Effects of Open-label vs Double-blind Treatment in IBS.
Phase: NA
Conditions: Irritable Bowel Syndrome, Placebo Effect, Placebos, Peppermint Oil
Sponsor: Beth Israel Deaconess Medical Center

Study Protocol, Version 6.0 
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CLINCAL STUDY PROTOCOL 
 
 
 
Efficacy of Open-label vs Double-blind Treatment in IBS. 
 
 
IND Number:  
126556 
NCT Number: 
NCT02802241 
 
Study Sponsor:  
Anthony Lembo, MD 
 
330 Brookline Avenue 
 
Boston, MA 02215 
 
Telephone: 617.667.2138 
 
Fax: 617.667.1171 
 
Date:  
June 15, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the ethical principles stated in the Declaration of Helsinki, and other applicable 
regulatory requirements. 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
Protocol 
Section 
Contents 
Protocol Page 
1 
Study Objectives  
3 
2 
Background and Rationale 
3 
3 
Study Design 
4 
4 
Selection and Enrollment of Participants 
5 
5 
Study Interventions 
6 
6 
Study Procedures 
7 
7 
Safety Assessments 
9 
8 
Statistical Considerations 
10 
9 
Administrative Requirements  
12 
Appendix 1 
Schedule of Study Procedures 
14 
Appendix 2 
IBS – Symptom Severity Scale 
14 
Appendix 3 
List of Evaluations to be Completed at Each Visit  
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol, Version 6.0 
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1. Study Objectives 
 
1.1 Primary Objectives 
The primary objectives of this study are to: (1) to determine whether 6 weeks of open-label 
placebo, double-blind placebo and no additional treatment control results in different clinical 
outcomes in patients with IBS and (2) assuming there are significant differences (a) to 
determine whether open-label placebo results in greater clinical improvement compared to no 
additional treatment control and (b) to determine if open-label placebo results in greater clinical 
outcome than double blind placebo.   
 
1.2 Secondary Objectives 
 
To confirm our previous finding that the COMT val158met polymorphism is associated with 
placebo response.   
 
To replicate our previous finding that certain personality traits (extraversion, agreeableness, 
openness) are associated with the placebo response in IBS.   
 
Using ethnographic interviews to obtain insight into patients’ experiences, including their 
views of the clinical encounter. 
 
An exploratory objective of the study is to obtain pilot data to assess whether double-blind 
peppermint oil results in greater clinical improvement compared to double-blind placebo in 
patients with IBS. 
 
2. Background and Rationale 
 
2.1 Background on IBS 
IBS is one of the top 10 reasons for seeing a primary care physician, and the symptoms of IBS 
are present in 7-15% of the North American population. IBS is a chronic functional 
gastrointestinal disorder that is not a disease since there is no definitive pathophysiology or 
biomarker. Endpoints in clinical trials with IBS are based on subjective responses and include 
abdominal pain, altered bowel habits and bloating. The average placebo response in 
randomized double-blind placebo controlled trials in IBS is approximately 41%, making IBS a 
particularly good population to study placebo. The explanation for the high placebo response in 
clinical trials such as IBS is unclear and attempts at reducing the placebo response in clinical 
trials have been largely unsuccessful. To date no studies have compared double-blind placebo 
to open-label placebo as proposed in this study. This information is critical to understanding the 
effects of placebo as it relates to the design of clinical trials. Likewise, this information is critical 
to clinical practice, since clinical practice is unblinded yet decisions are based on inferences 
made from blinded randomized controlled trials. Including both blinded and open-label arms will 
allow us to quantify, for the first time prospectively, the difference in efficacy between these 
kinds of administrations. Such knowledge will strengthen inferences on clinical practice that are 
based on blinded randomized controlled trials.   
2.2 Study Rationale 

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The vast majority of placebos are administered with concealment (i.e., blinded assignment in 
RCTs).  Most clinicians and researchers believe that either deception or concealment is 
necessary to achieve a placebo response. To date, few studies have directly compared the 
effects of open-label placebo and double-blind placebo. We propose a novel, multi-disciplinary 
design to answer multiple clinical and research design questions concerning placebo effects.  
3. Study Design 
 
