untoward medical occurrence in a study participant or clinical 
investigation study participant administered a pharmaceutical product regardless of its causal relationship 
to the study treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of medicinal 
(investigational) product.  The occurrence of an AE may come to the attention of study personnel during 
study visits and interviews of a study participant presenting for medical care, or upon review by a study 
monitor.  
All AEs including local and systemic reactions will be captured on the appropriate CRF.  Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, relationship to study 
product (assessed only by those with the training and authority to make a diagnosis, which would include 
MD, DDS, DMD, PA, Nurse Practitioner, or DO), and time of resolution/stabilization of the event.  All AEs 
occurring while on study must be documented appropriately regardless of relationship.  All AEs will be 
followed to adequate resolution.  
Any medical condition that is present at the time that the study participant is screened will be considered 
as baseline and not reported as an AE.  If a pre-existing condition or illness, which is not expected to 
exacerbate or worsen, deteriorates at any time during the study it should be reported as an AE. 
All AEs must be graded for severity and relationship to study product.  
Severity of Event:  All AEs will be assessed by the clinician using a protocol defined grading system.  
For events not included in the protocol defined grading system, the following guidelines will be used to 
quantify intensity.  
• 
Mild: Noticeable to the study participant, but does not interfere with study participant’s expected daily 
activities, usually does not require additional therapy or intervention, dose reduction, or 
discontinuation of the study. 
• 
Moderate: Interferes with the study participant’s expected daily activities, may require some 
additional therapy or intervention but does not require discontinuation of the study. 
• 
Severe: Extremely limits the study participant’s daily activities and may require discontinuation of 
study therapy, and/or additional treatment or intervention to resolved.  Severe events are usually 
incapacitating. 

 ____________________________________________________________________________________________ 
20 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of intensity to be performed.  
Relationship to Study Products:  The clinician’s assessment of an AE's relationship to test article 
(study drug) is part of the documentation process, but it is not a factor in determining what is or is not 
reported in the study.  If there is any doubt as to whether a clinical observation is an AE, the event should 
be reported.  All AEs must have their relationship to study product assessed using the terms: associated 
or not associated.  To help assess, the following guidelines are used. 
• 
Associated – The event is temporally related to the administration of the study product and no other 
etiology explains the event. 
• 
Not Associated – The event is temporally independent of study product and/or the event appears to 
be explained by another etiology.”= 
9.1.2 
Expected Adverse Reactions 
It is expected that study participants may discover they have an allergy to the adhesives used during on 
the ECG electrodes during the study.  
9.1.3 
Serious Adverse Events 
Serious Adverse Event (SAE): An SAE is defined as an AE that meets one of the following conditions: 
• 
Death during the period of protocol-defined surveillance 
• 
Life-threatening event (defined as a study participant at immediate risk of death at the time of the 
event) 
• 
An event requiring in study participant hospitalization or prolongation of existing hospitalization during 
the period of protocol defined surveillance  
• 
Results in congenital anomaly or birth defect 
• 
Results in a persistent or significant disability/incapacity 
• 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the study participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in study participant hospitalization, or the development 
of drug dependency or drug abuse/overdose or cancer. 
All SAEs will be: 
• 
recorded on the appropriate SAE Report Form and CRF 
• 
followed through resolution by a study clinician. The study clinician for this study is Dr. William Chey. 
The PI is a PhD. And not an MD. As an MD, Dr. William Chey will serve as the emergency contact 
person for the study. He is the lead of the GI physiology lab. 
• 
reviewed and evaluated by a study clinician. 

 ____________________________________________________________________________________________ 
21 
9.1.4 
Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
study participants or others to include, in general, any incident, experience, or outcome that meets all of 
the following criteria: 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the study participant population being 
studied; 
• 
related or possibly related to participation in the research (in the guidance document, possibly related 
means there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• 
suggests that the research places study participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
An incident, experience, or outcome that meets the three criteria above generally will warrant 
consideration of substantive changes in order to protect the safety, welfare, or rights of study participants 
or others.  Examples of corrective actions or substantive changes that might need to be considered in 
response to an unanticipated problem include:      
• 
changes to the research protocol initiated by the investigator prior to obtaining IRB approval to 
eliminate apparent immediate hazards to study participants 
• 
modification of inclusion or exclusion criteria to mitigate the newly identified risks 
• 
implementation of additional procedures for monitoring study participants  
• 
suspension of enrollment of new study participants 
• 
suspension of research procedures in currently enrolled study participants 
• 
modification of informed consent documents to include a description of newly recognized risks  
• 
provision of additional information about newly recognized risks to previously enrolled study 
participants. 
Unanticipated problems will be recorded and reported throughout the study. 
9.2 
Reporting Procedures 
9.2.1 
Serious Adverse Events 
The study will comply with IRB and FDA reporting requirements and guidelines. 
9.2.2 
Regulatory Reporting for Studies Not Conducted Under IND 
All AEs and SAEs will be reported to the University of Michigan IRB Med. 

