Zemedy - Evaluation of Zemedy, a Cognitive Behavioral Therapy-based Digital Therapeutic Application for the Treatment of Irritable Bowel Syndrome
Phase: NA
Conditions: IBS - Irritable Bowel Syndrome
Sponsor: Stanford University

 
 
 
 
Zemedy - Evaluation of Zemedy, a Cognitive 
Behavioral Therapy-based Digital Therapeutic 
Application for the Treatment of Irritable Bowel 
Syndrome 
 
 
Study Protocol and Statistical Analysis Plan 
NCT04723056 
April 19, 2022 

1
Zemedy Protocol 
Protocol VERSION 3, Amendment 2
Principal investigators: Irene Sonu, MD and Linda Nguyen, MD 
Sub-Investigators/ Co-investigators: Sean Spencer, MD
Collaborators: Bold Health 
Title: ZEMEDY--Evaluation of Zemedy, a cognitive behavioral therapy-based digital 
therapeutic application for the treatment of irritable bowel syndrome
Stanford IRB Protocol #: 59029  
Objective 
Evaluation of Zemedy, a cognitive behavioral therapy-based digital therapeutic 
application for the treatment of irritable bowel syndrome  
Background 
Irritable bowel syndrome (IBS) is defined as having recurrent abdominal pain associated 
with defecation or a change of bowel habits i It is a common syndrome affecting 11% 
(ranging 1.1% to 45%) in prevalence worldwide.ii  The pathophysiology of IBS is 
complex and likely due to a combination of factors including altered motility, visceral 
hypersensitivity, dysbiosis, altered mucosal and immune function and central nervous 
system processing. The complex interplay between  genetic, cultural, environmental and 
pyschosocial factors, also known as the biopsychosocial model of disease, can lead to 
the development of functional GI disorders like IBS (Figure 1).iii   
Treatment of IBS is multifaceted and ranges from exercise, dietary restriction, laxative or 
anti-diarrheal therapy, antispasmodics, Rifaximin, probiotics, and antidepressants.1
Psychological treatments to target the gut-brain axis such as cognitive-behavior therapy 
(CBT) have also been shown to be an effective therapy, and aims to address the 
psychological and environmental stressors that contribute to symptoms.iv,v,vi,vii,viii 
This study will investigate the effectiveness of Zemedy,  a mobile application that 
enables the digital delivery of a CBT program to people with IBS. CBT has been shown 
to reduce the severity of intractable IBS symptoms by as much as 70%, but the 
provision of the therapy is limited by the availability of qualified therapists to patients in 
need. Rooted in scientific evidence, Zemedy integrates the 8-week CBT program with 
other in-app features – such as educational modules and health trackers, to provide an 
end-to-end IBS management tool. The delivery of the CBT program in itself is guided by 
a chatbot persona, Elle, that mimics the conversation lead by a healthcare professional 
in a clinical therapy setting. Educational modules on the Zemedy app range from topics 
on IBS causes and symptoms, to topics on relevant exercise and diet regimens. Health 
trackers on the Zemedy app can be used to record flare-ups, mood, and lifestyle 
information, allowing data to drive the extraction of meaningful patterns in IBS symptom 
presentation. Therefore, the Zemedy app grants IBS patients the option of and access to 
invaluable treatment streams. 

2

3
Study Overview 
This is an interventional, randomized controlled study with two study arms. The study 
will utilize Zemedy which provides digital delivery of a CBT program to people with IBS, 
via a smartphone application.  
The study will involve a minimum of 44 individuals (randomized 22 in study group and 
22 in the control group) with irritable bowel syndrome, who will take part in the 
intervention for 8 weeks. The study group will receive treatment as usual (TAU) + 
Zemedy intervention and the control group will receive TAU. TAU for IBS is tailored to 
the patient and may involve dietary modification, exercise, antispasmodic medication, 
laxative therapy, anti-diarrheal therapy, and pain medication. Patients will be evaluated 
in clinic or via telehealth at the beginning of the study, and at weeks 8 and 24. Patients 
can contact the physician electronically via the MyHealth application in between visits. 
Figure 2: Overview of study design 
Study objectives 
•
Determine the efficacy of the Zemedy application in the reduction of irritable
bowel syndrome symptoms
*Optional stool sample collection
at Weeks 0, 8, and/ or 24