3.1 Overall Design and Plan of the Study 
This study aims to investigate the effects of open-label placebos with double-blind placebos as 
administered in a randomized controlled trial in a 6-week trial with 313 IBS patients on standard 
treatment for IBS randomly assigned to one of four arms: 
 
open-label placebo 
 
double-blind placebo 
 
double-blind peppermint oil 
 
no additional treatment control. 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2 Efficacy Assessments 
 
Primary Outcome Measure 
The primary outcome measure is the IBS symptom severity scale (IBS-SSS). The IBS-SSS is a 
questionnaire that measures the sum of the participant’s evaluation on a 100 point scale of each 
of five items: severity of abdominal pain, frequency of abdominal pain, severity of abdominal 
distension, dissatisfaction with bowel habits, and interference with quality of life. All five 
components contribute equally to the score, yielding a theoretical range of 0-500, in which a 
higher score indicates a more severe condition.  The responder will be considered a patient who 
has at least a 50 point decrease in their IBS-SSS from baseline to Visit 3. Using data from our 
previous IBS trial the calculated Cronbach's alpha is .70.  
 
Secondary Outcome Measures  
IBS-Adequate Relief: A single question: “In the last seven days, have you had adequate relief 
of your IBS symptoms?  Yes/No” 
 
IBS-Global Improvement: A single question: “Compared to the way you felt one week ago, 
have your symptoms over the past 7 days been: 1) Substantially Worse, 2) Moderately Worse, 
3) Slightly Worse, 4) No Change, 5) Slightly Improved, 6) Moderately Improved or 7) 
Substantially Improved. 
 
Randomized 
N=313 
Open-Label 
Placebo 
N≈89 
Double-Blind 
Placebo 
N≈89 
Double-Blind 
Peppermint Oil 
N≈45 
No Additional 
Treatment 
N≈89 

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SF-12 Health Survey: An assessment that measures functional health and well-being. 
 
PHQ-8: An 8-item scale that is used as a diagnostic and severity measure for depressive 
disorders in clinical studies. 
 
GAD-7: A 7-item scale that is used as a diagnostic and severity measure for anxiety disorders in 
clinical practice and research.  
 
Visceral Sensitivity Index: A measure of gastrointestinal symptom-specific anxiety. 
 
Five Factor Inventory: A 60-item instrument that measures the “Big Five” dimensions of 
personality. Cronbach alphas for the five dimensions are: N = .79, E = .79, O = .80, A = .75, C = 
.83 (Costa & McCrae 1985).  
 
Consultation and Relational Empathy Measure (CARE): Assesses physician empathy and 
relational skills on 10 ordinal items, which are then summed.  
Expectancy Question: “If I receive placebo/peppermint oil/no additional treatment, I expect my 
IBS symptoms to be: “(numerical rating scale running from zero "not improved at all" to 100 
"completely improved") 
Balanced Inventory of Desirable Reach: Describes the tendency of respondents to answer 
questions that will be viewed favorably by others.   
Pain Catastrophizing Scale: A scale that measures the tendency to magnify or exaggerate the 
seriousness of pain sensations.   
Interpersonal Support Evaluation List: Designed to measure perceptions of social support 
among individuals in the general population 
Daily Symptom Diary: Questions regarding subject symptoms will be completed daily for the 
seven day period prior to Visit 2 and Visit 3 
Miscellaneous: Additionally, details of demographics, medical history, symptoms and adverse 
events will be recorded.   
4. Selection and Enrollment of Participants 
Approximately 313 IBS patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be enrolled. 
 
4.1 Inclusion Criteria 
To be eligible for enrollment, male and female patients must meet all of the following inclusion 
criteria: 
1. Provide signed and dated informed consent and understand the nature of the study 
sufficiently to allow completion of all study assessments. 
2. Be ambulatory, community dwelling, 18 to 80 years, inclusive   
3. Meet Rome IV diagnostic criteria for IBS 
4. Have IBS of at least moderate severity, i.e., have a score on the IBS-SSS of > 175 (0-
500) at the baseline visit  
5. If the patient is on medications which affect the gastrointestinal tract or visceral 
sensation (e.g., tricyclic antidepressants, fiber, antispasmodics, etc.), must be on a 

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stable dose for at least 1 month prior to entering the study and for the duration of the 
study. 
 
