Using Single Subject (N-of-1) Designs to Answer Patient-Identified Research Questions--Aim 1: Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease
Phase: NA
Conditions: Inflammatory Bowel Diseases, Crohn Disease, Ulcerative Colitis, Indeterminate Colitis
Sponsor: Children's Hospital Medical Center, Cincinnati

 
 
 
 
 
Study Protocol Cover Page 
 
Official Study Title: Using Single Subject (N-of-1) Designs to Answer Patient-Identified Reseach 
Questions – Aim 1 
NCT03301311 
Latest IRB approval date: 1/31/2020 
 

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CLINICAL RESEARCH PROTOCOL
USING SINGLE SUBJECT (N-OF-1) DESIGNS TO ANSWER 
PATIENT-IDENTIFIED RESEARCH QUESTIONS—AIM 1
Principal Investigator:
Heather C. Kaplan, M.D., M.S.C.E.
Sponsor:
Cincinnati Children’s Hospital Medical Center
Funding Source:
The Patient Centered Outcomes Research Institute
Data and Site 
Coordinating Center:
Cincinnati Children’s Hospital Medical Center
Protocol Number:
2017-0683
Version 5.2

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Key Roles
Principal Investigators:
Heather C. Kaplan, MD, MSCE
Department of Pediatrics
Cincinnati Children’s Hospital Medical Center
Phone: (513) 803-0478
Email: heather.kaplan@cchmc.org
Lisa Opipari-Arrigan, PhD
Department of Pediatrics
Cincinnati Children’s Hospital Medical Center
Phone: (513) 802-8062
Email: lisa.opipari@cchmc.org
Biostatistician:
Christopher Schmid, PhD
Department of Biostatistics
Center for Evidence Synthesis in Health
Brown University School of Public Health
Phone: (401) 863-6453
Email: christopher_schmid@brown.edu
PRODUCE Co-
Investigators:
David L. Suskind M.D.
Professor of Pediatrics
Director of Clinical Gastroenterology
Division of Gastroenterology, Hepatology and Nutrition
Seattle Children's Hospital
University of Washington
Email: david.suskind@seattlechildrens.org
Kimberly L. Braly RD, CD, CNSC
Clinical Pediatric Dietitian 
Seattle Children's Hospital
Phone: (206) 987-1759
Email:  Kimberly.braly@seattlechildresns.org
Shehzad Saeed, M.D.
Professor of Pediatrics
Division of Pediatric Gastroenterology
Dayton Children’s Hospital
Wright State University
Phone: (937) 641-3090
Email: SaeedS@childrensdayton.org
Data and Site 
Coordinating Center
Cincinnati Children’s Hospital Medical Center

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Document History
Document
Date of 
Issue
Summary of Change
Original 
Protocol, V1.0
TBD
Not applicable
Protocol V2.0
TBD
Removal of Aims 2 and 3. The grant research plan was inclusive of Aims 1, 
2 and 3; however, it was decided that, because of the nature of the 
condition being studied in Aims 2 and 3 (i.e., adult atrial fibrillation), it would 
be more appropriate to submit Aims 2 and 3 as separate proposals. This 
decision was made by the co-PIs, and supported by the advice of the 
reviewing IRB member. The Title of the protocol was amended to reflect 
this change.  The estimate of the number of study sites was increased to 
reflect current site interest. The eligibility verification process was changed 
to have the site PI (not research coordinator) verify eligibility on page 17. 
Typographical errors were corrected in Figure 2 and on page 14 
(completion of final treatment period is week 34 not week 32).  A rationale 
is now provided (page 17) for the exclusion of non-English speakers.
Protocol v3.0
5/15/2017
Changed “liberal SCD” to “modified SCD” throughout the protocol, 
consents, and study materials/figures. Added and removed some study 
measures. Edited wording on some measures to improve clarity. Updated 
inclusion/exclusion criteria based on parent/patient and clinician 
stakeholder feedback to ensure study integrity and better account for 
participant safety. Process for diet staging is now specified in the protocol. 
Removed suggestions for timing of returning stools samples to enable more 
flexibility in the collection and shipping process. Altered the process for 
collecting and analyzing the food diaries to centralize the nutrient analysis 
and provide greater diet monitoring oversight from the study co-
investigators with expertise in the SCD (Suskind/Braly). Added a variable 
for data collection to track Vitamin D status per recommendations of DSMB. 
Edited Figure 2 to reflect a change in study process that will allow for 
education on both the A and B diet at enrollment. Refined the analytic plan 
related to the washout period and run-in period associated with the diet 
staging. Added multiple study documents that will be used for recruitment 
and diet resources. Updated consent forms to verify participant willingness 
to allow de-identified use of data in future studies. Expanded appendix to 
add: Eureka technology platform privacy statement provided in the app 
prior to patient use, another version of the study flyer, phone script, and a 
study letter. Added multiple study staff. Removed information about adding 
a study-specific Facebook group as there are no longer plans of perusing a 
study-specific Facebook group for this study.
Protocol v4.0
6/29/2017
Protocol: Added a signature page for site PIs. Modified Figure 1 and added 
changes in the text in order to have more flexibility for study site staff in 
their timelines for collecting data from participants. Modified Figure 2 and 
added more specific language regarding how often participants need to be 
tracking data to continue in the study as well as more specific language 
about collection of stool samples and how that relates to continuation in the 
study.  Made stipend remuneration consistent with expectations of data 
collection. Revised Appendix C language to be consistent with protocol and 
consents (i.e., using “modified” instead of “liberalized”). Added parent 
versions of relevant questionnaires under Appendix C, D, and H.  
Developed new diet diary for Appendix F, replacing previous version which 

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is attached as a separate document. Added language throughout specifying 
that a participant can be seen by a physician or advanced care provider.
Consents: Added language in the assent and consent forms to be 
consistent with expectations regarding tracking of diet and sending in stool 
sample. Added in Master Consent and Site Consent to footer for tracking 
purposes in both assent and consent. Added a line about no compensation 
from CCHMC or PCORI for injury in consent. Added language in consent 
regarding standard rates that may apply for data usage or text messaging 
related to the study. Added “provider” in addition to doctor throughout 
consent and assent to be consistent with the protocol that a participant can 
be seen by either a physician or advanced care provider throughout the 
study.
Protocol v4.1
9/12/2017
Minor clarifications to the modified SCD (removal of requirement for organic 
sweet potatoes, addition of a requirement for organic rice, addition of grade 
A maple syrup as an allowable food, and clarification of the 
minimum/maximum suggested serving amounts).  Adjustment of the diet 
staging to be less restrictive and to advance more quickly.  Modification of 
exclusion criteria to include those who are on another interventional study 
as the study procedures could affect the results of the individual N-of-1 
study if a participant is exposed to an intervention at different times in the 
N-of-1 protocol.  Addition of pregnancy and ≥7.5% weight loss as criteria for 
automatic withdrawal in order to ensure participant safety. Clarified adverse 
events procedures including specifying expected adverse events.  Updated 
Appendix G with results review. Updated 1 question in Appendix C in the 
expectation of benefit questionnaires for both patient and parent. In 
Appendix D, we reordered the weekly questionnaires moving all the parent 
questionnaires together. We did not change the wording of any of the 
questions. Updated the DSMB charter (Appendix M). Updated Appendix I-
added new study staff and reordered staff members. Removed a site that is 
no longer participating and added a new site that is. Other changes were 
cosmetic consistent with what is stated under Appendix I section below. 
Also added minor wording updates to Appendices J and B (SCD Summary 
and SCD Detailed Summary) to be consistent with the allowed foods in the 
protocol and the dates of the study. Make changes to Appendix B stages 
for the PRODUCE study to be consistent with the staging as it is described 
in the protocol. 
Assent: Added in “organic” rice, took out “organic” for sweet potatoes and 
added in “Grade A” for maple syrup. Consent:  Added in “organic” rice, took 
out “organic” for sweet potatoes and added in “Grade A” for maple syrup. 
Changed description of fistula. Added interventional study exclusion.
Protocol v4.2
11/27/2017
Protocol: Added changes about the timing of the diet diary being sent to the 
study site and communication between the site and participant around the 
diet diary. Added verbiage that a less than 5% weight loss is expected in 
the study and greater than that will be reported as an AE. Clarified wording 
around SPDCAI and PUCAI regarding when score needs to be obtained 
related to study enrollment, and clarified what qualifies as mild to moderate 
disease activity. Added information regarding NiMBAL book being used as 
compensation for the study. Changed “Increase in corticosteroids within 4 
weeks of screening…” to “within 4 weeks of enrollment”. Added more 
specific language regarding cocoa and cacao that can be used by 
participants. Updated version number and dates where necessary. Clarified 
patient symptom tracking. Added information about a video we may make 
and included the video script as an Appendix B. Clarified screening visit 
timing. Clarified information regarding the statistical methods in the study. 
Appendix B Changed documents include: Brandlist PRODUCE, SCD 