 ____________________________________________________________________________________________ 
22 
9.2.3 
Other Unanticipated Problems 
Incidents or events that meet the OHRP criteria for unanticipated problems require the completion of an 
unanticipated problem report form.  OHRP recommends that investigators include the following 
information when reporting an adverse event, or any other incident, experience, or outcome as an 
unanticipated problem to the IRB: 
• 
appropriate identifying information for the research protocol, such as the title, investigator’s name, 
and the IRB project number; 
• 
a detailed description of the adverse event, incident, experience, or outcome;  
• 
an explanation of the basis for determining that the adverse event, incident, experience, or outcome 
represents an unanticipated problem;  
• 
a description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the unanticipated problem.” 
9.2.4 
Reporting of Pregnancy 
If a study participant is pregnant she will be excluded from the study. If a study participant becomes 
pregnant during the study she will excluded from the remainder of the study. 
9.3 
Type and Duration of Follow-up of Study participants after Adverse Events 
All AEs will be followed until resolved or considered stable. Follow up will be conducted by Dr. William 
Chey. He will determine the rate of contact by accessing the severity of the AE.  The reporting of AEs to 
IRB Med will be conducted by the study coordinator.  
9.4 
Safety Oversight  
 
Data and Safety Monitoring Board (DSMB) 
The first DSMB meeting will occur one month after recruitment begins. In addition to reviewing Serious 
Adverse Events (SAEs), the first DSMB meeting will focus on over all safety of the trial and study agent 
and will make a determination as to whether or not the study should proceed.  The DSMB will then meet 
once every 6 months throughout the remainder of the study and at any time during the study in which an 
unexpected and possibly related SAE occurs. 
The DSMB will be composed of the following members: 
 
Irene Sarosiek, MD: a Gastroenterologist and Professor of Medicine from the Division of Gastroenterology, 
Texas Tech University Health Science Center. Dr. Sarosiek is an established clinical investigator in the field 
of functional gastrointestinal diseases. She will serve as the Chair of the committee. 
   
Thomas Abell, MD: a Gastroenterologist and Arthur M. Schoen, M.D., Chair in Gastroenterology 
Gastrointestinal Motility Clinic from the Division of Gastroenterology at the University of Louisville. Dr. Abell 
is an expert in functional gastrointestinal diseases and has extensive experience in clinical trials and clinical 
research. He will serve as a member of the committee. 
 

 ____________________________________________________________________________________________ 
23 
Gengqing Song, MD, PhD: an Assistant Professor of Medicine and Director of Gastrointestinal Motility, 
Division of Gastroenterology and Hepatology MetroHealth Medical Center,  Case Western Reserve 
University, Cleveland, Ohio. He will serve as a member of the committee  
 
Blair Richards: a lead statistician from University of Michigan, Michigan Institute for Clinical & Health 
Research. He has over 15 years of experience on translational and health research projects across 
various disease area. He will serve as a member of the committee. 
 
 
 