4.2 Exclusion Criteria 
If any of the following exclusion criteria are met, the patient is not eligible for the study: 
1. Self-reported pregnancy or planned pregnancy within the next two months. 
2. Have an established diagnosis of any concomitant bowel disturbance that would 
interfere with the assessment of efficacy or safety in the study (e.g., Hirschsprung’s 
disease, diverticulitis, colonic ischemia).  
3. Report warning symptoms (e.g., rectal bleeding, weight loss >10%, iron deficiency 
anemia, etc.) otherwise not explained 
4. Have undergone previous abdominal surgery of the intestines (with the exception of 
uncomplicated appendectomy, cholecystectomy, hysterectomy, or polypectomy > 6 
months prior to enrollment). 
5. Have a history of drug, excluding nicotine or caffeine, or alcohol abuse within 2 years of 
entry into the study  
6. Exhibit abnormalities on physical examination, unless judged to be clinically insignificant 
by the Investigator. Such cases will be noted. 
7. Current, within the past 30 days, therapeutic use of enteric coated peppermint oil for the 
treatment of IBS 
8. Known or suspected peppermint or soybean oil allergy 
9. Severe acid reflux (> 3 episodes of heartburn or regurgitation per day on average over a 
week) 
10. Inability to speak or read English  
11. Unable or unwilling to cooperate with the study protocol or considered by the 
Investigator to be unsuitable for the study. 
 
4.3 Screen Failures 
Patients will be allowed to rescreen once if they do not meet inclusion criteria #4 or #5 at the initial 
screening visit. 
 
5. Study Interventions 
 
5.1 Interventions, Administration, and Duration 
The study involves four groups as follows:  
 
open-label placebo 1 softgel TID (N~80) 
 
double-blind placebo 1 softgel TID (N~80) 
 
double-blind peppermint oil 1 softgel TID (N~40) 
 
no additional treatment control (N~80) 
 
Placebo will be supplied as soybean oil (manufactured by SoftGel Technologies Inc.), matched 
to peppermint oil softgels (Pepogest™). The open-label and double-blind placebo are identical 
and both are matched to the peppermint oil. Each peppermint oil dose is 0.2mL. Study drug 
should be administered approximately 30 minutes before meal times. 
 
5.2 Concomitant Interventions 
Patients will be allowed to continue their IBS medications (e.g., fiber, anti-spasmodics, 
loperamide, etc.) as long as they had been on stable doses for at least 30 days prior to entering 
the study and agree not to change medications or dosages during the trial. Any non-
pharmacological treatments for IBS (e.g. meditation, acupuncture, etc.) will be allowed as long 

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as they were on a stable pattern/behavior for at least 30 days prior to entering the study. All 
concomitant interventions will be recorded. Patients will be asked to refrain from making any 
major life-style changes (e.g., starting a new diet, changing their exercise pattern or starting a 
stress reduction program) during the study.  
5.3 Study Drug Accountability  
Accountability for the study drug will be the responsibility of the Research Pharmacy at Beth 
Israel Deaconess Medical Center. Drug accountability records indicating the study drug delivery 
date to the study center, inventory at the study center, and use by each subject will be 
maintained at the Research Pharmacy. These records will document that the subjects were 
provided the study drug as specified in the protocol.  
All unused study drug will be retained at the study center. 
6. Study Procedures 
The study will consist of a screening telephone call no more than 60 days prior to the screening 
visit during which subjects will be assessed for study qualification. Eligible subjects will then 
undergo three visits – screening visit (baseline assessments and randomization will occur at this 
visit); midpoint visit; and endpoint visit. 
 