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Detailed Summary, SCD Summary, and Stages for the PRODUCE Study. 
Appendix B new documents include: 3 Week Meal Plan Ideas, Blurb for 
Clinic Newsletter, Family Tried and True Recipe Links, Making SCD Yogurt, 
Next Steps Figure, SCD Resources, and Script for PRODUCE Patient 
Video. Added changes to Appendix E-Stool Collection Instructions. Added 
changes to Appendix F-3-Day Diet Diary. Added changes to Appendix I-
Trifold Flyer. Added changes to Appendix J-Introductory Flyer. Added 
changes to Appendix K- PRODUCE Recruitment Letter. Finally, added 
changes to Appendix L- Phonescript. All appendices are uploaded as 
separate documents.
Protocol v4.3
4/30/2018
Added the lab test lactoferrin as an option for establishing evidence of 
active inflammation for study inclusion. Added language in the Study 
Procedures section allowing dietitians to carry out standard of care 
activities during participant contact. Added language in the Participation 
Selection and Withdrawal section clarifying that GI care providers will 
determine if a patient and their family’s treatment decisions may be 
informed by the results of this study. Updated screenshots of the Eureka 
app in Appendix A. Added in that dietitian phone follow-up visits can also be 
done in-person, in-clinic.
Protocol v4.4
Added the clarifier “nonintentional” to “≥ 7.5% weight loss” in section 3.5.4 
Early Withdrawal of Participants to clarify that the ≥ 7.5% weight loss will 
only result in a participant’s early withdrawal if the weight loss was 
unintentional. Changed exclusion criteria from a BMI in the 10th percentile to 
the 5th percentile. Change inclusion criteria from “Past or present history of 
intra-abdominal abscess, fistula, stricturing CD, or ostomy” to “Currently or 
within the past 9 months has had an intra-abdominal abscess, fistula, 
stricturing CD, or ostomy” and added the exclusion criteria “Ever had history 
of full colectomy”.
Protocol v4.5
9/19/2018
Changed the inflammation criteria for the study: evidence of acute 
inflammation and/or elevated acute phase reactant as measured by Fecal 
calprotectin 1.5 (formerly 2) times the upper limit of normal, Lactoferrin 1.5 
(formerly 2) times the upper limit of normal, CRP 1,15 (formerly 1.25) times 
the upper limit of normal, or ESR 1.15 (formerly 1.25) times the upper limit 
of normal (based on local reference ranges) obtained within 8 weeks of 
enrollment. 
Protocol v4.6
10/24/2018
Added using social media as a way to disseminate flyers already approved 
by the IRB, as well as a newly created poster. Created a poster(s) to 
advertise study (Appendix O). Added a letter written by parent partners for 
study participants and potential participants (Appendix P). Changed the 
baseline period from a minimum of 2 weeks to a minimum of 1 week. 
Changed the inclusion/exclusion criteria to include patients that are already 
on the SCD or modified SCD but are not compliant with the diet per the site 
dietitian or primary GI physician. Made edits to the statistical analysis plan. 
Changed the wording surrounding the standard of care visits to make only 
the first SOC visit necessary, the others are only if/as needed. 

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Protocol v4.7
12/7/2018
Removed “Mild to moderate disease activity as measured by a short Pediatric 
Crohn’s Disease Activity Index (SPCDAI) score of 15-45 or Pediatric 
Ulcerative Colitis Activity Index (PUCAI) score of 10-60 assessed within 3 
weeks of enrollment” from inclusion criteria and added “Severe disease 
activity as measured by a short Pediatric Crohn’s Disease Activity Index 
(SPCDAI) score of >45 or Pediatric Ulcerative Colitis Activity Index (PUCAI) 
score of >60 assessed within 3 weeks of enrollment” to the exclusion criteria. 
Changed inclusion criteria from 7-17 years to 7-18 years.
Protocol v4.8
2/18/19
Decreased the sample size from n=120 to n=50. Revised sample size 
calculation demonstrates adequate power at this smaller sample size. Edited 
the study timeline by adding more time to our enrollment period (enrollment 
now ends 10/31/19). Increased the number of participating study sites from 
12 to 21. Changed the due date for diet diary entries from specifying 
submission 3-5 weeks after starting a new diet phase to allowing submission 
anytime during the diet phase. Changed the dietitian in-clinic visit to allow 
this visit to be able to take place by phone, video call or telemedicine. 
Changed the dietitian phone follow-ups to allow this visit to be completed 
either by the site dietitian or the site coordinating center dietitian. 
Protocol v4.9
3/26/19
Changed the dietitian in-clinic visit and dietitian portion of the enrollment visit 
to allow these visits to be conducted via phone or video call by the site 
coordinating center dietitian, in the event that the site dietitian is absent or 
unavailable to conduct the visit. Changed the wording around subject 
disposition and withdrawal, allowing subjects who have completed at least 
one full treatment period of each diet to discontinue study participation and 
terminate the protocol early, rather than withdraw completely from the study. 
Subjects who discontinue study participation and terminate the protocol early 
will be able to review their final results with their site PI or study clinician and 
complete the final survey questionnaire about their N-of-1 experience.  
Protocol v5.0
5/27/19
Removed the word “intra-abdominal” from the study exclusion criteria related 
to fistulas or abscesses in order to clarify that all abscesses and fistulas are 
study exclusion criteria. 
Protocol v5.1
11/11/2019
Increased the sample size from 50 to 60.  Removed the provider end of study 
survey in the study procedures section. 

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Protocol v5.2
1/29/2020
Edited the study procedures section (3.4) to include that we will obtain data 
using sources outside of what is listed in the outcome measures section if 
needed and added the option of conducting the final results review virtually.

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Investigator Signature Page
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable US federal regulations and ICH guidelines. 
PRODUCE Study
Version 5.2, January 29, 2020
I agree to conduct the study in accordance with the relevant, current protocol and will not make changes 
to the protocol without permission, except when necessary to protect the safety, rights, or welfare of study 
participants. 
I agree to personally conduct or supervise this study. 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations. 
Lead Site Investigator: ________________________________________________________ 
(Printed name, Title) 
Signed:_____________________________
Date: ________________________

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Table of Contents
1
AIM 1 SUMMARY.........................................................................................................................10
2
OVERALL STUDY INTRODUCTION .................................................................................................11
2.1
OVERALL STUDY OBJECTIVES ..............................................................................................................11
2.2
OVERALL STUDY AIMS:......................................................................................................................11
3
AIM 1: PRODUCE STUDY ..............................................................................................................11
3.1
BACKGROUND..................................................................................................................................11
3.1.1
Pediatric Inflammatory Bowel Disease (IBD) ........................................................................11
3.1.2
A Critical Research Gap.........................................................................................................12
3.1.3
Potential to improve health care and outcomes...................................................................12
3.1.4
Study Setting.........................................................................................................................13
3.2
STUDY OBJECTIVE .............................................................................................................................13
3.3
STUDY DESIGN .................................................................................................................................13
3.3.1
Basic PRODUCE Study Design:...............................................................................................13
3.3.2
Technology Platform Configuration......................................................................................14
3.3.3
Interventions and Comparators ............................................................................................15
3.4
STUDY PROCEDURES .........................................................................................................................16
3.5
PARTICIPANT SELECTION AND WITHDRAWAL.........................................................................................19
3.5.1
Inclusion Criteria ...................................................................................................................20
3.5.2
Exclusion Criteria...................................................................................................................20
3.5.3
Participant Pre-screening and Recruitment ..........................................................................21
3.5.4
Early Withdrawal of Participants..........................................................................................21
3.5.5
Duration of Participation ......................................................................................................21
3.6
STATISTICAL PLAN.............................................................................................................................21
3.6.1
Sample Size Determination ...................................................................................................21
3.6.2
Statistical Methods ...............................................................................................................22
3.7
SAFETY AND ADVERSE EVENTS (AE).....................................................................................................23
3.7.1
AEs ........................................................................................................................................23
3.7.2
Adverse Event Reporting.......................................................................................................24
3.7.3
Investigator reporting...........................................................................................................24
3.7.4
Sponsor reporting..................................................................................................................24
3.7.5
Data and Safety Monitoring Plan..........................................................................................24
3.8
DATA HANDLING AND RECORD KEEPING...............................................................................................25
3.8.1
Confidentiality.......................................................................................................................25
3.8.2
ICN Registry...........................................................................................................................25
3.8.3
Study REDCap Database .......................................................................................................25
3.8.4
Source Documents ................................................................................................................25
3.8.5
Patient Surveys and Questionnaires......................................................................................26
3.8.6
Records Retention.................................................................................................................26
3.9
DATA SECURITY FOR EUREKA TECHNOLOGY PLATFORM...........................................................................26
3.9.1
Eureka Risks: .........................................................................................................................26
3.9.2
Eureka Efforts to Minimize Risk: ...........................................................................................26
3.9.3
Confidentiality Measures: .....................................................................................................27
3.9.4
Data Storage & Security:.......................................................................................................27
3.10
ETHICAL CONSIDERATIONS..............................................................................................................27

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3.10.1
Conflict of Interest.................................................................................................................28
3.10.2
Participant Stipends or Payments .........................................................................................28
5
STUDY FINANCES .........................................................................................................................29
5.1
FUNDING SOURCE.............................................................................................................................29
6
PUBLICATION PLAN......................................................................................................................29
7
REFERENCES.................................................................................................................................29
8
APPENDICES.................................................................................................................................31
 