4
Study design 
•
Single-blind randomized controlled trial
•
Duration: 24 weeks, intervention is 8 weeks long
Primary Endpoint 
•
Change in IBS symptoms based on the IBS symptom severity score (SSS) score
at week 8 compared to baseline
Secondary Endpoints 
•
Change in IBS symptoms based on the IBS-SSS- at week 24 compared to 
baseline
•
Cohen Perceived Stress Questionnaire (PSQ)
o
Measures degree situation’s in one’s life are seen as stressful
o
Survey will be distributed at weeks 0 and 24 of the study
•
Work and social adjustment scale (WSAS)
o
Measures the effect of IBS on ability to work and manage at home, 
participate in social and private leisure activities and maintain 
relationships.
o
Survey will be distributed at weeks 0 and 24 of the study
•
Subject’s Global Assessment of Relief (SGA)
o
Assesses global symptoms relief asking the question, “Overall, how do 
you feel?”. Scale of -2 to +2 , from completely worse to completely 
better.1–2 considered responders and 4–5 non-responders.
o
Survey will be distributed at weeks 0 and 24 of the study
•
Hospital Anxiety and Depression Scale (HADS).
o
Assesses mood measured by the total distress score (<7 normal, 8-14 
borderline, 15 or >15, abnormal)
o
Survey will be distributed at weeks 0, 8 and 24 of the study
•
Work Productivity and activity impairment (WPAI) questionnaire
o
Assesses work productivity based on number of days taken off from work 
due to health
o
Survey will be distributed at weeks 0, 8 and 24 of the study
•
Fecal Sampling and Microbiome analysis (optional; opt-in)
o
Assessment of any changes in gut flora  (baseline vs after intervention)
o
Stool self collection will occur at weeks 0 and 8 of the study. An additional 
collection may occur at week 24, contingent on PI judgment.
•
Adherence to intervention assessed by use of Zemedy application in the Zemedy 
arm
•
Decreased urgent care/ER/physician appointments due to the patient’s IBS
•
Application is considered to be safe without adverse events such as worsening 
irritable bowel syndrome symptoms, hospitalizations, worsened or new mood 
changes
Patient recruitment 

5
•
Patients recruited via advertisements online (clinicaltrials.gov) and in the clinics in 
the Digestive Health Center at Stanford Healthcare as well as social media
(eg. Twitter, Facebook)
•
Individuals screened by research assistant to assess eligibility
•
Individuals invited for an assessment conducted by a study physician
•
Those wishing to proceed sign a consent form to demonstrate their informed 
consent.
•
Inclusion criteria
o
Male and female patients >=18 years old
o
Meet Rome IV criteria for IBS for at least 6 months
▪
No restrictions on type of IBS
o
English proficiency (in order to understand use of the application)
o
Patient must be on a stable regimen for IBS for at least 30 days
o
Patients must own a smartphone (iOS or Android) in order to participate in the 
CBT application
•
Exclusion criteria
o
Laboratory or imaging evidence of an alternative explanation of patient’s 
symptoms
o
Active gastrointestinal disease such as Crohn’s disease, ulcerative colitis, history 
of complete colon resection, acute infection, or any disease that precludes 
participation in CBT application
o
Patient already undergoing cognitive behavioral therapy
o
Psychiatric hospitalization within 10 years
o
Current or past diagnosis of a major mental illness such as schizophrenia, bipolar 
disorder, personality disorder or substance abuse
o
Active (within the past 3 months) suicidal ideation
o
Prisoners or other detained individuals.
o
Adults unable to consent
o
Pregnant people.
Randomization 
•
Random assigned to CBT vs TAU group using randomization software
Patient visits 
•
Patients will be seen in clinic at weeks 0, 8 and 24. Patients will be seen either in 
person or via telehealth. Consent will be obtained at the initial clinic visit either 
online via Recap or by paper. Optional microbiome analysis samples will be self-
collected by patients at weeks 0 and 8 (and possibly 24) and returned by mail or 
in person. Stool collection kits will be given or mailed after consent, and CBT 
patients instructed to begin use of the app only after the first stool collection. The 
physician assessment will include a safety assessment for suicidal ideation.
Compensation 
•
Patients enrolled in the trial will receive a total of 
 each upon
completion of the study. A 
 will be given at week 8 and week
24.
Interventions 
1. Zemedy application