 ____________________________________________________________________________________________ 
24 
10 
Statistical Considerations 
Analysis of variance (ANOVA) will be performed to investigate the difference in each of the outcomes 
among 4 different sessions. Tukey’s test will be used for study the differences in each of the 
measurements between two stimulation points (same stimulation parameters) and between two 
stimulation parameter sets (same stimulation points). The Pearson correlation analysis will also 
be performed to investigate the correlation between each of HRV parameters and the pain score 
or sensation threshold 
. 10.1 
Study Hypotheses 
TEA at acupoints ST36 (a point below the knee cap) or PC6 (a point in the wrist) will be effective in 
reducing abdominal pain induced by rectal distention in patients with IBS-C.  This hypothesis is based on 
published literature and our Dr. Jiande Chen’s experience with EA and TEA at the Johns Hopkins.  Dr. 
Chen’s previous experience with EA and TEA includes: animal studies in which electrical acupuncture at 
ST36/PC was shown to reduce abdominal pain in a rodent model of IBS and functional dyspepsia and 
preliminary clinical study in patients with IBS-C showing the reduction of overall symptoms of IBS, 
including abdominal pain.  
10.2 
Sample Size Considerations 
The study team plans for a 20% participant dropout or incompletion rate. For this reason, they will enroll 
25 study participants when in actuality they need 20 study participants to complete the study.  If 20 study 
participants complete the study and there are still 5 active participants, the active participants will still 
complete the study.  
This is not a clinical trial to investigate the efficacy of the therapy for the treatment of IBS-C. Instead, this 
is a pilot study to determine which method of TEA (4 different modalities and 1 placebo) is more effective 
in treating  abdominal pain in patients with IBS-C by studying patients’ sensation to rectal distention with 
different methods of treatment. The findings of this pilot study will be used to determine which treatment 
to use in a future clinical trial. No preliminary data are available for the calculation of the sample size. The 
simple size stated in this study was based the PI’s experience in other neuromodulation studies involving 
methodological optimization.  
10.2.1 
Safety Review  
Study enrollment and/or study visits will halt to at if the study team feels the study is unsafe.  This would 
include if study participants are experiencing serious adverse events. The DSMB will meet every 3 
months during the study enrollment/study visit period. If needed, the DSMB will meet more frequently to 
monitor the study. 
This is an acute study involving 5 sessions on separate days. No treatment or intervention will be given in 
between sessions.  
The risks involved in the study include rectal distention (a clinically approval procedure) and delivery of 
weak electrical current via skin surface electrodes. Any acute study session will be terminated if the 
patient is not tolerable to the procedure or decides to withdraw. If the safety is a concern, the remaining 

 ____________________________________________________________________________________________ 
25 
study sessions will be cancelled for that particular subject. The study enrollment will be halted if serious 
adverse events are reported.  
Safety outcome measures will include 1) pain/discomfort level during rectal distention, 2) any signs or 
symptoms of possible perforation or rupturing of the rectum during insertion of the rectal catheter and 
during rectal balloon distention, 3) any side effects due to weak electrical stimulation, such as rash or 
discomfort in the area of stimulation.  
10.2.2 
Efficacy Review 
This pilot study does not assess efficacy of the proposed TEA treatment. 
The study outcomes include rectal sensation and pain during rectal distention, autonomic functions 
noninvasively assessed from the ECG.  
10.3 
Final Analysis Plan 
Analysis of variance (ANOVA) will be performed to investigate the difference in each of the outcomes 
among different sessions. Tukey’s test will be used for study the differences in each of the measurements 
between two stimulation points (same stimulation parameters) and between two stimulation parameter 
sets (same stimulation points). The Pearson correlation analysis will also be performed to investigate the 
correlation between each of autonomic function parameters and the pain score or sensation threshold. 
11 
Source Documents and Access to Source Data/Documents 
 Only members of the study team will have access to source data.  This includes: all information, original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.   
12 
Quality Control and Quality Assurance 
• 
The study team will be present for each visit and follow the visit CRFs. The study team will go through 
the procedures with the GI physiology lab staff members to ensure that there is adherence to the 
protocol. 
• 
The study team will sign the bottom of each study CRF at the end of the visit. 
13 
Ethics/Protection of Human Study participants 
13.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set forth in 
The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Study participants of 
Research, as drafted by the US National Commission for the Protection of Human Study participants of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46; 62 Federal 
Regulations 25691 (1997) and the Declaration of Helsinki and Good Clinical Practice (GCP).  
13.2 
Institutional Review Board 
The TEA device is similar to a TENS unit which is a non-significant risk but is not approved by the FDA. 

 ____________________________________________________________________________________________ 
26 
 
As the device is not approved by the FDA the study team will have it reviewed by the Clinical Engineering 
Department for them to check into the safety. I have the device now. It is similar to a TENS device (non-
significant risk) but not FDA approved.  
 