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List of Abbreviations 
ACRONYM
Long name
PCORI
Patient Centered Outcomes Research Institute
PPRN
Patient powered research network
ICN
ImproveCareNow
IBD
Inflammatory Bowel Disease
SCD
Specific Carbohydrate Diet
CD
Crohn’s Disease 
UC
Ulcerative Colitis
IC
Indeterminate Colitis
AWS
Amazon Web Services
PRO
Patient reported outcome
sCDAI
Short Crohn’s Disease Activity Index 
sPCDAI
Short Pediatric Crohn’s Disease Activity Index
PUCAI
Pediatric Ulcerative Colitis Activity Index 
CRP
C Reactive Protein
ESR
Erythrocyte Sedimentation Rate
MCMC
Markov chain Monte Carlo
HTE
Heterogeneity of Treatment Effects
DSMB
Data Safety Monitoring Board
UCSF
University of California San Francisco
RCT
Randomized Controlled Trial

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1
Aim 1 Summary
Title
Personalized Research On Diet in Ulcerative Colitis and Crohn’s Disease
Short Title
PRODUCE Study
Protocol 
Number
2017-0683
Methodology
Series of N-of-1 trials
Study 
Duration
4 years
Study 
Centers
Multi-center with estimated 21 centers
Objectives
Use a series of N-of-1 trials to determine the effectiveness of a specific carbohydrate diet 
(SCD) in reducing symptoms and inflammatory burden in patients with IBD versus a 
modified SCD at both the individual and population level.
Number of 
Participants
Up to 60 recruited across all sites 
Diagnosis 
and Main 
Inclusion 
Criteria
Age 7-18 years; IBD; Stable medications
Statistical 
Methodology
Analysis of individual trial results using Bayesian models to estimate treatment 
differences; Meta-analysis of series of N-of-1 trials using multilevel mixed models

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2
Overall Study Introduction
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (Food and Drug Administration Title 
21 part 50, part 56 and International Conference on Harmonization guidelines), applicable 
government regulations and Institutional research policies and procedures. 
2.1
Overall Study Objectives
The overall study is designed to enable patients and clinicians to collaborate in using mobile 
heath (mHealth) technology supported N-of-1 trials to answer patient-generated research 
questions from two national patient powered research networks (PPRNs)—the 
ImproveCareNow (ICN) network of children with inflammatory bowel disease (IBD) and the 
Health eHeart (HeH) network of adults with cardiovascular disease. By using a common 
method to answer research questions from two very different PPRNs, this study will provide 
evidence in support of N - o f - 1 methods as an approach to advance personalized and 
patient-centered outcomes research. This protocol details the study being conducted in the 
ICN network only (Aim 1)
2.2
Overall Study Aims:
Aim 1:  Use a series of N-of-1 trials to determine the effectiveness of a specific carbohydrate 
diet (SCD) in reducing symptoms and inflammatory burden in patients with IBD versus a 
modified SCD at both the individual and population level.
Aim 2: Test the comparative effectiveness of N-of-1 trials versus data tracking alone to 
identify and eliminate individual-level triggers and reduce atrial fibrillation (AF) frequency and 
severity.
Aim 3:  Assess the feasibility, acceptability, and impact of using N-of-1 methodology across 
diverse populations (pediatric IBD and adult AF) to answer different types of patient-initiated 
questions and provide meaningful data for all PPRN stakeholders.
This protocol details Aim 1 only (study being conducted in ICN).  The activities of Aim 
2 (study being conducted in HeH) and Aim 3 (N-of-1 Evaluation) are outlined in 
separate protocols.
3
Aim 1: PRODUCE Study  
3.1
Background
3.1.1
Pediatric Inflammatory Bowel Disease (IBD)
Pediatric Inflammatory Bowel Disease (IBD) is a debilitating condition that negatively impacts the 
health of children. IBD includes Crohn’s disease (CD) and ulcerative colitis (UC) and affects 1.4 
million children and adults in the US, at an overall cost of more than $1.7 billion1. Childhood IBD 
is particularly aggressive, with significant impacts on both physical and psychosocial well-being 
that influence individuals over their entire lifespan2,3. Typical symptoms, such as abdominal pain 

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and bloody diarrhea result in significant morbidity, including hospitalization and surgery, missed 
school, and decreased quality of life3,4. While treatment options have improved, over 40% of 
patients still have frequent, troubling symptoms that negatively impact their health and daily 
functioning5-7. 
While IBD treatment has improved, evidence regarding the role of diet in managing IBD is lacking. 
The mainstays of IBD treatment have been anti-inflammatory, immunomodulators, and biologic 
medications, but specific types of nutritional therapy (formula based enteral nutrition)8 are as 
effective in reducing symptoms and inducing remission as steroids for pediatric patients with 
CD9,10. Patient and family interest in examining the impact of diet on IBD symptoms is high. 
Between 36%-50% of pediatric IBD patients use complementary and alternative therapies11. Yet, 
studies of the efficacy of diet in treating and controlling IBD symptoms remain limited9. Preliminary 
data regarding the specific carbohydrate diet (SCD) suggests that it may result in clinical benefit 
and improvement in inflammatory biomarkers10. The diet eliminates grains, including but not 
limited to wheat, barley, corn and rice, sugars except honey, and limits milk products except fully 
fermented yogurt and aged cheeses (>30 days)12. Several small retrospective and prospective 
studies conducted by a study co-investigator (David Suskind) suggest improvement in clinical 
symptoms and inflammatory markers within 2-3 months of initiating the SCD10,13.  Despite the 
promise of SCD, there is no evidence of its effectiveness compared to unrestricted diets from 
controlled, large scale, multi-center studies. There is also little evidence about the effectiveness 
of the SCD as compared to more liberalized, or modified, versions of the diet, which is important 
given the burden associated with the SCD. Therefore, determining the effectiveness of the SCD 
diet in reducing symptoms and improving inflammation in IBD in a large scale study will address 
an important gap in care. If an exclusionary diet can effectively induce and maintain remission, 
then patients will have another viable therapy.
3.1.2
A Critical Research Gap 
The role of diet in managing IBD is important to ICN patients and families. To identify research 
questions important to the community, ICN used a formal research prioritization process that 
engaged all stakeholders. Participating clinicians, parents, and patients were identified through 
listservs, social media, community meetings, monthly newsletters, and emails from network 
leaders. Respondents (94 clinicians and 116 parents/patients) identified 210 research questions 
of interest. An expert stakeholder panel classified the questions using the taxonomy of the James 
Lind Alliance14 and eliminated redundancies and topics with sufficient evidence14.  Sixty-two 
network stakeholders, including parents, clinicians, and researchers, subsequently rated these 
learning objectives at ICN’s biannual Community Conference. We identified the subset of 
questions amenable to N-of-1 study. Among these, the effectiveness of diets in reducing the 
symptoms of IBD was rated the highest. 
3.1.3
Potential to improve health care and outcomes
By using an N-of-1 approach, we will generate individualized evidence about the effectiveness of 
diet in managing IBD. This methodology provides a direct benefit to patients by helping provide 
them a greater certainty about their treatment choices, including the relative benefits vs. burdens 
of maintaining an exclusively SCD diet. This has tremendous potential to improve their individual 
health in a way that is truly personalized and patient centered. 
By examining diet in IBD, we will add to the body of knowledge about effective treatments, 
especially for children and parents who are either reluctant to use standard immunomodulators 
or who continue to have mild to moderate disease activity despite standardized therapy. A 
preliminary analysis of our ICN registry found that >2,000 (20%) patients on stable medication 

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regimens still had mild to moderate disease activity. These children and their families would 
benefit from additional treatment choices that would enable them to achieve remission and 
improved health outcomes. 
3.1.4
Study Setting
Aim 1 will take place in the ImproveCareNow (ICN) Learning Network whose mission is to 
transform the health, care and costs for all children and adolescents with IBD by enabling 
patients, families, clinicians and researchers to work together to accelerate innovation, 
discovery and application of new knowledge15.  ICN’s organizational structure ensures that all 
stakeholders are engaged in its governance. A major advantage of conducting this trial within 
ICN is that infrastructure has been optimized to support all components of this study – 
screening, enrollment, follow-up, and data collection/management. The study will take 
advantage of the ICN registry that contains standardized, IBD-specific data from >15,000 
patients who have consented for research. ICN represents an ideal setting for this diet trial 
because: (1) a collaborative network of highly engaged providers, researchers, patients, and 
caregivers has already been established; (2) the network is large and diverse, so results are 
likely to be generalizable; and (3) mechanisms of patient identification, follow-up, and data 
collection (including measurement of several study outcomes) are already built into routine 
clinical care.
3.2
Study Objective
Use a series of N-of-1 trials to determine the effectiveness of a specific carbohydrate diet (SCD) 
in reducing symptoms and inflammatory burden in patients with CD and UC versus a modified 
SCD at both the individual and population level.
3.3
Study Design
3.3.1
Basic PRODUCE Study Design:
This study will employ a series of individual N-of-1 trials that compare the SCD to a modified SCD 
using a collaborative approach between patients, parents, and their clinical team. Patients will 
enter the study on a usual (non-SCD) diet and will have a minimum 1-week run in period for diet 
planning and baseline data collection before beginning their assigned treatment.  Treatment 
periods will be assigned in blocks of two (e.g., AB) with the goal of each patient completing two 
balanced treatment blocks (e.g., ABAB) where treatment ‘A’ represents SCD and treatment ‘B’ 
represents modified SCD. Patients will be randomized to either the SCD or modified SCD as their 
starting intervention and alternate between these two conditions for four 8-week treatment 
periods.  The study design is summarized in Figure 1.