6
a. A mobile application that enables the digital delivery of a CBT program to
people with IBS. Zemedy integrates the 8-week CBT program with other
in-app features – such as educational modules and health trackers, to
provide an end-to-end IBS management tool. The delivery of the CBT
program in itself is guided by a chatbot persona, Elle, that mimics the
conversation lead by a healthcare professional in a clinical therapy setting.
Educational modules on the Zemedy app range from topics on IBS causes
and symptoms, to topics on relevant exercise and diet regimens. Health
trackers on the Zemedy app can be used to record flare-ups, mood, and
lifestyle information, allowing data to drive the extraction of meaningful
patterns in IBS symptom presentation. Therefore, the Zemedy app grants
IBS patients the option of and access to invaluable treatment streams.
Patients will be guided on how to onboard the app after randomization.
Outcome assessment 
•
Assess outcomes at weeks 8 and 24, after randomization by randomization
software
Table 1: Collection of Questionnaire Data
Questionnaire 
Week 0
(Day 0)
Week 4
(Day 28)
Week 8
(Day 56)
Week 24
(Day 168)
Demographic information 
x 
Prior IBS Medication Usage x 
Current medication usage 
x 
x 
x 
IBS-SSS 
x 
x 
x 
x 
PSQ 
x 
x 
WSAS 
x 
x 
SGA 
x 
x 
HADS 
x 
x 
WPAI 
x 
x 
x 
Power 
We estimate that with an initial sample size of 22 participants per intervention group and 
22 per control group, we will have 80% power (alpha 0.05) to detect the minimal 
clinically important difference on the IBS-SSS. We expect a minimum reduction in score 
X

7
of 50 points, which is considered to be a considerable improvement.ix In order to 
account for patient withdrawal from the trial we aim to enroll 30 patients in each study 
group. 
Statistical evaluation 
The statistical analyses will be done in cooperation with a statistician. The analyses will 
compare scores in each evaluation point between evaluation points between the 
intervention and the control group. Outcomes will be assessed at weeks 8 and 24 of the 
study. Analyses will be conducted on the full sample (intent to treat analysis).
Roles and resourcing of the study 
Principal Investigators (PI) Irene Sonu, MD and Linda Nguyen, MD will be responsible 
for the oversight of the study, and are responsible for approving all candidates to 
become study participants. Both PIs are responsible for making sure that the study is 
conducted in an ethically sound manner as well as is safe for the participating patients. 
Ethical considerations
Completing the questionnaires, taking part in the digital program, being in the control 
group, and all other time spent related to the study are additional efforts to the treatment 
the subjects would otherwise receive. In our view, the burden of taking part in the study 
is moderate for the participant. They are advised to contact the study PIs at any point if 
any questions or adverse effects arise. An interim safety analysis will be performed 
under consultation with the team gastroenterology psychologist.
All participating individuals will sign an informed consent to take part in the study and 
they will have an appropriate amount of time to familiarize themselves with the study 
before making the decision to participate. The study and all related activities such as 
extra phone consultation are completely free of charge for the participants. The results 
are confidential and will be kept in a safe and encrypted storage within the Redcap 
system (more information in the Data collection chapter). The statistical analyses will be 
performed without any personal identification information by assigning anonymous 
identification codes to all subjects.
Data collection 
All captured study data and personal information (such as the participant's name, phone 
number, address and any free-text entered by the participants) will be stored in the 
Redcap system. It will be blinded from any analysis or data extraction. Patient identifiers 
and contact information will only be available to the study investigator, study therapist or 
any support staff working directly with patients that need this information for logistical or 
patient support purposes. All data used for reporting or publications will be anonymized.
All Zemedy related data (such as exercises related data or patient nick name) will be 
stored in the Zemedy application system. The Zemedy application system is not 
collecting or maintaining personal identifiable information and is thus not a patient 
registry. 