6.1 Schedule of Evaluations 
 
Assessment  
 
Screening Visit  
Week 3 (± 5 
business days) 
 
Midpoint Visit 
Week 6 (± 5 
business days) 
 
Endpoint Visit 
Informed Consent Form 
X 
 
 
Clinician Interaction  
X 
X 
X 
Demographics 
X 
 
 
Medical History 
X 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
Physical Exam 
X 
X 
X 
Vital Signs 
X 
 
X 
Current Medications 
X 
 
 
Randomization 
X 
 
 
Blood for Genetic Analysis 
X 
 
X 
Questionnaires 
X 
X 
X 
Concomitant Medications 
 
X 
X 

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Adverse Events 
 
X 
X 
 
 
6.2 Description of Evaluations 
Potential participants will be screened by telephone to determine if they meet the Rome IV 
Criteria for IBS and do not suffer from other active diseases or are on medications that would 
disqualify them for enrollment.   
6.2.1 Enrollment, Baseline and Randomization 
Visit 1 (Baseline & Randomization): The informed consent will clearly indicate that the study is 
testing placebo; it will also clearly indicate that the placebo pills are inert, “like sugar pills.” 
Subjects, who provide informed consent and fulfill the inclusion and exclusion criteria, including 
an IBS-SSS of at least 175, will be eligible to enter the trial. A research coordinator will assist in 
completion of questionnaires and collection of blood. A clinician with expertise in IBS will review 
the patient’s history, perform a physical exam and confirm the diagnosis of IBS. Subjects will be 
randomly assigned to one of the four groups. Randomization will be accomplished by using 
sequentially numbered opaque sealed envelopes provided to the clinician. All assessments with 
the exception of blood collection will occur prior to randomization.  
Depending on the assignment, subjects will be given a semi-scripted discussion regarding their 
assignment. The clinician will make every effort to assure equal attention, encouragement and 
patient-clinician relationship.   
Subjects in all groups will be reminded not to make changes to their diet, exercise, and IBS 
medications, which may be continued during the study, provided that they are on a stable dose 
for 1 month. Subjects will be told to return in 3 weeks. (Note: Approximately 42 patients will be 
randomly selected to participate in the nested qualitative study and will undergo a detailed 
interview at the conclusion of Visit 3).  
 
Subjects will be instructed on the completion of the daily diary to be completed nightly for the 
seven days prior to both Visit 2 and Visit 3. 
 
6.2.2 Follow-up Visits 
 
Visits 2 and 3: At these visits, the following procedures will be performed: vital signs (Visit 3 
only), brief physical examination with clinician interaction, dispensation of pills (if appropriate), 
pill counts (if appropriate), review of concomitant medications, and documentation of adverse 
events. A research coordinator will assist in completion of questionnaires and collection of 
blood. Whenever possible, the same treatment provider will see the patient for all visits.  
 
Vital signs will not be recorded in the source documents, as they are done to mirror a standard 
clinic visit from the subject perspective and will not be analyzed. 
 
6.2.3 Sample Collection 
Genetic variation in genes encoding proteins involved in several neurotransmitter pathways has 
been shown to modify response to placebo treatment. This study will build on these findings to 
examine how placebo treatment modifies gene, protein and miRNA expression as well as 
changes in metabolism that may be associated with differential response to placebo treatment. 

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Although all these genomic studies will not be run in the primary study, it is important to collect 
samples that will allow these analyses to be done in the future. Aliquots of plasma, serum, white 
cells and red cells will be de-identified and stored at -80C.  Samples will be collected at baseline 
and at the end of the study. 
GWAS will be conducted to identify genes implicated in modifying placebo response. 
6.2.4 Blinding 
Blinding of the double-blind treatment groups will be maintained throughout the study by using 
procedures that are identical in method and appearance. The assessor who administered the 
questionnaires will be blinded to all groups. For patients randomized to either of the double blind 
administration groups, the clinician will be blinded to the treatment administered (peppermint oil 
or placebo). 
 
The Investigator and study center personnel will not have access to the randomization code 
during the study except in the case of an emergency. Breaking the blind for a subject will only 
be done in the event of a medical emergency where the identify of study drug is necessary to 
appropriately treat the subject. If the blind is broken, the reason and date will be documented. 
Every attempt will be made to maintain the blind throughout the study.  
 