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Figure 1
By completing an N-of-1 study, each individual will have a personalized answer regarding the 
comparative effectiveness between a highly restrictive diet (SCD) and a more broadly sustainable 
middle ground option (modified SCD) as compared to their baseline diet. In addition, we will 
aggregate the results of the completed N-of-1 trials across all patients to estimate the population 
level comparative effectiveness of these dietary treatments and the effectiveness of each 
compared to a typical, non-SCD, diet. As there is uncertainty regarding whether the sequencing 
of the intervention is important (e.g., whether patients must initiate a full SCD diet before modifying 
the diet to be less restrictive), we opted to randomize the initial treatment to be able to examine 
whether effects differ based on the initial diet type. Although using an ABAB/BABA design without 
randomization of treatment periods may result in patients anticipating their next intervention 
period, we do not believe this will result in increased dropout rates or failure to complete all 
treatment periods because patients and parent stakeholders expressed that they are interested 
in testing both diets—those who improve on SCD will be interested in determining whether they 
can maintain improvements on the modified SCD and those who improved on the liberal SCD will 
be interested in determining whether they can achieve greater improvements on a more strict 
SCD. The rationale for the duration of each treatment period (8-weeks) was based on the concern 
that patients would be unlikely to stay on a diet for more than 8 weeks if they did not observe a 
benefit and based on information from Breaking the Vicious Cycle and preliminary studies from 
research co-investigators indicating the symptoms improve within ~1 month and markers of 
inflammation by 2 months.
3.3.2
Technology Platform Configuration 
Study participants will use the Eureka N-of-1 platform (website and mobile app) to execute the 
research proposed in this study.  The Eureka N-of-1 platform will enable participants and their 
clinicians to collect outcome data, track intervention/exposure status, and review collected data 
in real time. Upon trial completion, Eureka will present N-of-1 results to patients and providers 
with easy-to-understand graphics that include probabilistic assessments of the benefits of the 

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intervention.  Eureka will configure a study-specific version of the platform to execute the 
research proposed in this study. Screen shots of the Eureka app are provided in Appendix A.
The Eureka Research Platform is a digital research platform developed at the University of 
California San Francisco as part of a cooperative agreement with the National Institutes of Health. 
The purpose of the platform is to facilitate mobile health research for any interested investigator. 
The Eureka platform includes a participant-facing “front end,” with mobile app and web-based 
interfaces, an investigator portal, and a secure “back end” for data storage and analyses. The 
platform is designed as an all-inclusive, configurable, easily-scalable research platform, inclusive 
of all aspects of research—from participant enrollment, onboarding and consent, to multi-modal 
data collection, study administration/management, and data extraction.  The platform’s front end 
can be customized by individual investigators to implement their specific research project. Existing 
functionality includes the ability to obtain remote consent (although in-person consent can also 
be used), deploy participant surveys, message participants via push notifications, texts, or emails, 
integrate with external apps, sensors, and Bluetooth enabled devices, and capture data collected 
from smartphones (such as geolocation data or accelerometer/ activity data). The investigator 
portal provides a secure website wherein investigators, coordinators or other individuals with 
appropriate permissions can visualize relevant participants’ data and study status. The back end 
of the Eureka platform is a multi-tenant system that enables data collection, management and 
storage derived from multiple sources and from studies of various forms. This architecture rests 
on a secure and HIPAA-compliant Amazon Web Services (AWS) cloud with the capacity to curate 
dense data from more than 1 million participants. In addition to providing data as needed to 
investigators, the infrastructure houses a de-identified data repository that is publicly available to 
help fulfill the general mission of advancing science and wellness. 
As part of design sessions held prior to enrollment, members of the research team including 
patients, parents, and clinicians will provide input regarding the study-specific configurations of 
the Eureka platform. Study specific configurations will include: (1) trial specific onboarding page, 
(2) code to generate and perform analyses of trials based on a trial-specific template, (3) server 
workflow that automates execution of the personal trials, and (4) customization of the user 
interface for prompts, reminders, forms, surveys, and visualizations. Final configurations will 
depend on input from key stakeholders. Technology modifications will be done via iterative, rapid 
development and testing cycles 
3.3.3
Interventions and Comparators
The diets are defined as follows: 
1.
Usual Diet (Baseline Condition): Patient eats a typical, non-SCD, diet. Diet may include some 
restrictions (which is common in IBD) such as seeds/nuts or gluten, but exclusions will not be 
as broad as with the SCD and Modified SCD (e.g., patient still eating grains and/or dairy).  
May include full or partial exclusive enteral nutrition as the currently available liquid 
supplements are not SCD compatible.  
2.
Specific Carbohydrate Diet (SCD): The dietary program will follow recommendations outlined 
in Breaking the Vicious Cycle by Elaine Gottschall12. Allowed foods include meat/fish/poultry, 
eggs, some legumes (e.g., lentils and split peas are permitted, chickpeas and soybeans are 
not), fully fermented yogurt, non-starchy vegetables, ripe fruit, nuts/seeds, honey and nut 
flours (e.g. almond flour or coconut flour).  SCD compatible vitamins are allowed and will be 
recommended on as needed basis by study dietitians. Restricted foods include all grains, milk 

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products aside from 24-hour fermented SCD yogurt and cheeses aged greater than 30 days, 
starchy vegetables, processed foods with food additives and sweeteners other than honey.16
3.
Modified Specific Carbohydrate Diet (SCD):  A more liberal, and thus, perhaps more 
sustainable version of the SCD.  In addition to the foods in the SCD, allowed foods will expand 
to include organic rice, oats, sweet potatoes, Grade A maple syrup and 100% unsweetened 
cocoa powder (not Dutch processed) or 100% cacao powder, nibs, or butter (no sugar added) 
for this group.  For oats, organic rice, and sweet potatoes, patients will be instructed to 
consume a minimum of 3 servings and a maximum of 6 servings of any combination of these 
items per week.  On any given day, they should not have more than 2 servings of any 
combination of these items.  A serving size is 1 cup.  For maple syrup and 100% unsweetened 
cocoa powder (not Dutch processed) or 100% cacao powder, nibs, or butter (no sugar added), 
patients will be asked to consume a minimum of 2 Tablespoons of each item per week and a 
maximum of ½ cup of each per week.  The reasons for the minimum amount of these food 
items each week is to distinguish the diet from the SCD enough to provide a useful 
comparison.  Gluten, corn products, milk products (except yogurt and aged cheeses), 
sweeteners (except honey), and process foods will still be restricted.
3.4
Study Procedures 
Baseline evaluation: Study participants will complete a routine clinical assessment including 
disease activity measures and standard lab tests that assess inflammation and disease status 
(per center standard of care). Participants must have documented evidence of acute inflammation 
and/or elevated acute phase reactant as measured by Fecal calprotectin 1.5 times the upper limit 
of normal, Lactoferrin 1.5 times the upper limit of normal, CRP 1.15 times the upper limit of normal, 
or ESR 1.15 times the upper limit of normal (based on local reference ranges) within 8 weeks of 
enrollment. Potential participants who are close to meeting one of the acute inflammation and/or 
elevated acute phase reactant markers and who meet all other study criteria will be considered 
for study participation on a case by case basis by the investigative study team in consultation with 
the patient’s primary gastroenterologist.  A stool sample for fecal calprotectin and banking for 
microbiome analysis will be collected by the patient at home and sent in for analysis. A trained 
dietitian will provide 1:1 diet training and resources, including print and web-based materials 
(Appendix B). The dietitian will send the participant home with a 3-day diet recall to be returned 
to clinic (see process outlined in section on “Diet Monitoring”). In the event that the site dietitian 
is unavailable for the baseline training, it may be conducted by the site coordinating center dietitian 
via video call (i.e., Zoom, Skype) if permission is granted by the patient’s primary GI physician or 
advanced care provider.  Patients and parents will be trained in the use of the Eureka N-of-1 app. 
Participants will be randomized to either the SCD or modified SCD as their starting intervention 
with a 1:1 allocation ratio. We will utilize a centralized, stratified, block randomization approach. 
We will stratify within sites and by disease type (UC/IC or CD).  Patients and parents will also 
complete psychological assessments and questions regarding their baseline expectation of 
benefit related to diet (see Table 1, Appendix C) via paper, tablet, website, or Eureka app at the 
baseline visit.  Following the baseline evaluation, participants will spend a minimum of 1 week 
(maximum of 4 weeks) collecting baseline data and preparing to begin their first assigned diet 
treatment. They will be asked to not change their diet until they begin their first treatment period. 
The baseline period is defined as the period from enrollment to the start of the N-of-1 trial (1- to a 
maximum of 4 weeks).
Diet Staging:  At the start of the initial diet treatment block (either SCD or modified SCD), 
participants will gradually transition from their usual diet to their initial diet intervention.  For 

