Self-Administered Hypnotherapy for Functional Dyspepsia
Phase: NA
Conditions: Functional Dyspepsia
Sponsor: Sarah Kinsinger

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
Protocol Outline 
 
Protocol Title: Self-Administered Hypnotherapy for Functional Dyspepsia 
Protocol Version: 4.0 
Protocol Date: 4/13/20 
Principal Investigator: Sarah Kinsinger, PhD 
Research Team: Sarah Kinsinger, PhD, Mukund Venu, MD, Olafur Palsson, PsyD 
(University of North Carolina, Chapel Hill) 
 
I. 
Abstract 
 
Functional dyspepsia (FD) is a very common health problem, affecting up to 20% of 
the world’s population, characterized by upper gastrointestinal (GI) tract symptoms, 
including epigastric pain, postprandial fullness, and early satiety1.  These symptoms 
occur in the absence of any structural abnormalities2.  FD has significant economic 
impact due to financial cost related to health care utilization as well as indirect cost 
associated with missing work and impaired work performance.  Patients with FD also 
report significant reductions in quality of life and increased rates of psychological 
distress3.  There are few effective treatment options for FD.  Medications typically 
include trials of proton pump inhibitors, prokinetic agents, or tricyclic antidepressants4.  
However, there is limited efficacy for these pharmacological treatments and current 
treatment approaches are considered unsatisfactory4,5.     
Psychological treatments have demonstrated good efficacy for functional GI disorders 
such as irritable bowel syndrome (IBS).  For example, gut-directed hypnotherapy has 
been studied extensively as a treatment for IBS with over 24 published trials, 10 of which 
are randomized controlled trials6. These studies consistently demonstrate significant 
improvements in central IBS symptoms (abdominal pain, bowel habits) following a 
course of hypnotherapy6.  FD and IBS are thought to have overlapping pathophysiology, 
including altered gut motility, visceral hypersensitivity, and abnormal central processing 
of visceral signals.  Many of these underlying mechanisms in FD can potentially be 
targeted by hypnotherapy via brain-gut pathways.  For example, hypnosis has been 
shown to decrease gastric emptying time in patients with dyspepsia.7   
To date there has only been one published trial of gut-directed hypnotherapy for 
functional dyspepsia, but with promising results8.  Calvert and colleagues found that 73% 
of patients in the hypnotherapy group had significant improvement in dyspeptic 
symptoms at long-term follow-up, compared to 34% of patients receiving supportive 
therapy plus a placebo pill and 43% of patients receiving medical treatment.  
Additionally, patients in the hypnotherapy group had dramatic reductions in medication 
use and physician consultations at follow up.   
The goal of the current study is to develop and conduct a pilot test of effectiveness of 
a self-administered gut-directed hypnotherapy intervention for treatment of FD, with the 
aim of assessing its potential as an inexpensive, easy-to-use and efficacious treatment for 
the disorder.   
 
 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
II. 
Background and Significance/Preliminary Studies 
 
Background and Significance  
Both patients and providers are frustrated by the limited treatment options for FD.  
This is a chronic condition and many patients continue to seek medical care for poorly 
managed symptoms, including multiple physician office visits and investigative 
procedures.  More effective treatment options are needed to reduce this health care 
burden.  Behavioral treatments (e.g., gut-directed hypnotherapy) are highly effective for 
other functional gastrointestinal disorders and have shown promise for FD.6  However, 
additional research is needed to establish behavioral treatment as an efficacious and 
realistic approach for this condition.   
There have been a few trials of very diverse forms of psychotherapy in FD with 
varying degree of reported success8-18; however, no treatment has had adequate testing 
and all of them involve a course of many visits to a highly specialized mental health 
professional which is expensive and not available in most places.  To date, one of the 
most successful and best designed trials of this kind has been Calvert et al.’s randomized 
controlled study of hypnotherapy for FD8.  This trial found significant improvements in 
FD symptoms and significant reductions in health-care utilization following a course of 
hypnotherapy with superior results compared to the two control groups and there was full 
maintenance of the treatment effect beyond one year follow-up.  These therapeutic effects 
demonstrate impressive potential for hypnosis as a therapy option in FD.  However, it is 
notable that the intervention tested by Calvert et al. consisted of a 12-session course of 
treatment with a specialized GI hypnotherapist, which means that generalizability of this 
approach is very limited due to significant cost barriers and limited availability of therapy 
expertise.  However, other work in GI hypnosis, including two studies of co-investigator 
Palsson, has demonstrated that hypnosis treatment that is self-administered by patients 
via audio recordings without any therapist involvement can be highly efficacious in 
improving GI symptoms19,20.  That form of delivery could make hypnotherapy a much 
more widely available treatment option if proven effective, as it could be delivered in a 
very inexpensive and easily disseminated form.  Our present study therefore aims to 
replicate the findings by Calvert et al. demonstrating that hypnosis treatment (HYP) can 
lead to clinically significant improvements in dyspeptic symptoms, while testing it in an 
audio-recorded easy-to-use self-administered format.  
Patients are increasingly skeptical of long-term medication use for conditions such as 
FD due to concerns about risks and side-effects of medications like proton pump 
inhibitors.  A large number of patients with FGIDs are already using complementary and 
alternative medicine approaches21 and we suspect that patients will be receptive to a non-
pharmacological treatment program that they can participate in from home.       
The results of the current study have the potential to significantly impact the clinical 
management of patients with FD.  Although there is strong scientific support for the role 
of interventions targeting brain-gut pathways and psychological factors in symptom 
severity for patients with FD, psychological treatments are not commonly recommended 
for this population.  Our study would provide further support for hypnotherapy as a 
behavioral treatment for this condition and our proposed administration of the treatment 
(self-administered via audio recordings) would increase the generalizability and 
accessibility of this treatment.  