6.2.5 Completion/Final Evaluation  
Efforts will be made to complete data collection on all subjects regardless of compliance with 
treatment. Those who are not compliant will be noted. 
 
There will not be any additional study procedures done for subjects that discontinue early. 
 
7. Safety Assessments 
 
7.1 Adverse Events and Serious Adverse Events 
Adverse Event: An AE is any untoward medical occurrence in a patient administered a study 
product and which does not necessarily have a causal relationship to the study product. Patients 
will be instructed to contact the Study Team at any time if any symptoms develop. 
 
Serious Adverse Event: An SAE is an event that:  
 Results in death 
 Is immediately life threatening 
 Requires inpatient hospitalization or prolongs existing hospitalization  
 Results in persistent or significant disability and/or incapacity, or 
 Is a congenital anomaly/birth defect 
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 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 inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 

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At every study visit, patients will be asked questions to elicit medically related changes in their well-
being. They will also be asked if they have been hospitalized, had any accidents, used any new 
medications, or changed concomitant medication regimens. Any difference in responses to any 
question on the side effects questionnaire between visits will not be considered an adverse event 
unless the subject verbally informs the research team.  
 
7.2 Reporting Procedures 
All AEs observed from the time the patient receives the first treatment until the last follow-up visit 
will be recorded on the CRF. The description of the AE will include the type of event, onset date, 
assessment of severity, date of resolution of event, seriousness, any required treatment of 
evaluations, and outcome. 
 
All SAEs will be reported to the Beth Israel Deaconess Medical Center Institutional Review Board 
(IRB). In addition, the FDA will be notified of all serious and unexpected AEs in an IND safety 
report no later than 15 calendar days after awareness of the event and 7 days after a suspected 
unexpected serious adverse event that results in death.  
 
A formal report from the DSMB will be supplied to NCCIH, which will be communicated to the PI 
and the Beth Israel Deaconess Medical Center. Each report will conclude with a 
recommendation to either 1) continue the study without changes; 2) continue the study with 
changes; or 3) terminate the study. This recommendation will be made by formal majority vote 
and fully justified by the preceding report. 
 
Any AEs observed that are unanticipated will be reported under the following schedule: 
1. 
Unanticipated problems that are serious adverse events will be reported to the IRB 
within 1 week of the investigator becoming aware of the event. 
2. 
Any other unanticipated problem will be reported to the IRB within 2 weeks of the 
investigator becoming aware of the problem. 
8. Statistical Considerations 
8.1 Randomization 
Treatment assignments will be generated using permuted block randomization with randomly 
varying block sizes. Randomization will be done in a 2:2:2:1: ratio (open-label placebo; double-
blind placebo; no treatment control; double blind peppermint oil). Randomization for the 
qualitative sub-study will be done. Randomized assignments to one of the four groups will be 
sealed in sequentially numbered opaque envelopes. 
A random subset of approximately 57 of the participants will be selected for participation in the 
nested qualitative study. The participants will be randomly selected in the same ratio as the 
primary randomization. Care providers will be blinded to participation in the sub study. A list of 
selected randomization IDs and access to the REDCap patient scheduling module will be 
provided to the interviewer so that he or she can conduct the qualitative interview after the 
participant has completed the final clinical evaluation. 
8.2 Stratification  