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patients randomized to the SCD, they will restrict their diet to the most easily digestible foods such 
as broths, fruit juice, ripe, peeled and cooked fruits, squash and carrots, and non-fried lean meat, 
fish, poultry and eggs for the first 2-3 days. After this initial step, participants will expand their diet 
to include all remaining SCD approved foods. For patients randomized to the modified SCD, for 
the first 2-3 days, they will restrict their diet in the same manner as those randomized to the SCD. 
Then, they will expand their diet to include all remaining SCD approved foods for another 2-3 days 
before adding the additional foods allowable on the modified SCD. Thus, by 5-7 days into the 
treatment, participants randomized to start with the modified SCD will have advanced to the full 
modified SCD diet. 
Follow Up contact:  Based on standard of care for initiating a new dietary treatment, patients will 
be evaluated by the dietitian and/or physician or advanced practice care provider (i.e., nurse 
practitioner or physician’s assistant) at 2 ± 1 weeks after starting each new diet. This visit may be 
completed by phone call, video call or telemedicine visit, per the discretion of the primary GI 
physician or advanced care provider. If this appointment does not take place in-clinic, it is the 
site’s research staff’s responsibility to make sure that the patient’s weight is obtained using the 
same scale at every weigh in and that the patient reports the measured weight to the study staff. 
Participants will also have a phone or in-person follow-up with either their site’s dietitian or the 
site coordinating center dietitian in each treatment period. The dietitian will evaluate patient weight 
(on clinic scale at follow up visits and if available by home scale) and nutritional intake.  S/he will 
prescribe SCD compatible nutritional supplements as needed based on review of the diet recall. 
In addition, at the clinic visits, follow up phone calls or visits, and during any other patient contact, 
the dietitian will carry out standard of care activities including, but not limited to, evaluating the 
participant’s nutrition and overall health, assessing the participants nutritional and dietary needs, 
providing diet advice, sharing sample meal plans, developing new meal plans, and sharing 
recipes from books, online resources, or other personal sources.  In the event that the site dietitian 
is unavailable for follow-up contact, these visits may be conducted by the site coordinating center 
dietitian via video call (i.e., Zoom, Skype) if permission is granted by the patient’s primary GI 
physician or advanced care provider.
Symptom tracking: Participants will use the Eureka N-of-1 mobile app to execute the N-of-1 
protocol, track treatment periods, and track daily and weekly symptoms and disease activity. 
Participants and their clinician will be able to visualize the tracked data in real-time via the Eureka 
N-of-1 app and on the web portal. Parents of participants will always track symptoms using the 
mobile app. Patients ≥14 to 18 years will have the option of tracking for themselves (in addition 
to their parent).  Patients < 14 years will have parents track for them with child input. The questions 
to assess symptom and disease activity metrics are included in Appendix D.  Participants will be 
asked to start tracking at the baseline visit. Patients will be asked to complete a minimum of 2 
weeks of symptom tracking in the baseline period (14 daily measures, 3 weekly measures) and 
will be asked to continue with tracking once they initiate the N-of-1 Trial via the Eureka app.
Stool Collection: Participants will collect a home-based stool sample for fecal calprotectin analysis 
and biobanking for future analysis during the baseline period and the end of each treatment 
period.  Stool specimens will be accepted as early as up to 2 weeks before the end of the 
treatment periods. Active participants will not be able to advance to their next treatment block until 
stool is collected and sent. If a patient elects to terminate a treatment condition early, they will be 
asked to submit a stool specimen at that time, prior to changing treatment conditions. Participants 
who discontinue the study after the first crossover (e.g., completion of baseline, Diet A1, and Diet 
B1) and terminate the protocol early may advance to the end of the study without additional stool 
collection. Patient instructions for stool collection are documented in Appendix E. Fecal 

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calprotectin results will be made available to the clinicians as the results are returned from the 
lab.
Clinical Evaluations: Participants will be seen for clinic visits as needed throughout the study. 
Based on standard of care for initiating a new dietary intervention and the fact that patients 
enrolled in this study have mild or moderate disease activity, close follow up is recommended.  
Participants will have a follow up visit 8 ± 2 weeks from initiation of the first diet period and then 
as needed over the remainder of the study, with timing based on each individual center’s standard 
practice and patient need. This pragmatic design allows us to test the use of the N-of-1 
methodology for diet intervention as it would be delivered in regular clinical care. Data collected 
at routine clinic visits is standardized and includes weight, height, current medications, laboratory 
assessment, and disease activity (PUCAI and SPCDAI). This data is entered in the ICN registry.  
Assessment of Vitamin D levels is performed per local site standard of care.  This data is not 
collected in the ICN registry.  The date and results of all Vitamin D levels collected at regular 
clinical evaluations will be entered in the REDCap database by the research coordinator or 
dietician at each site.
Diet Monitoring: Patients will complete a 3-day diet diary at baseline and during each diet period, 
ideally around the mid-point of that period (approximately 3-5 weeks after transitioning to the new 
diet). The questions that will be used in the 3-day diet diary are included in Appendix F. The 
participant will return their completed diet diary to the local center dietitian or research coordinator 
via email/scan/text/mail. Once received from the patient and verified for completeness, the center 
dietitian or research coordinator will email the patient’s completed 3-day diet diary to the study’s 
central email at CCHMC and it will be triaged to approved research staff at Seattle Children’s 
Hospital all using a secure and IRB-approved email system. The research staff member at Seattle 
Children’s Hospital will enter the data from the 3-day diet diary into a nutrient composition 
program. Output from the nutrition composition program (e.g., total calories, percent calories from 
fat, percent calories from carbohydrates, percent calories from protein, micronutrient composition) 
will be communicated back to the patient’s site dietitian (using IRB-approved communication 
channels) and will be entered into a REDCap database by the research staff at Seattle Children’s 
Hospital or exported electronically and sent to CCHMC. The site dietitian or site coordinating 
center dietitian (if local dietitian is unavailable) will follow up with the patient via telephone or in-
clinic to discuss any issues with the diet, discuss nutritional adequacy of diet, and recommend 
any adjustment in dietary intake or vitamin supplements. The dietitian will continue to attempt 
contact until the participant is reached.
Study Completion and N-of-1 Results Review: Following the final treatment period, participants 
will return to clinic within 4 weeks to complete a standard physical exam including weight, height, 
medications, and clinical measure of disease activity. They will review the results of their trial via 
the Eureka N-of-1 platform with their clinician (Appendix G) and will complete a final questionnaire 
regarding their experience with the N-of-1 trial via tablet, website, Eureka app, or paper. If the 
final results review is unable to be conducted in person with the study physician, the results can 
be provided via phone call, video call or telemedicine visit, per the discretion of the primary GI 
physician or advanced care provider. If the results are provided virtually, the site is still required 
to schedule an in-person clinician visit to complete a standard physical exam with the participant.
The overall study procedure timeline is summarized in Figure 2.
Figure 2*

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Patients will be supported in their adherence to the diet through a variety of means.  
Dietitian/physician or advanced practice provider involvement and follow-up (as described above) 
is a key component to providing supportive coaching for patients and families.  In addition, 
resources, including print and web-based materials (Appendix B), will be made available for 
patients to support them in learning about the diet, provide ideas for meal planning, offer 
approaches for teaching other family members and friends about the SCD, handling family 
gatherings and special occasions, etc.16  
Outcome Measures 
Study outcomes and mediating factors are detailed in Table 1. Primary outcomes across all 
patients will include patient reported outcomes (PROs) of stool frequency, stool consistency, 
pain interference and GI symptom severity (see Appendix D), and fecal calprotectin. Secondary 
outcomes will include patient-reported disease activity scores as measured by the Pediatric 
Ulcerative Colitis Activity Index (PUCAI)17,18 and Short Crohn’s Disease Activity Index (SCDAI)19, 
clinically-evaluated disease activity scores contained in ICN registry (PUCAI and  sPCDAI), 
growth, laboratory markers of inflammation and disease status [C Reactive Protein (CRP), 
Hematocrit, Erythrocyte Sedimentation Rate (ESR), Albumin]. Fecal calprotectin was selected as 
the central marker of intestinal inflammation because it correlates well with both clinical and 
histologic remission, is noninvasive and objective, and has been shown to be a useful tool to 
monitor response to therapy20,21.  Safety Outcomes: The major safety concerns for patients with 
IBD participating in a diet intervention include weight loss and inadequate nutrition. Weight loss 
typically occurs within the first few weeks of starting the diet.  Weight will be assessed at all 
clinic visits and at the dietitian follow up visits (weeks 4 and 12) and by weekly weights entered 
in the Eureka app if there is a home scale available. If a home scale is available, patients will be 
instructed to obtain an initial weight on their home scale at the beginning of the baseline period 
and use the same home weighing scale throughout the study period. Nutrition intake will be 
monitored by the dietitian regularly for all enrolled patients and will be assessed via 3-day diet 
diaries conducted at specified intervals (baseline and in weeks 3-5 of each treatment period) and 
weekly weight tracking (if available).  In addition, we will collect results of any serum Vitamin D 
level monitoring conducted as part of routine care and will report these results to the DSMB. 
Mediating factors: We will collect demographic data from the ICN registry including age, gender, 