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
A common criticism of psychological treatments for GI disorders is poor 
dissemination and access to treatment, in part due to the cost of treatment, which 
generally requires between 6 and 12 sessions with a therapist.  For example, gut-directed 
hypnotherapy and cognitive behavioral therapy are well established evidence-based 
treatments for IBS; however, these treatments are unavailable to many individuals.  
Barriers to accessing these treatments include a limited number of well-trained 
psychologists to offer these specialized treatments and the significant cost and time 
commitment required of patients.  Our study aims to address these barriers by offering a 
self-administered treatment.  Patients would administer the hypnotherapy treatment in 
their home by using convenient, web-based audio recordings.  This methodology has 
been used previously in hypnotherapy trials for IBS and pediatric abdominal pain with 
good results22,23.  If the self-administered home hypnosis treatment tested in this trial 
proves efficacious, this will reduce treatment cost and enable us to make it available 
nationwide to the many patients who live too far from a specialized center to be able to 
attend multiple therapist sessions typically required.  This innovative delivery method 
will also have the potential to improve the care of large numbers of patients by 
establishing a highly generalizable and inexpensive non-pharmacological treatment for 
this population. 
Additionally, our study is innovative in that we will test delivery of the treatment with a 
custom-designed easy-to-use secure online platform that can be used on practically any 
device and is designed to help motivate patients and direct them through the treatment 
course (an important consideration in self-administered treatment) by providing 
adherence feedback and presenting them automatically with the right content at the 
appropriate time points in the treatment course. 
 
Preliminary Studies 
A published pilot study of hypnotherapy for IBS delivered entirely through audio 
recordings by co-investigator Palsson and his colleagues serves as a model for the 
hypnosis treatment in this FD trial19.  That study found that IBS patients who completed a 
seven-session self-administered audio home hypnosis treatment course were twice as 
likely (53% vs 26%) to have a reduction in their gastrointestinal symptoms by half or 
more at 6 months compared to matched control patients of the same age and sex and 
equal symptom severity who only received standard medical care.  We will script the 
audio-recorded hypnosis protocol in the present trial to be similar in structure and therapy 
approach, as IBS and functional dyspepsia are both functional GI disorders and have 
many similarities and a high degree of overlap (the intervention tested in the prior 
hypnosis trial by Calvert et al., that showed high success in FD treatment, also utilized 
modified IBS hypnosis treatment for that purpose). 
 
 
III. 
Study Aims 
 
The purpose of this pilot study is to develop and test a hypnotherapy (HYP) treatment 
program for functional dyspepsia (FD) that can be self-administered using on-line audio 
recordings.  We hypothesize that patients will be receptive to the self-administered 
treatment design and willing to participate and complete the 12-week treatment program.  

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
Furthermore, we expect that patients will experience a significant reduction in FD 
symptoms following the intervention.  Our specific aims include: 
 
Aim 1: Feasibility and Acceptability of Treatment 
The study will assess whether patients with FD will be willing to participate in the on-
line treatment program and the majority of patients enrolled in the study will complete 
the 12 week program, utilize the materials sufficiently, and report average to above 
average satisfaction with treatment. 
 
Aim 2: Treatment Effectiveness 
The primary endpoint for Aim 2 is significant reduction in pre- to post- treatment FD 
symptom scores.  Secondary endpoints include significant improvements in pre- to post- 
treatment score on psychological indices (e.g., anxiety) and disease-specific quality of 
life.   
 
IV. 
Administrative Organization 
 
All administrative activities related to the study will take place within the Division of 
Gastroenterology and Nutrition at Loyola University Medical Center (LUMC).  
Administrative offices for the division are located in the Fahey Building on the LUMC 
campus where office furniture, file cabinets, and use of essential equipment (e.g., copier, 
fax, phone, computer) will be provided.   
 