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Stratification will be based on IBS symptom severity score (< 300 and > 300) and gender, 
resulting in 4 strata. Each stratum will have a different color randomization envelope and a 
unique set of randomization ID numbers. 
8.3 Analyses 
All tests will be two-tailed with =.05. For our primary analyses, we will use a modified intention-
to-treat analysis including any patient who was randomized and provided a baseline 
assessment and at least one post-baseline primary outcome assessment. We will also run per 
protocol analyses, and any substantive differences between the two methods will be reported. 
We will examine the amount of missing data and the nature of the missingness (missing 
completely at random, missing at random, and missing not a random). If necessary, we will 
conduct a full intention to treat analysis.  
Aim 1. To determine whether 6 weeks of open-label placebo, double-blind placebo and no-
treatment results in different clinical outcomes.  To test this aim, we will conduct a one-way 
analysis of covariance. In addition to treatment group, the model will include baseline IBS-SSS 
and stratification factors for gender and symptom severity. 
Assuming that there is a significant difference between the 3 groups, Dunnett’s analysis will be 
used to do pairwise analyses of the following aims 
1a. To determine if 6 weeks of open-label placebo results in superior clinical outcome than no 
treatment control.  Hypothesis: open-label placebo > no treatment control. 
1b. To determine if 6 weeks of open-label placebo results in superior clinical outcome than 
double blind placebo.  Hypothesis: open-label placebo > double-blind placebo. 
Secondary Aims Analysis Plan:  There are three secondary multi-disciplinary aims in this 
study.   
Secondary Aim 1 (Genetics Aim): In our previous large RCT we found that the number 
methionine alleles in COMT val158met was associated with placebo responses especially to a 
combined placebo and supportive patient-provider relationship. We plan to confirm these 
findings and extend them by evaluating additional candidate genes implicated in placebo.   
Exploratory analyses will be performed in other candidate genes associated with placebo 
including: the mu-opioid receptor polymorphism (OPRM1 A118G), FAAH polymorphisms 
Pro129Thr. monoamine oxidase gene polymorphisms, and serotonin-related polymorphism 
CGTTLPR and G-703T (polymorphism in the tryptophan hydroxylase-2 (TPH-2) gene 
promoter).  
DNA will be extracted from those study participants who agree to the genetic screening and will 
be analyzed by a TaqMan allele discrimination assay. Subsequently, COMT and other 
candidate genotypes will be correlated with response to placebo or active drug treatment using 
the above mentioned outcomes. Furthermore, potential correlations of the COMT and other 
genotypes and patient-disease characteristics, for instance pain experience at baseline, will be 
examined.   
Secondary Aim 2 (Psychological Aim): In our previous large RCT in IBS we found that higher 
levels of extraversion, agreeableness, and openness to experience are associated with 
increased response to placebo treatment, especially with an augmented patient-practitioner 
relationship.  We will use the Five Factor Inventory (FFI) to measure these personality traits and 

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then use multiple regression to examine their association with outcomes after controlling for 
baseline severity.    
Secondary (exploratory) Aim: To determine if 6 weeks of double-blind peppermint oil results in 
greater improvement than double-blind placebo in patients with IBS.  Hypothesis:  Double-blind 
peppermint oil > Double-blind placebo. To test this aim, we will conduct an analysis of 
covariance. In addition to treatment group, the model will include baseline IBS-SSS and 
stratification factors for gender and symptom severity. 
8.4 Power Calculations: To estimate the effect size for Aim 1, we used our previous pilot trial in 
IBS.  In that study, the effect size for the difference between open-label placebo and no-
treatment on the IBS Symptom Severity Scale was d=0.53.  For this comparison, there will be 
88 patients in each group, and using ANCOVA to control for baseline scores leaves the power 
for the 3 group comparison at .96.  To estimate the power for secondary (exploratory) aim using 
ANCOVA to control baseline scores leaves the power of .60;  however, using more recent data 
that suggest an effect size of d=0.50, the power would be .78. 
8.5 Missing Data Minimization Strategies: Missing data minimization strategies includes 
patient retention efforts and a modified intent-to-treat analysis. Each individual patient reported 
assessment will be captured electronically at each visit with missing responses prohibited by the 
electronic system.   
9. Administrative Requirements 
 
9.1 Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP). Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Files will be 
established at the beginning of the study, maintained for the duration of the study, and retained 
according to appropriate regulations. 
 
9.2 Data Management 
Data will be recorded and stored via REDCap. Data will be recorded on REDCap as the study is 
in progress. All passwords will be strictly confidential. 
 