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race, ethnicity, family education level, disease type, disease location, medications, and disease 
characteristics at baseline.  Dietitians will use data from 3-day diet diaries to assess deviation 
from the prescribed diet (Appendix F). We will also measure the patient and parent psychological 
well-being and expectations regarding benefit of diet as a treatment strategy as these may 
mediate adherence to the diets.
If a measure is missing in any of the sources listed below, we will obtain the data using other 
sources which could include secured email correspondence with the site and/or screening and 
eligibility verification case report forms.  The screening and eligibility verification case report form 
is a non-patient facing tool currently used by the site coordinator to verify participant eligibility.  
This form is uploaded to OneDrive so that the site coordinating center can confirm eligibility; thus, 
it is data the site coordinating center already routinely receives.
Table 1: Outcome Measures
Construct
Measure(s)
Timing
Source
OUTCOMES
Stool Frequency
Single integer count
Daily
N-of-1 App
Stool Consistency
Bristol Stool Scale20
Daily
N-of-1 App
Pain Interference
PROMIS® Pain 
Interference22
Weekly
N-of-1 App
IBD Severity
PROMIS® Gastrointestinal 
(GI) Symptoms*
Weekly
N-of-1 App
Growth
Weight+
Weekly
N-of-1 App
Self-Report Disease 
Activity
 Pediatric Ulcerative Colitis 
Activity Index (PUCAI)17,18
Short Crohn’s Disease 
Activity Index (sCDAI)19
Weekly
N-of-1 App
Intestinal Inflammation
FecalCalprotectin
Baseline and at the end of 
each treatment period 
Lab
Disease Activity
sPCDAI23, PUCAI18
Sporadic, Clinic Visits
Registry
MEDIATORS
Psychological Well-
being (Parent)
PROMIS® Anxiety
PROMIS® Depression
Baseline
Web-survey or N-of-1 App
Psychological Well-
being(Child)
PROMIS® Anxiety
PROMIS® Depression
Baseline
Web-survey or N-of-1 App
Expectations of Benefit
Treatment expectations and 
preferences (adapted from 
published study)24,25
Baseline
Web-survey or N-of-1 App
*Measure was validated in a sample of 1,007 children and youth in ICN ages 8-24.  The scale exhibits acceptable internal consistency with a with a 
Cronbach’s alpha of 0.74.  The measure is highly responsive to differences in clinical status as assessed by both the patient and their physician/advanced 
practice care provider using validated measures and produces reliable estimates of GI symptom T-Scores ranging from 45 to 80.
+Optional, only if home scale available
3.5
Participant Selection and Withdrawal
From ICN, we will recruit up to 60 patients with IBD and their families (primary caregivers) whose 
treatment decisions may be informed by the results of this study as determined by their GI care 
team. We will not exclude patients based on sex or race/ethnicity.  We intend to enroll evenly 
across ICN centers, but will allow for fewer or more participants per site based on numbers of 
eligible patients and success with recruitment.  
3.5.1
Inclusion Criteria

Diagnosis of CD or UC or Indeterminate colitis (IC)

Age 7-18 years

Enrolled in the ImproveCareNow ICN2 registry; and

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
Evidence of acute inflammation and/or elevated acute phase reactant as measured 
by Fecal calprotectin 1.5 times the upper limit of normal, Lactoferrin 1.5 times the 
upper limit of normal, CRP 1.15 times the upper limit of normal, or ESR 1.15 times 
the upper limit of normal (based on local reference ranges) obtained within 8 weeks 
of enrollment. 
o
Potential participants who are close to meeting one of the acute inflammation 
and/or elevated acute phase reactant markers and who meet all other study 
criteria will be considered for study participation on a case by case basis by 
the investigative study team in consultation with the patient’s primary 
gastroenterologist.  
3.5.2
Exclusion Criteria
Complex and Unstable IBD:

Currently or within the past 9 months has had an abscess, fistula, stricturing CD, or 
ostomy

Ever had history of full colectomy

Severe disease activity as measured by a short Pediatric Crohn’s Disease Activity 
Index (SPCDAI) score of >45 or Pediatric Ulcerative Colitis Activity Index (PUCAI) 
score of >60 assessed within 3 weeks of enrollment

Hospitalization or surgery planned within 3 months

Ongoing active gastrointestinal infection

Severe Malnutrition (BMI less than 5th percentile)

Recent medication changes including:
o
Thiopurines, natalizumab, or methotrexate started within 8 weeks prior to 
enrollment
o
Anti TNF (infliximab, adalimumab) started within 8 weeks prior to enrollment
o
Vedolizumab started within 16 weeks prior to enrollment
o
Increase in corticosteroids within 4 weeks of enrollment or have dose >20 mg 
prednisone or equivalent
Evidence of Other Complicating Medical Issues:

Other serious medical conditions, such as neurological, liver, kidney, or systemic 
disease

Serious psychological or psychiatric conditions such as eating disorders or self-harm

Pregnancy

Tobacco, alcohol, or illicit drug abuse
Inability to Complete the Protocol

Non-English speaking participants will be excluded because the mobile app only 
supports English speakers. The study timeline and funding prohibits development of a 
bi-lingual app.

On SCD or modified SCD anytime within 8 weeks of enrollment
o
If an otherwise eligible patient is on SCD or modified SCD within 8 weeks of 
enrollment but they are noncompliant per the determination of the patient’s 
dietitian/primary gastroenterologist, then this patient is eligible to participant in 
the study.

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
Participants on a vegan diet will be excluded as the added restrictions of the SCD (on 
top of a vegan diet) would not provide these participants with the essential nutrients 
needed for a healthy diet  

Lack of smart phone and data plan for participating caregiver

Participating in another interventional study
3.5.3
Participant Pre-screening and Recruitment
We will recruit patients from participating ICN clinical sites. To introduce the study and provide 
information about dietary management for IBD/SCD, participating ICN clinics will mail a study flyer 
(Appendix J) to clinic patients prior to their upcoming appointment, call them by phone, and/or 
approach them at their clinic visit. Additionally, the study flyer will be available on various social 
media platforms. There will also be a study poster available for participating ICN clinics for use in 
advertising the study to potential participants (Appendix O). For those families who may be 
interested in a parent perspective of the SCD diet, a letter from our parent partners will be 
available (see Appendix P). Potential participants will also be informed about the study opportunity 
via several established channels within the ICN network, including monthly newsletters and blogs. 
In addition, we hope to make a short, animated video that will be used to recruit patients. The 
script for the video is attached as an Appendix B. As with our other patient-facing materials, since 
the study is pragmatic and minimal risk, we request to use this script as a template. It may have 
minor edits to the script which would not require IRB approval.  Eligible participants will be 
identified through the standardized ICN pre-visit planning process. The site principal investigator 
will verify eligibility at the clinic visit. Study participants will enroll in the trial with their clinical team 
at a regularly scheduled clinic visit or at another visit within 2 weeks of a regularly scheduled visit 
if more convenient for the participant. Local clinic research coordinators will maintain a screening 
log in REDCap to track those that are screened, those who are excluded (and for what reasons), 
those that decline, and those who have enrolled. Most ICN clinic sites have obtained HIPAA 
waivers that allow study coordinators to identify potential study participants, evaluate patients for 
study eligibility at pre-visit planning meetings, and discuss participation in studies prior to consent 
being signed. For those who decide to participate, informed consent (and assent where 
applicable) will be obtained prior to initiation of study procedures.  
3.5.4
Early Withdrawal of Participants
If a patient experiences symptom flare, leading to either the diet intervention being stopped, 
medication being changed, or the need for surgical intervention, their participation in the N-of-1 
protocol will be discontinued. In addition, patients who become pregnant during the study will be 
automatically withdrawn, as will patients that have ≥ 7.5% nonintentional weight loss.  Patients 
may also withdraw if they feel that they are unable or unwilling to continue the assigned diet or 
data collection. Participants will be dropped from the study if they have a symptom tracking 
response rate of <50% in the baseline period that does not improve after reasonable attempts by 
research coordinators (as outlined in the study SOPs) to assist participants in improving data 
collection. Because completion of stool fecal calprotectin is required to advance from one 
treatment period to another, a participant who never collects and sends in a stool specimen will 
be dropped at that point in the study. All data from such participants will be retained and analyzed. 
Patients who wish to terminate a treatment period early (and switch to the next assigned 
treatment) will not be considered withdrawals. Participants who wish to end their study 
participation early, but have completed at least two full diet treatment periods (i.e., A1 and B1), 
will have the option to discontinue participation and terminate the protocol early.  Participants who 
choose to discontinue from the study in these instances will schedule a time to come into clinic to 