The study will be reviewed for IRB approval. The study will not begin until IRB approval is granted. 
13.3 
Informed Consent Process  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation.  Extensive discussion of risks and possible 
benefits of this therapy will be provided to the study participants and their families. Consent forms (written 
in non-technical language) describing in detail the study interventions/products, study procedures, and 
risks are given to the study participant and written documentation of informed consent is required prior to 
starting intervention/administering study product.  Consent forms will be IRB-approved and the study 
participant will be asked to read and review the document.  Upon reviewing the document, the study team 
member will explain the research study to the study participant and answer any questions that may arise.  
The study participant will sign the informed consent document prior to any procedures being done 
specifically for the study.  The study participants should have the opportunity to discuss the study with 
their surrogates or think about it prior to agreeing to participate.  The study participants may withdraw 
consent at any time throughout the course of the trial.  A copy of the informed consent document will be 
given to the study participants for their records.  The rights and welfare of the study participants will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
This study will exclude women who are pregnant. This is for their safety and the safety of their fetus(es).   
The study also excludes children. This is because the population being studied are adults with IBS-C.  
13.5 
Study Participant Confidentiality 
Study participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents.  This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participating study participants. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence.   
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be de-
identified of any protected health information (PHI) and replaced with study identifier to maintain study 
participant confidentiality.  Information will not be released without written permission of the participant , 
except as necessary for monitoring by IRB, the FDA, OHRP and/or any other government officials, safety 
monitors/committees that may need the information to make sure that the study is done in a safe and 
proper manner, learn more about side effects, and/or analyze the results of the study. 

 ____________________________________________________________________________________________ 
27 
13.6 
Study Discontinuation 
In the event that the study is discontinued: 
• 
The study participants will not be able to continue with TEA. 
• 
The study will not compensate study participants for incomplete visits. 
14 
Data Handling and Record Keeping 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of the data 
reported.  All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Dark ink is required to ensure clarity of reproduced copies.  When making changes 
or corrections, cross out the original entry with a single line, and initial and date the change.  DO NOT 
ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
14.1 
Data Management Responsibilities 
The study coordinator will be responsible for data collection and management.  The study coordinator will 
use the CRFs to document study participant visit. They will also review data for completeness prior to 
signing the bottom of the CRF. Periodically, every six months, the primary investigator or co-investigators 
will review the CRFs and for completeness. The barostat measurements will be saved as part of the 
research file by the GI physiology lab staff at the end of each visit. 
14.2 
Types of Data 
Data for this study will include safety, barostat measurements, and survey results. 
14.3 
Timing/Reports 
The primary investigator will review the study documents with the study coordinator every six months. 
14.4 
Study Records Retention 
Study documents should be retained for a minimum of 3 years after the final study publication. 
14.5 
Protocol Deviations 
Protocol deviations will be documented in a deviation log kept on the shared drive with all other study 
documents. Deviations will be reported to the IRB for review as required. 

 ____________________________________________________________________________________________ 
28 
15 
PUBLICATION POLICY 
Following completion of the study, the investigator is expected to publish the results of this research in a 
scientific journal.  The International Committee of Medical Journal Editors (ICMJE) member journals have 
adopted a trials-registration policy as a condition for publication.  This policy requires that all clinical trials 
be registered in a public trials registry such as ClinicalTrials.gov*, which is sponsored by the National 
Library of Medicine.  Other biomedical journals are considering adopting similar policies.  For grants and 
cooperative agreements, it is the Institution’s responsibility to register the trial in an acceptable registry.  
In addition, NIH Public Access Policy requires the principal investigator to submit journal articles that arise 
from NIH funds to the digital archive PubMed Central.  
The ICMJE defines a clinical trial as any research project that prospectively assigns human study 
participants to intervention or comparison groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome.  Studies designed for other purposes, such as to study 
pharmacokinetics or major toxicity (e.g., Phase I trials), would be exempt from registering trials in a public 
registry such as ClinicalTrials.gov.  
 
SUPPLEMENTS/APPENDICES 
Appendix A: Schedule of Events  
 

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29 
APPENDIX A: SCHEDULE OF EVENTS 
A detailed schematic describing all visits and assessments. 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Informed 
consent 
X 
 
 
 
 
Documentation 
of current IBS-
C symptoms 
via the IBS 
(GSRS-IBS) 
X 
X 
X 
X 
X 
Documentation 
of current 
laxative and/or 
antispasmodic 
use 
X 
X 
X 
X 
X 
Rectal Enema 
X 
X 
X 
X 
X 
Baseline 15 
minutes 
X 
X 
X 
X 
X 
Experimental 
Protocol – 
Example of 
randomized 
TEA 
ST36-100Hz 
ST36-25Hz 
PC6-100Hz 
PC6-25Hz 
Sham-TEA 
Pregnancy Test 
(if participant is 
a woman with 
child bearing 
potential. If the 
woman is not 
on a birth 
control method) 
X 
X 
X 
X 
X