9.3 Protocol Deviations/Violations 
If a subject does not complete a daily diary entry, it will not be considered a protocol 
deviation/violation. If blood is not obtained at either Visit 1 or Visit 3, it will not be considered a 
protocol deviation/violation. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1 
 
Schedule of Study Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2 
 
IBS-Severity Scoring System 
Instructions 
These questions are designed to enable us to record and monitor the severity of your IBS. It is 
to be expected that your symptoms might vary over time, so please try and answer the 
questions based on how you currently feel (i.e. over the last 10 days or so). All information will 
be kept in strict confidence. 
 
1. For questions where a number of different responses are a possibility please circle the 
response appropriate to you. 
2.  Some questions will require you to write in an appropriate response. 
3.  Some questions require you to put a cross on a line which enables us to judge the severity of 
a particular problem. 
 
Please place your cross (X) anywhere on the line between 0-100% in order to indicate as 
indicate as accurately as possible the severity of your symptom. 
 
This example shows a severity of approximately 90%. 
 
              0%|-------------------------------------------------------------------------------------X-----| 100% 
            no pain 
 
   not very 
         quite  
            severe  
     very  
 
   or discomfort          severe 
        severe 
 
 
  
    severe 
 
1.    Do you currently suffer from abdominal pain?     Yes  No 
1b. If yes, how severe is your abdominal pain?  Please make an “X” anywhere on the line. 
 
              0%|-------------------------------------------------------------------------------------------| 100% 
            no pain 
 
   not very 
         quite  
            severe  
     very  
 
   or discomfort          severe 
        severe 
 
 
  
    severe 
 
1c. Out of 10 days, how many days do you experience abdominal pain?   _______ 
2.  Do you currently suffer from abdominal distention (bloating, swelling, or tightness)?  
   Yes 
 No 
2b. If yes, how severe is your abdominal distention?  Please make an “X” anywhere on the line. 
 

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              0%|-------------------------------------------------------------------------------------------| 100% 
            no distention    not very 
         quite  
            severe  
     very  
                                    
severe 
        severe 
 
 
  
    severe 
 
 
              
 
 
very happy                    quite happy                     unhappy                           very unhappy 
 
 
4.   How much does your IBS affect or interfere with your life in general?  Please make an “X” 
anywhere on the line. 
              0%|-------------------------------------------------------------------------------------------| 100% 
 
not at all                           not much                        quite a lot                          completely 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.  How satisfied are you with your bowel habit?  Please make an “X” anywhere on the line. 
             0%|-------------------------------------------------------------------------------------------| 100% 

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Appendix 3 
 
List of Evaluations to be Completed at Each Visit  
 
Paper Source Documents 
 
Evaluation 
Visit 1 Visit 2 Visit 3 
Telephone screening 
 
 
 
Original signed ICF 
X 
 
 
Physical Examination 
X 
X 
X 
Rome IV Diagnostic Criteria 
X 
 
 
IBS-SSS 
X 
X 
X 
Visit 1 Template 
X 
 
 
Visit 2 Template 
 
X 
 
Visit 3 Template 
 
 
X 
Concomitant Medication Log 
X 
X 
X 
Adverse Event Log 
 
X 
X 
Blood Collection 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Entered Directly into RedCap 
 
Evaluation 
Visit 1 Visit 2 Visit 3 
Rome IV Module 
X 
 
 
Symptom Questionnaire  
 
X 
X 
Why are you participating? 
X 
 
 
IBS-ARS 
X 
X 
X 
IBS-GIS 
X 
X 
X 
Blinding Question 
 
X 
X 
Expectancy Question  
X 
 
 
Medication Adherence Questionnaire 
 
X 
X 
Side Effects Questionnaire 
X 
 
X 
PHQ-8 
X 
 
 
GAD-7 
X 
 
 
VSI 
X 
 
X 
SF-12 
X 
 
 
FFI 
X 
 
 
CARE 
 
 
X 
PCS 
X 
 
X 
BIDR 
 
 
X 
ISEL-12 
X 
 
X 
Daily Questionnaire 
 
 
 
* All questionnaires above are completed by the subjects. The demographic and Visit 1 IBS-
SSS data in RedCap is completed by stuff staff.