 
V. 
Study Design 
a. Experimental design of the study: 
This is a non-randomized observational study designed to provide preliminary 
data on the feasibility and effectiveness of a self-administered HYP treatment 
for FD.   
 
b. Study population general description 
Eligible patients will be referred by Gastroenterologists within the Digestive 
Health Program at Loyola University Medical Center and will have received a 
diagnosis of functional dyspepsia.  Additionally, any patients with functional 
dyspepsia referred by outside providers to Dr. Kinsinger's GI Behavioral 
Medicine Service at LUMC will be made aware of the study. 
 
c. Sample size determination and power analyses 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
We will enroll 23 adults with FD from the Loyola University Medical Center 
outpatient gastroenterology practices, with the aim of assessing feasibility and 
acceptability of HYP treatment using on-line audio recordings.  Sample size 
was determined for aim 1 of the study.  Allowing for up to 20% drop-out and 
having at least 16 patients complete the study through the end of treatment 
(where the primary endpoint will be measured) will provide sufficient 
participant feedback on the web interface as well as the pilot data needed to 
power a future randomized controlled trial.    
 
 
d. Study outcomes/endpoints 
The primary endpoint for this study will be FD symptom scores.  Secondary 
endpoints will be disease-specific quality of life, psychological indices, and 
patient satisfaction. 
 
VI. 
Study Procedures 
a. Subject selection procedures: 
 
We will enroll 23 adults with FD. 
 
Inclusion criteria 
(1) Diagnosis of functional dyspepsia by a gastroenterologist 
(2) Meeting ROME IV diagnostic criteria for functional dyspepsia 
(3) At least 18 yrs of age (no upper age limit) 
(4) Able to give informed consent 
(5) English speaking 
(6) Have daily personal access to the Internet via laptop or desktop 
computer, tablet or a smartphone. 
Exclusion criteria 
(1) Concomitant organic gastrointestinal disease 
(2) Diagnosed or presenting with serious mental illness (e.g., 
eating disorder, schizophrenia, psychosis, obsessive-
compulsive disorder, post-traumatic stress disorder, or a 
dissociative disorder) 
(3) Cognitive or language barriers that make completion of 
questionnaires difficult or limit understanding of a verbal 
intervention (hypnosis) 
i. Recruitment procedures 
1. Where will recruitment occur? 
Participants will be recruited from the Loyola University 
Medical Center outpatient gastroenterology practices.  Dr. 
Mukund Venu, Director of Clinical Operations for the 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
Division of Gastroenterology will be actively recruiting 
patients in his clinics and will encourage our 
gastroenterology colleagues (15 gastroenterologists and 5 
mid-level providers) to refer patients to the study.  The 
research coordinator for the study will review patient charts 
in our division's outpatient gastroenterology practices to 
pre-screen for eligibility.  We will obtain a waiver of 
consent for this process. 
We will also advertise the study on social media (Loyola 
Medical Center twitter handle and facebook page) and 
through the Loyola University student listserv.  We will 
obtain IRB approval for all advertisements. 
2. Where and when will consent be obtained? 
Consent will be obtained either at the patient's outpatient 
visit with their gastroenterologist or at the time of the 
screening evaluation visit with Dr. Kinsinger.  The research 
coordinator will recruit patients from designated 
gastroenterology clinics and consent patients at those visits.  
If patients are referred for the study from other 
gastroenterology clinics that are not staffed by the research 
coordinator, Dr. Kinsinger will obtain consent at the time 
of the screening visit.  The consent process will occur prior 
to beginning the screening evaluation. During the COVID-
19 health crisis, all screening visits will be conducted 
electronically via telemedicine and consent will be obtained 
orally.  The study coordinator will email participants a PDF 
copy of the consent form prior to their telehealth screening 
visit to review.  The study investigator (Dr. Kinsinger) will 
then review the consent form at the start of the video 
screening visit and ask the participant to state their consent 
verbally on the video in response to the following question: 
“Have you read the consent form and do you understand 
the procedure, risks, and benefits of the research study and 
agree to participate?”.  The study investigator will 
document the patient’s verbal consent.  
 
 
3. Who will obtain consent?  Dr. Kinsinger or the research 
coordinator will obtain consent. 
4. What is the advertising plan, if applicable? 
a. Social media (Loyola Medical Center twitter handle 
and facebook page; Dr. Kinsinger's LUMC 
webpage) 
b. Loyola University student listservs 
c. Display brochures in gastroenterology outpatient 
clinics 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
 
5. What recruitment materials will be provided to the potential 
participant (brochures/information sheets/video 
presentation)? 
a. Website describing the study 
b. Brochures with study information 
c. Brief video conducted by Dr. Kinsinger describing 
the study (see Appendix A for a script of this video; 
filming will be done after IRB approval is obtained) 
d. We are in the process of developing these marketing 
materials and will submit all advertisements to the 
IRB to obtain approval prior to use.  
 
ii. Screening procedures 
1. What procedures are required for screening? 
 