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receive their final study results and complete the end of survey questionnaire regarding their N-
of-1 experience. These participants will not be considered withdrawals.
3.5.5
Duration of Participation
Full participation in the study will last a minimum of 34 weeks from the baseline visit to the 
completion of the N-of-1 trial.  Participation may last more than 34 weeks if a family experiences 
delays at any phase of the study.
3.6
Statistical Plan
3.6.1
Sample Size Determination
The primary goal of Aim 1 is to determine effectiveness of the SCD vs. modified SCD vs. usual 
diet for an individual patient. Because the focus is on the immediate decision of which treatment 
to select, or if the treatments were different than the patient’s usual diet, it is not necessary to 
protect against a false-positive decision as in standard hypothesis tests used in clinical trials; thus 
sample size calculations are not recommended for individual N-of-1 trials26. For obtaining an 
estimate of the population average effects of the SCD vs. modified SCD on improving symptoms, 
a total of up to 60 patients will participate in the two- treatment crossover study.  Using the weekly 
PROMIS pain interference T-score measure (standardized mean of 50 and standard deviation of 
10) and incorporating aspects of the design related to the number of planned crossovers, washout 
periods, and autocorrelation from repeated measures, we will have 90% power with a two-sided 
5% alpha to detect a mean difference of 3 points between groups which corresponds to the 
minimally important difference on the PROMIS measures, except in the case when 
 and 
𝜎𝑡= 5
 when the minimal detectable difference is above 3 to obtain 90% (but not 80% power).
𝜌> 0.5
3.6.2
Statistical Methods
An overview of the statistical analysis can be found below. A formal data and statistical analysis 
plan will be prepared as a separate document
Analysis of Individual N-of-1 Trials: For the first treatment period only, there will be a 1-week run-in 
period as the participant gradually transitions from their usual diet to the intervention diet.  A 
gradual transition is not needed beyond the first treatment period.  For the first period, we will 
discard the first 7 days of data including the first weekly measurement.  Based on clinical 
experience we expect that diet effects on symptoms wash out by 1 week. Thus, for all subsequent 
treatment periods we will discard the first 7 days of data including the first weekly measure during 
each treatment period. At the end of each person’s N-of-1 trial, statistical analysis will be 
performed to compare results on the two treatments. Each N-of-1 trial requires a separate 
analysis which is automated to run in the background once each trial is completed. The analysis 
consists of running Bayesian models that compare the average response on each of the two 
treatments and baseline diet. Models will incorporate the appropriate scales for the outcomes 
(e.g. normal distributions for continuous variables, multinomial distributions for categorical 
variables) and the appropriate representation of the function linking the expected outcome to the 
predictors (e.g., cumulative logit link for ordinal outcomes).  
Results will be reported for all study measures (stool frequency, stool consistency, PROMIS Pain 
interference, PROMIS GI Symptoms, fecal calprotectin) to enable patients to weigh symptoms 
that are most important to them. For each outcome, each patient will be provided with an estimate 

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of the (1) difference in efficacy between the two diets; and (2) probability that each treatment is 
better than the other; as well as the (3) difference in efficacy between each diet and the baseline 
level; and (4) probability that each treatment is better than the baseline. Results will be portrayed 
numerically and graphically. We will develop educational materials to aid patients and clinicians 
in interpretation (Appendix B). Posterior probabilities of outcomes will be calculated using an 
interface that incorporates open-source R software interfacing through Rjags with open-source 
JAGS software.27 The R code creates the Bayesian model, loads the stored data and chooses 
intelligent starting values that are then fed into JAGS to return the Markov chain Monte Carlo 
(MCMC) simulations of the joint posterior distribution. The R package will accept input from the 
Eureka platform to construct models and return results back to Eureka for display. 
Statistical analyses will be completed and patients will be given results of their individual N-of-1 
studies if they complete at least one paired treatment period and there is enough data in both 
treatment periods to perform valid statistical analysis.
Meta-Analysis of N-of-1 Trials: The collection of individual N-of-1 trials can be thought of as a set 
of studies whose results can be combined as in a meta-analysis. The data can be considered as 
a multilevel structure in which a set of patients is studied with each patient having a set of 
measurements. Standard multilevel mixed model methods will be used to estimate the average 
effect and variance within and across patients. Across patient values estimate the average effect 
in the population of patients studied, while the within-patient estimates describe an improved 
estimate of each patient’s true effect assuming exchangeability across patients. We will fit these 
models using a Bayesian multilevel model with non-informative priors in order to obtain posterior 
distributions of the within and between effect sizes. We will then compare the multilevel patient 
estimates with those from the patient’s data alone in order to determine how much the effects 
change and how much additional precision these estimates gain. We will also include between-
patient covariates to account for variability and to test for heterogeneity of treatment effects (HTE). 
We hypothesize that HTE may exist based on age, sex, disease (CD or UC/IC), disease activity 
(mild or moderate), maintenance medication use, disease location, and disease type 
(inflammatory or penetrating). The model will include the baseline levels of the outcomes which 
will enable estimates of the effect of the study diets relative to the unrestricted diet. We will also 
fit models that adjust for trends over time and account for correlation and carryover. Analyses will 
use the appropriate probability distribution and link function for the outcome variable type (e.g. 
normal distributions for continuous outcomes and ordinal logistic regression with a cumulative 
logit link for scales).
Missing data: Based on our experience, the overall completion rates of daily symptom trackers 
and weekly surveys by ICN patients and parents is >80%, we have found that when participants 
are working on a specific test or personal experiment with their physician, adherence increases 
to >90%. In cases of missing outcome data, we will ignore the missing values in the analysis of 
individual N-of-1 trials which is equivalent to treating them as being missed at random since the 
analysis is not adjusted for covariates. In the meta-analysis, we will explore the association of 
missingness with observed variables and condition analyses on these variables as appropriate. 
We will also explore treating the missing observations as latent parameters and estimate them as 
part of the Bayesian model assuming them to be missing at random.  If patients decide to stop a 
treatment before 8 weeks, we will analyze the data available. Since effect modifiers in the meta-
analysis are collected at the patient level, we expect them to be completely collected (e.g., there 
will not be a need for a statistical approach to address missing data for these variables). In the 
meta-analysis, we will perform the following sensitivity analyses for different types of missing data: 

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(1) analysis of all available data; (2) analysis excluding patients who withdrew early from the trial; 
(3) analysis of patients who completed the entire protocol, i.e. excluding those who withdrew early 
and those who terminated any treatment periods early.  
3.7
Safety and Adverse Events (AE)
3.7.1
AEs
Clinical adverse events (AEs) will be monitored throughout the study. Since the study procedures 
are not greater than minimal risk, significant AEs are not expected. Potential AE’s could include 
allergic reaction to a component of the diet, significant intolerance of the diet other than as an 
allergic reaction, and/or unintentional weight loss of ≥ 5%.
Expected adverse events include:

Mild to moderate increase in abdominal pain, diarrhea, gas/bloating within the first 3-4 
weeks of starting the new diet

Weight loss of less than 5% in the first 3-4 weeks of starting the new diet

Worsening of IBD due to failure of the diet to improve the disease. This could be 
manifested as new onset or worsened, bloody stools, diarrhea, abdominal pain, fistula, 
abscess, or bowel obstruction

Hospitalization or surgery due to failure of the diet to improve the disease
Serious adverse events are not expected. However, if an SAE occurs and is determined to be 
possibly or definitely related to study treatment, it will be reported in accordance with CCHMC’s 
IRB SOPs (as described in Section 3.7.2).
3.7.2
Adverse Event Reporting
As the study is being conducted with the engagement of the participant’s clinical 
team/gastroenterologist, the medical team will seek information on AE’s as a part of regular 
contact with the participant (any patient or clinician initiated phone call or email, or at scheduled 
clinical visits). The Investigator is responsible for recording and reporting anticipated and 
unanticipated problems related to research that occur during and after study treatment. All AE’s 
will be reported to the data coordinating center at CCHMC, including relationship of the AE to the 
study procedures (definitely related, possibly related, unlikely related, or not related).  AE’s that 
are unexpected (not included in list of expected adverse events in Section 3.7.1) and are deemed 
by the site PI as either possibly or definitely related to the intervention will be summarized in 
narrative or other format and submitted to the IRB at the time of continuing review.  All SAEs 
(CCHMC or relying sites) deemed possibly or definitely related to the intervention will be reported 
to the IRB in accordance with CCHMC IRB policies. Since the study procedures are not greater 
than minimal risk, SAEs are not expected. If any unanticipated problems related to the research, 
involving risks to participants or others, happen during this study (including SAEs), these will be 
reported to the IRB in accordance with CCHMC IRB SOPs 
3.7.3
Investigator reporting
Investigators are responsible for safety reporting to the central and/ or local IRBs. Investigators 
are responsible for complying with the central and/or local IRB’s reporting requirements, though 
must submit the required reports no later than 10 working days.  Copies of each report and 
documentation of IRB notification and receipt will be kept in the investigator’s study file. 

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3.7.4
Sponsor reporting
The study sponsor will notify all participating investigators, as well as the central IRB, of relevant 
DSMB safety reports as described in section 6.2.3.
3.7.5
Data and Safety Monitoring Plan
A DSMB will regularly review interim data to monitor safety. The DSMB has overall responsibility 
for interpreting data on adverse events. Committee members are independent experts chosen on 
the basis of their expertise and scientific rigor. The Committee has the responsibility to review the 
research protocol and to evaluate the progress of the trial overall and at each participating clinical 
center. This includes accrual, data quality and completeness, episodes of hospitalization, and 
protocol violations. Serious unexpected events will be disclosed to the committee between 
meetings. The Committee will begin its work on this trial by identifying key data points that will be 
monitored at each of the interim meetings. The DSMB will work closely with the investigators and 
biostatistician. Following each meeting, its chair will prepare a report on the questions raised by 
Committee members and monitoring recommendations. This report will be distributed 
confidentially to meeting participants. The Committee also will prepare a redacted summary of 
this report, focusing on safety issues, for distribution to clinical site co-investigators and their IRBs. 
Finally, the DSMB will make recommendations to the ICN study leadership team regarding actions 
to ensure that participants are not exposed to undue risks. The DSMB Charter is provided in 
Appendix M.
3.8
Data Handling and Record Keeping
3.8.1
Confidentiality
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed participant’s authorization informing the participant of the following: 

What protected health information (PHI) will be collected from participants in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of participant 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the participant is alive) 
at the end of their scheduled study period.
3.8.2
ICN Registry
In 2007, ICN established a standardized, web-based clinical registry that enabled collection of 
standardized, IBD-specific data about processes and outcomes of care (e.g., disease 
characteristics, patient well-being, laboratory results, and medications). In 2010, with AHRQ 
funding, ICN developed a modular, open-source, registry that can be linked to an electronic 
health record (EHR) to minimize the burden of manual data entry. This allows for a significant 
portion of registry data to be transferred electronically via a secure web portal to the registry, 
and stored for re-use in QI, chronic care delivery, and comparative effectiveness research. 