8
Data to be collected include age, gender, comorbidities, medications (prescription and 
over the counter) and diagnostic testing performed (bloodwork, procedures) 
Quality assurance
All data captured in the study will be in electronic format and stored in the Redcap
system and/or in the Zemedy Program system. All patient identifiable information and 
data will be stored in the Redcap system which is a safe server-system with appropriate 
data protection, privacy and information security features. 
Adverse experience reporting
Any adverse experiences with the Zemedy Program will be monitored during the study 
by the study investigators.
Human subjects
Ethical committee review and informed consent
This protocol and the informed consent document and any subsequent modifications 
will be reviewed and approved by the IRB committee responsible for oversight of the 
study.  A consent form will be obtained from the subject. The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be given to the subject, or legal guardian, 
and this fact will be documented in the subject’s record.
Confidentiality
All captured data will be identified only by the Study Identification Number to maintain 
subject confidentiality. All captured data will be encrypted in the database. Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by IRB, the sponsor, or the sponsor’s designee.
Study modification/discontinuation
The study may be modified or discontinued at any time by the IRB, the sponsor, as part 
of their duties to ensure that research subjects are protected. 
Study completion 
Patients who have completed all of the IBS-SSS at weeks 0, 4, 8, and 24 will be 
considered completers of the study.  
PIs will consult with the team's Gastroentrology psychologist. 

9
X

10
Amendment Summary
Amendment 1 (Protocol Version 2)
•
Addition of Sean Spencer, MD as sub-investigator
•
Addition of fecal sampling (weeks 0, 8, and possibly 24) and microbiome 
analysis
o
Optional; patient must be willing and able to provide stool sample
o
Stool kits will be given or mailed after consent
•
Adjustment to exclusion criteria
o
Current or past diagnosis of a major mental illness such as 
schizophrenia, bipolar disorder, personality disorder or substance 
abuse
o
Prisoners or other detained individuals.
o
Adults unable to consent
o
[Pregnant] "people"
•
Correction of scheduling typos in secondary endpoint section
•
Addition of HADS assessment to Week 8 visit in the schedule of 
assessments
•
Adjustment to HADS abnormal threshold ( >15 instead of >11)
•
Adjustment to exclusion criteria
o
Removal of

Severe anxiety or depression assessed by the HADS 
scale
o
Addition of 

Psychiatric hospitalization within 10 years

Active (within the past 3 months) suicidal ideation
•
Addition of safety assessment for suicidal ideation to Physician's Visit
•
Addition of gastroenterology psychologist consult
o
for adverse events
o
for interim safety analysis
Amendment 2 (Protocol Version 3)

11
References 
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ii Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: 
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iii Drossman D. Functional Gastrointestinal Disorders: History, pathophysiology, clinical 
features, and Rome IV. Gastroenterology 2016; 150: 1262-1279.  
iv Moss-Morris R, McAlpine L, Didsbury LP, Spence MJ. A randomized controlled trial of 
a cognitive behavioural therapy-based self-management intervention for irritable bowel 
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v Drossman DA, Toner BB, Whitehead WE, Diamant NE, Dalton CB, Duncan S, Emmott 
S, Proffitt V, Akman D, Frusciante K, Le T, Meyer K, Bradshaw B, Mikula K, Morris CB, 
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vii Everitt HA et al. Assessing telephone-delivered cognitive–behavioural therapy (CBT) 
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Katz LA, Krasner SS, Ma CX, Radziwon CD, Sitrin MD. Improvement in Gastrointestinal 
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ix Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a 
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