Eligible participants referred by a Loyola 
Gastroenterologist will meet with Dr. Kinsinger for a 
screening evaluation.  The purpose of this appointment is to 
determine appropriateness for behavioral treatment and 
provide education on FD, inform potential participants 
about the study and complete written or oral consent if they 
choose to participate and are eligible.  Patients that learn 
about the study from outside of Loyola will need to meet 
with a Gastroenterologist (Dr. Venu, Co-I) to confirm 
diagnosis of functional dyspepsia prior to being enrolled in 
the study. 
 
Dr. Kinsinger has dedicated space within the Loyola 
Outpatient Center for patient care that can be utilized for 
the screening evaluation where patient privacy and 
confidentiality can be maintained.  
 
During the COVID-19 health crisis, the screening visit will 
be conducted electronically via one of the telehealth video 
platforms approved by Loyola Medicine for use with 
patients during the pandemic (doxy.me, Doximity, Skype, 
FaceTime, or Zoom). 
 
Following this screening appointment, enrolled patients 
will receive an email with information for accessing the on-
line platform where they will complete pre-treatment 
assessment forms and access treatment materials.  
 
2. What is the screening schedule (number of visits, length of 
visits)? Screening will involve a single, 1 hr appointment. 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
 
3. Which screening tests/procedures are part of standard care 
and which are for research purposes only?  The screening 
will be for the purpose of the research study. 
 
4. What happens with screen failures (including any data 
gathered during screening)?  Data will not be collected on 
patients that are screened as ineligible for the study.  
However, these patients will be provided with 
recommendations for alternative treatment options by their 
gastroenterologist (medications, diet changes), alternative 
psychological treatments within the Loyola GI behavioral 
medicine program, or a referral to an outside provider 
depending on patients' needs. 
b. Randomization procedures (if applicable): N/A 
c. Study Intervention 
 
Patients will be given access to a password protected website containing HYP 
treatment materials.  They will be instructed by the study coordinator to log on 
to the website within 1 week to complete baseline assessment questionnaires 
and watch an instructional video.  This video will be pre-recorded by Dr. 
Kinsinger (study PI).  The content of the video will include educational 
information about the patient's diagnosis, provide rationale for hypnotherapy 
treatment, set expectations for treatment, and dispel myths about 
hypnotherapy.  The video will also provide instructions on implementing the 
treatment protocol, including guidance on selecting a time and place to 
practice hypnotherapy and recommendations for weekly practice with audio 
recordings (5x per week).  See Appendix B for a full script of this 
introductory video (video will be filmed after we receive IRB approval).   
 
We have developed a 7- session, hypnosis protocol for functional dyspepsia 
that is similar to an evidence-based protocol for irritable bowel syndrome 
developed by co-investigator Dr. Palsson, which has been found to be 
efficacious in 7 published studies24.  This protocol was jointly scripted by Drs. 
Kinsinger and Palsson, and is based on the successful scripted therapy 
approach for IBS, with appropriate adaptations.  See Appendix C for the full 
scripted protocol of the 7 hypnotherapy sessions as well as the shorter practice 
session that will be audio recorded.  This will be the full content of the audio 
recordings, subject to final minor edits and polishing, prior to recording which 
will be scheduled after we receive IRB approval. 
 
Participants will have access to audio recordings of the protocol (pre-recorded 
by Dr. Kinsinger, study PI) via secure streaming online that will work on any 
computer or mobile device with internet access. Patients will be assigned a 
new hypnotherapy session to listen to every 2 weeks and these will become 
automatically available in the correct sequence.  Each hypnotherapy session 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
will be approximately 30 mins in length.  The hypnotherapy sessions are 
verbally guided exercises, similar to guided meditation.   The hypnotherapy 
sessions encourage patients to enter a state of focused mental attention and 
deep physical relaxation during which images and verbal suggestions are used 
to positively influence emotional and physical symptoms.  The session 
developed for this intervention will specifically focus on mechanisms that 
contribute to functional dyspepsia symptoms, such as impaired relaxation of 
the stomach and pain sensitivity.  For example, after facilitating a deeply 
relaxed state patients will be asked to visualize drinking a cool liquid that has 
a therapeutic effect on the stomach (i.e., decreases pain, allows the stomach to 
stretch and make room for food).  Each of the 7 sessions will utilize different 
imagery. 
Patients will be instructed to practice a shorter 10-12 minute audio recording 5 
times per week in between the longer sessions.  After the 12-week treatment 
course is completed, patients will be able to continue to listen to the shorter 
home hypnosis recordings as often as they choose for up to one year.   
The web page will give patients pop-up notices to encourage them to increase 
their frequency of practice if their weekly frequency drops below the 
recommended 5 days of home practice.  Patients who do not log into the 
online system to complete a hypnosis exercise for 7 consecutive days will be 
contacted by the study coordinator to discuss whether the patient is interested 
in continuing with the trial.   
Additionally, patients will receive phone or MyLoyola messaging (patient 
preference) from a study coordinator every 2 weeks to encourage adherence 
and troubleshoot any difficulty using the recordings and assess any adverse 
effects.  If they have any difficulties or discomforts associated with the self-
administered hypnosis intervention during the trial, they will have an 
opportunity to talk with Dr. Kinsinger on the phone to resolve these. 
 
The Study Website 
The patient portal where study participants will access the hypnosis audio 
recordings and study questionnaires is www.FDHypnosis.com. It is a secured 
web page where the patients log in with their unique study ID and password. 
Once patients log-in, they are presented with an online audio player that 
enables them to either play one of seven main hypnosis sessions, which are to 
be completed in a fixed sequence --  one every two weeks during the 
intervention period, or they will be presented instead with the shorter hypnosis 
exercise to be completed five times a week in between the main hypnosis 
session. Which type of session is presented at a given time is automatically 
determined by the web page software. This ensures that the participants 
complete the main intervention sessions approximately on schedule. When it 
is time for participants to complete study questionnaires, a study questionnaire 
button will also become visible within this patient portal, with instructions to 
click it to complete the study questions. In this way, the patient portal ensures 
that patients complete their study tasks at the right times. The web system will 
record patient completion of hypnosis practice sessions. Patients are asked to 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
press a button after listening to each audio session to indicate that they have 
completed that session successfully.  The web audio player is a streaming 
internet player, but it completes background download of the whole hypnosis 
session file in use soon after playing of the session starts, so the audio 
recording will continue playing to completion of the session even if Internet 
connection is interrupted during the listening.  
 
To safeguard the privacy of study participants online, they will complete all 
study tasks in the online patient portal in a de-identified manner. No 
information that can reveal their personal identity is collected by the portal 
web page or the online study questionnaires: No IP addresses, names, e-mail 
addresses, dates of birth or any such identifying information is collected 
online. Patients are only identified in the online study system by their 
randomly assigned study ID number. 
 
In a separate study management web page, study staff will be able to log in to 
see which main hypnosis sessions each patient has completed and whether 
they are significantly overdue for completing the next session, and also 
whether they have completed the study questionnaire at the expected time 
points, and the frequency of practice of the shorter exercises for each 
individual. This information will alert the study staff to contact patients who 
are not keeping up with study tasks with reminders.  
 
d. Study Assessments and Activities 
Study Assessments: 
At baseline (week 0), week 6 (mid-treatment), week 12 (post-treatment), 
and at 12 weeks following end of treatment (i.e., 3 month follow up) 
participants will be asked to complete a set of questionnaires listed below. 
See Appendix D for a complete list of survey items and questionnaires. 
Study assessments will be administered electronically through the 
password-protected online platform via highly secure Qualtrics Research 
Suite Software, and all questionnaire data will be collected in a fully de-
identified manner that neither obtains nor stores online any information 
that can reveal the personal identify of participants.  Participants will be 
assigned a unique subject code that will be associated with his/her 
questionnaire data.   
 
Patients will be paid for completing each of the assessments: They will 
receive Amazon gift certificates in the amount of $25 each time, except 
the amount will be $50 at the  end-of-treatment point (as this is the most 
important assessment time point).  Thus, patients will receive a total 
compensation of $125 for completing all 4 assessments in the study.   
 
Additionally, participants will be invited to participate in a phone 
interview to provide qualitative feedback about their experience with the 
intervention and using the web interface.  This will be a semi-structured 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
interview with the research coordinator to assess patient experience and 
satisfaction.  The interview will take place within one month following the 
final hypnotherapy session. 
 
Patients will complete the following questionnaires: 
 Demographics and psychosocial history (administered at week 0 
only): basic demographic data (e.g., age, gender, education) as well as 
disease related information (symptom severity, medication use).     
 The Rome IV Dyspepsia Module will be administered at baseline to 
confirm diagnosis of functional dyspepsia.  This self-report 
questionnaire is used to diagnosis functional GI disorders based on 
Rome IV criteria.2 
 The Patient Assessment of Upper Gastrointestinal Symptom 
Severity Index (PAGI-SYM) will be administered to assess symptom 
severity.  The PAGI-SYM measures 20 dyspeptic symptoms on a 6-
point Likert scale, 0 (no complaints) – 5 (severe complaints), 
subdivided into six subscales: heartburn/regurgitation, 
nausea/vomiting, postprandial fullness/early satiets, bloating, upper 
abdominal pain, and lower abdominal pain.  The measure has 
demonstrated good reliability and validity for measuring symptom 
severity in patients with functional dyspepsia.25  
 The Short Form Napean Dyspepsia Index (NDI-SF) is a 10-item 
disease specific quality of life questionnaire developed for clinical 
trials in functional dyspepsia.  The NDI has been established to have 
excellent psychometric properties26 and responsiveness to treatment 
change has been confirmed27 and the 10-item short form is 
recommended for use in clinical trials.28 
 Visceral Anxiety (VSI): The VSI is a 15-item questionnaire that will 
be used to assess gastrointestinal specific anxiety29 .  This measure 
assesses fears of GI symptoms and is a predictor of symptom severity 
in patients with functional GI disorders.  The VSI  uses a 6 point likert 
scale response format with total scores ranging from 0 to 75; higher 
scores indicate more severe symptom-related anxiety.   
 The Brief Symptom Inventory (BSI) will be used to assess 
depression, anxiety, and somatization.30  The BSI is an 18-item 
questionnaire using a 5-point likert scale with scores ranging from 0 to 
68; higher scores indicate higher levels of distress.   
 Thought Impact Scale- Short Form (TIS-SF).  This 17-item 
questionnaire is a short-form version of the Thought Impact Scale, a 
newly validated measure designed to predict clinical response to 
hypnosis treatment.  The TIS-SF will be administered at baseline only 
to assess whether the traits that it measures (i.e., subconscious 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
connectedness) correlates with the degree of FD symptom 
improvement in the study.31 
 Adherence to Hypnosis Practice: Use of hypnosis sessions will be 
recorded automatically by the audio player page on the treatment web 
page, to track frequency of home practice of hypnotherapy by the HYP 
intervention participants.   
 Health care utilization: Patients will be asked at baseline, end of 
treatment and at 3-month follow-up to report the number of outpatient 
visits and procedures they have had within the last 3 months related to 
their functional dyspepsia symptoms.  They will also be asked to 
report any changes in medications they have taken related to their 
functional dyspepsia symptoms. 
 Satisfaction with the treatment and global outcome: At the end of 
treatment only (12 weeks), patients will be asked additional two 
questions to assess how satisfied they were overall with their assigned 
treatment (on a 7-point scale from "Extremely dissatisfied" to 
"Extremely satisfied") and how they feel their FD symptoms have 
changed overall since before the start of treatment (from "very much 
worse" to "very much improved"). 
 Satisfaction with web-based platform. At the end of treatment only 
(12 weeks), patients will be asked an open-ended question to obtain 
feedback on their experience using the web-based platform for 
treatment (“Please describe any difficulties you had using the web 
interface and/or suggestions on ways we could improve the website.”). 
 
VII. 
Safety Monitoring Plan 
a. Definition of adverse events, serious adverse events 
 
 Participant risks in this study are minimal. We will screen individuals 
prior to enrolling them in the study and any patients with 
psychological comorbidities that increase risk of adverse events 
associated with hypnotherapy (e.g., post-traumatic stress disorder) will 
be ineligible to participate.   However, even with careful screening, it 
is possible that participants may experience emotional discomfort or 
increased anxiety as a result of participating in the hypnotherapy 
treatment or completing study questionnaires. We will encourage 
participants to contact us should they experience discomfort or 
emotional distress during course of treatment.  Dr. Kinsinger, study PI 
and licensed clinical psychologist, will be available to discuss these 
concerns and further assess the patients psychological functioning and 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
discontinue treatment if necessary.  We will also provide referrals for 
counseling outside of the study if needed.   
 
 We will take steps to reduce the risk of discomfort associated with 
answering questions on assessment measures related to psychological 
functioning by allowing participants to leave blank any questions that 
may make them uncomfortable.  The participant will be reminded that 
s/he has the option of stopping treatment and can refuse to answer any 
questions s/he is asked that s/he finds distressing. However, the study 
team shall determine if the extent of refusal may warrant removal of 
the participant from the research study to ensure complete and accurate 
data collection.  
 
b. What procedures will be used to monitor subject safety?   
 Participants will be given contact information for study personnel and 
encouraged to reach out if they experience an increase in 
psychological distress related to the treatment.  Participants will be 
told that they are welcome to withdraw from the study at any time.   
 We plan to use an electronic platform for this study to deliver the 
hypnotherapy sessions as well as to conduct all patient evaluations 
online. It is same technology as Dr. Palsson has used successfully for 
online data collection in multiple NIH-funded RCT clinical trials. All 
study questionnaires will be administered electronically in the 
password-protected online portal via highly secure Qualtrics Research 
Suite software, and all questionnaire data will moreover be collected in 
a fully de-identified manner that neither obtains nor stores online any 
information that can reveal the personal identity of participants. This is 
accomplished by associating patient responses only with their 
randomly assigned study ID numbers.   
 The online hypnotherapy program is considered an investigational 
device under the Food and Drug Administration (FDA) regulations 
and is categorized as a nonsignificant risk device. 
 Patient names will be keyed into unique subject code and the keyed 
file will be kept separate from the data file to ensure patient 
confidentiality.  Data downloads will be stored in a secure study folder 
in HIPAA-compliant LUMC file server space, with study folder access 
restricted to IRB-approved study personnel. Any non-electronic study 
data will be stored in locked filing cabinets, accessible only by IRB-
approved study personnel.  Data will be stored for 7 years after study 
completion per IRB policy.  
 
c. Who (list names) will identify, document, and report adverse events? 
Dr. Sarah Kinsinger, study PI 
 
d. What is the frequency for review of summarized safety information and 
who will perform the review (e.g., safety monitoring board)? 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
 
e. What are the stopping rules with regard to efficacy and safety? 
Patients are free to withdraw from treatment at any time. 
 
VIII. Analysis Plan 
Aim 1: Feasibility and Acceptability of Treatment.  Methods: Eligible and enrolled 
patients will be followed to assess the percentage who log-in to the web interface, utilize 
the materials sufficiently, complete the 12 week program, and report at least average 
satisfaction with treatment.  We will present descriptive statistics to report treatment 
satisfaction and patient-reported global ratings of outcome, both of which will only be 
assessed at 12 weeks.  Feasibility will be calculated as the proportion of participants who 
complete the FD HYP treatment program in comparison to those who drop out before 
treatment is completed.  We expect that the proportion of participants who are retained 
will be 80%, demonstrating feasibility of recruitment and retention. Treatment 
satisfaction will be calculated as the proportion of patients who started treatment 
(dropouts included) who report that they are satisfied with the treatment (i.e., endorse the 
response either options “Somewhat satisfied”, “Very satisfied” or “Extremely satisfied” 
on the 7-point treatment satisfaction measure). We expect that the majority of patients 
will report satisfaction with the treatment.  Sample size justification: For the aim of 
retention, a sample size of n=23 achieves 92.8% power for a one-sided exact test for a 
proportion retained of 80%.  This test assumes the null hypothesis proportion retained is 
50%, and we will reject the null hypothesis and conclude retention is acceptable should at 
least n=16 (69.6%) be retained.  Similarly, for the aim of satisfaction, a sample size of 21 
achieves 90.5% power for a one-sided exact test for a proportion satisfied of 50%.  This 
assumes 20% satisfaction under the null hypothesis, and we will reject the null hypothesis 
if at least 39% of the sample report they are satisfied with treatment.  Both tests were 
targeted at an =0.05 significance level.   
 
Aim 2: Treatment Effectiveness.  Methods: The primary analyses to estimate treatment 
effects in this study will be linear mixed effects regression analysis.  Mixed effects 
regression is flexible for modeling linear and nonlinear trends over time and robust to 
data missing at random.  A separate mixed effects model will be specified for each of our 
primary outcome variables (DSSI and NDI-SF).  Residual analysis will be performed and 
transformations of outcome measures will be applied as necessary.  These models will 
estimate treatment effects at each follow-up time point controlling for baseline score. 
Secondary endpoints include significant improvements in pre- to post- treatment score on 
psychological indices (e.g., anxiety) and disease-specific quality of life.  We will apply a 
similar approach using mixed effects regression analyses for these outcomes.  Analyses 
will be performed using SAS 9.4 (SAS Institute, Cary, NC). 
 
 
IX. 
Literature Cited 
1. Ford AC, Marwaha A, Sood R, Moayyedi P. Global prevalence of, and risk factors for, 
uninvestigated dyspepsia: A meta-analysis. Gut. 2015;64(7):1049-1057. 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
2. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal disorders. 
Gastroenterology. 2016;150(6):1380-1392. 
3. Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. Initial poor quality of life and 
new onset of dyspepsia: Results from a longitudinal 10-year follow-up study. Gut. 
2007;56(3):321-327. 
4. Vakil NB, Howden CW, Moayyedi P, Tack J. White paper AGA: Functional 
dyspepsia. Clin Gastroenterol Hepatol. 2017;15(8):1191-1194. 
5. Camilleri M, Stanghellini V. Current management strategies and emerging treatments 
for functional dyspepsia. Nat Rev Gastroenterol Hepatol. 2013;10(3):187-194. 
6. Palsson OS. Hypnosis treatment of gastrointestinal disorders: A comprehensive review 
of the empirical evidence. Am J Clin Hypn. 2015;58(2):134-158. 
7. Chiarioni G, Vantini I, De Iorio F, Benini L. Prokinetic effect of gut-oriented hypnosis 
on gastric emptying. Aliment Pharmacol Ther. 2006;23(8):1241-1249. 
8. Calvert EL, Houghton LA, Cooper P, Morris J, Whorwell PJ. Long-term improvement 
in functional dyspepsia using hypnotherapy. Gastroenterology. 2002;123(6):1778-1785. 
9. Orive M, Barrio I, Orive VM, et al. A randomized controlled trial of a 10 week group 
psychotherapeutic treatment added to standard medical treatment in patients with 
functional dyspepsia. J Psychosom Res. 2015;78(6):563-568. 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
10. Faramarzi M, Azadfallah P, Book HE, Rasolzadeh Tabatabai K, Taherim H, 
Kashifard M. The effect of psychotherapy in improving physical and psychiatric 
symptoms in patients with functional dyspepsia. Iran J Psychiatry. 2015;10(1):43-49. 
11. Kawata H, Oka T. The use of psychotropic drugs for functional gastrointestinal 
disorders: Are they beneficial? Nihon Rinsho. 2012;70(1):84-88. 
12. Faramarzi M, Azadfallah P, Book HE, Tabatabaei KR, Taheri H, Shokri-shirvani J. A 
randomized controlled trial of brief psychoanalytic psychotherapy in patients with 
functional dyspepsia. Asian J Psychiatr. 2013;6(3):228-234. 
13. Jee SR, Jung HK, Min BH, et al. Guidelines for the treatment of functional dyspepsia. 
Korean J Gastroenterol. 2011;57(2):67-81. 
14. Hjelland IE, Svebak S, Berstad A, Flatabo G, Hausken T. Breathing exercises with 
vagal biofeedback may benefit patients with functional dyspepsia. Scand J Gastroenterol. 
2007;42(9):1054-1062. 
15. Haag S, Senf W, Tagay S, et al. Is there a benefit from intensified medical and 
psychological interventions in patients with functional dyspepsia not responding to 
conventional therapy? Aliment Pharmacol Ther. 2007;25(8):973-986. 
16. Hamilton J, Guthrie E, Creed F, et al. A randomized controlled trial of psychotherapy 
in patients with chronic functional dyspepsia. Gastroenterology. 2000;119(3):661-669. 
17. Haug TT, Wilhelmsen I, Svebak S, Berstad A, Ursin H. Psychotherapy in functional 
dyspepsia. J Psychosom Res. 1994;38(7):735-744. 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
18. Arn I, Theorell T, Uvnas-Moberg K, Jonsson CO. Psychodrama group therapy for 
patients with functional gastrointestinal disorders--a controlled long-term follow-up 
study. Psychother Psychosom. 1989;51(3):113-119. 
19. Palsson OS, Turner MJ, Whitehead WE. Hypnosis home treatment for irritable bowel 
syndrome: A pilot study. Int J Clin Exp Hypn. 2006;54(1):85-99. 
20. van Tilburg MA, Chitkara DK, Palsson OS, et al. Audio-recorded guided imagery 
treatment reduces functional abdominal pain in children: A pilot study. Pediatrics. 
2009;124(5):e890-7. 
21. Stake-Nilsson K, Hultcrantz R, Unge P, Wengstrom Y. Complementary and 
alternative medicine used by persons with functional gastrointestinal disorders to 
alleviate symptom distress. J Clin Nurs. 2012;21(5-6):800-808. 
22. Rutten JM, Vlieger AM, Frankenhuis C, et al. Gut-directed hypnotherapy in children 
with irritable bowel syndrome or functional abdominal pain (syndrome): A randomized 
controlled trial on self exercises at home using CD versus individual therapy by qualified 
therapists. BMC Pediatr. 2014;14:140-2431-14-140. 
23. van Tilburg MA, Chitkara DK, Palsson OS, et al. Audio-recorded guided imagery 
treatment reduces functional abdominal pain in children: A pilot study. Pediatrics. 
2009;124(5):e890-7. 
24. Palsson OS. Standardized hypnosis treatment for irritable bowel syndrome: The north 
carolina protocol. Int J Clin Exp Hypn. 2006;54(1):51-64. 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20 
 
25. Rentz AM, Kahrilas P, Stanghellini V, et al. Development and psychometric 
evaluation of the patient assessment of upper gastrointestinal symptom severity index 
(PAGI-SYM) in patients with upper gastrointestinal disorders. Qual Life Res. 
2004;13(10):1737-1749. 
26. Talley NJ, Verlinden M, Jones M. Validity of a new quality of life scale for 
functional dyspepsia: A united states multicenter trial of the nepean dyspepsia index. Am 
J Gastroenterol. 1999;94(9):2390-2397. 
27. Talley NJ, Tack J, Ptak T, Gupta R, Giguere M. Itopride in functional dyspepsia: 
Results of two phase III multicentre, randomised, double-blind, placebo-controlled trials. 
Gut. 2008;57(6):740-746. 
28. Talley NJ, Verlinden M, Jones M. Quality of life in functional dyspepsia: 
Responsiveness of the nepean dyspepsia index and development of a new 10-item short 
form. Aliment Pharmacol Ther. 2001;15(2):207-216. 
29. Labus JS, Mayer EA, Chang L, Bolus R, Naliboff BD. The central role of 
gastrointestinal-specific anxiety in irritable bowel syndrome: Further validation of the 
visceral sensitivity index. Psychosom Med. 2007;69(1):89-98. 
30. Derogatis LR, Melisaratos N. The brief symptom inventory: An introductory report. 
Psychol Med. 1983;13(3):595-605. 
31. Palsson OS. Development and validation of the thought impact scale: A measure of 
subconscious connectedness. American Journal of Clinical Hypnosis. 2019. 

 
Protocol Version #: 4.0 
  Version Date: 4/13/20