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Data captured through EHR-linkage or web-based forms consist of discrete elements that 
conform to a standardized data model. As previously described, this study will use data on 
demographics, baseline characteristics, and changes to disease activity/inflammation and 
medications as collected from the ICN Registry.
3.8.3
Study REDCap Database
The study will utilize a REDCap database for data collection.  The REDCap database will be 
designed and housed at CCHMC on a secure server.  Access to the database will be limited to 
members of the research team at each site.  Each team member will have an individual login ID 
and password.  Data on screening and enrollment (including patient name linked to study ID), 
nutritional assessments (including Vitamin D levels obtained as part of routine care), and AE 
reporting will be collected at the ICN site by the local study coordinator, dietitian, and/or central 
research coordinator at Seattle Children’s Hospital (for nutritional assessments only) and will be 
entered into the REDCap database.  
3.8.4
Source Documents
Source data is all information, original records of clinical findings, observations, or other activities 
necessary for the reconstruction and evaluation of the research.  Source data are contained in 
source documents.  Examples of these original documents and data records include: Eureka N-
of-1 app and database, the ImproveCareNow registry, clinical and office charts, memoranda, 
participants’ diaries (including 3-day food diary), output from the nutrition analysis program, 
recorded data from automated instruments, patient reported data recorded in the N-of-1 app, 
electronic case report forms, and records kept at laboratories and at medico-technical 
departments involved in the study.
3.8.5
Patient Surveys and Questionnaires
Surveys and questionnaires to collect patient reported outcomes data (as described in Table 1) 
will be administered through the Eureka N-of-1 app, weblink, or paper/pencil as previously 
described. Symptom tracker and PRO questions that will be administered through the Eureka app 
are documented in Appendix D.  The surveys to assess experience with the N-of-1 app are 
provided in Appendix H.  The questions to assess baseline expectations are provided in Appendix 
C.
3.8.6
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by their institution or as required by local and national governing regulations, whichever 
is longer. Study records include consent forms and source documentation. The investigator must 
contact the sponsor prior to destroying any records associated with the study.
3.9
Data Security for Eureka Technology Platform
Data on patient symptoms and PRO’s will be collected via the Eureka platform. The Eureka 
mHealth Research Platform Resource is a mobilized cohort and infrastructure used to carry out 
clinical research studies using mobile and digital technology.  Patients will submit their data via 
SMS text messages, via mobile applications, via secure websites, or will upload their data from 
other services they may authorize.  Simple, non-PHI carrying messages are sent by the system, 
and typically unidentifiable numeric responses are returned.  The only PHI involved in the 

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transaction is the phone number or unique ID used to identify the patient’s phone.  This data is 
then stored on the study platform as previously described.
Eureka will support a registration procedure that will allow registration with identifying information 
that will generally include name, date of birth, and mobile phone number or email address. Eureka 
also provides investigators with the option of requiring confirmation of mobile phone numbers and 
email addresses.   In registering for our study, the Eureka Privacy Policy and Data Security 
Measures will be presented to participants (Appendix N).
3.9.1
Eureka Risks:
The risk of loss of privacy in our study hosted by the Eureka Research Platform will be present 
for all persons participating. Loss of privacy could occur by compromise of the Eureka technical 
system or if Eureka is required by law to disclose data to authorities, e.g. to prevent serious harm 
to the participant or others. This is the primary reason for the Eureka Privacy Policy and Data 
Security Measures (attached document).
3.9.2
Eureka Efforts to Minimize Risk:
To minimize risk of loss of privacy, Eureka takes the following steps:
Technical system security: Information will be transmitted and stored using state-of-the-art 
security systems similar to those that protect websites used by banks and electronic health record 
systems.  Specifically, the Eureka Platform is hosted on Amazon Web Services (AWS), a cloud-
based server system and computing services that are HIPAA compliant, and Eureka follows 
security guidelines of the U.S. Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Specifically, all research data are stored behind a secure firewall, guarded by intrusion 
detection software, and encrypted at rest and in transit in our Amazon Virtual Private Cloud.
Inform patients: As described above, we will include the Eureka Privacy Policy and Data Security 
Measures that will be referenced in study onboarding and viewable at any time.  The statement 
will inform patients of the risks of loss of privacy, including via technical compromise or legal 
requirements.  We will also make them aware that they are responsible for keeping their login 
credentials secure.
3.9.3
Confidentiality Measures:
Identifying information (name and email address) will be stored in separate (but linked) data tables 
so that health-related data can be viewed by approved staff as needed without inadvertent 
association with identifiers when such linkage is not required.
In the event of a data break, the Eureka Research Platform Team will notify all Study Teams and 
Study Participants in accordance with UCSF guidelines.
3.9.4
Data Storage & Security:
Data is stored on Amazon Web Services (AWS or Amazon Cloud).  AWS is FEDRAMP compliant 
and has an Authorization to Operate from the Department of Health and Human Services.  The 
security controls in place meet or exceed HIPAA compliance. Data are coded; data key is kept 

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separately and securely.  Electronic data are protected with a password.  Data are stored on a 
secure network
3.10 Ethical Considerations
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 50, part 56 and ICH guidelines), applicable government regulations 
and Institutional research policies and procedures.
This protocol and any amendments will be submitted to a centralized, properly constituted 
independent Ethics Committee (EC) or IRB, for formal approval of the study conduct.  The 
decision of the EC/IRB concerning the conduct of the study will be made in writing to the 
investigator and a copy of this decision will be provided to the sponsor before commencement of 
this study.  The sponsor and investigator will maintain a list of the central EC/IRB members and 
their affiliates in their files.
All participants (and/or the participant’s legally authorized representative) for this study will be 
provided a consent form describing this study and providing sufficient information for participants 
(and/or their legally authorized representative) to make an informed decision about their 
participation in this study. The sponsor will provide the investigator with appropriate sample 
informed consent forms. These consent forms will be submitted with the protocol for review and 
approval by the EC/IRB for the study.  The formal consent of a participant (and/or the participant’s 
legally authorized representative), using the EC/IRB-approved consent form, must be obtained 
before that participant undergoes any study procedure.  The consent form must be signed by the 
participant (and/or the legally authorized representative), and the investigator-designated 
research professional obtaining the consent. 
All participants enrolled as children and who turn 18 during the study will be consented as adults 
at the earliest opportunity (but no later than 6 months after reaching age of consent). The same 
process will be followed if parents/patients need to be re-consented during the study for any other 
reason (i.e. new information becomes available).
.
3.10.1 Conflict of Interest
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
study specific conflict management plan that has been reviewed and approved by the IRB 
providing oversight for that investigator prior to participation in this study. This information shall 
also be made available to the study sponsor upon request or as required under any separately 
executed agreement between the sponsor and study site.
3.10.2 Participant Stipends or Payments
Patients participating in the study will be given incentives for continued participation.  They will 
receive a $25 gift card when they have returned their stool samples at the end of the first three 
diet treatment phases and when they return to review results with their provider following the 
fourth and final diet treatment phase. If a participant completes the entire study s/he will have 
received a total incentive of $100. In addition, participants will receive a Nutrition in Immune 

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Balance (NiMBAL) Therapy: Using Diet to Treat Inflammatory Bowel Disease book at the start of 
the study as a resource to help them with the diet. 

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5
Study Finances
5.1
Funding Source
This research study is partially funded through a Patient- Centered Outcomes Research Institute 
(PCORI) Award (PCS-1406-18643). The Patient-Centered Outcomes Research Institute (PCORI) 
is an independent, nonprofit organization authorized by Congress in 2010. Its mission is to fund 
research that will provide patients, their caregivers, and clinicians with the evidence-based 
information needed to make better-informed healthcare decisions. PCORI is committed to 
continually seeking input from a broad range of stakeholders to guide its work.
6
Publication Plan
Dissemination of study results is an essential component of this research project.  Regardless of 
the outcome of the trial, we submit study findings to high-impact, peer-reviewed journals and 
present results in the form of abstracts at scientific meetings.  We will also make our research 
findings publically available on the ICN and PCORI websites, including lay summaries of relevant 
findings.  
7
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2010;35(15):1471-1477.
26.
Kravitz RL, Duan N, eds. and the DEcIDE Methods Center N-of-1 Guidance Panel (Duan 
N, Eslick I, Gabler NB, Kaplan HC, Kravitz RL, Larson EB, Pace WD, Schmid CH, Sim I, 
Vohra S). Design and Implementation of N-of-1 Trials: A User’s Guide. AHRQ Publication 
No. 13(14)-EHC122-EF.  www.effectivehealthcare.ahrq.gov/N-of-1-Trials.cfm. Rockville, 
MD: Agency for Healthcare Research and Quality; 2014.
27.
Plummer M. JAGS: a program for analysis of Bayesian graphical models using Gibbs 
sampling. Proceedings of the 3rd International Workshop on Distributed Statistical 
Computing (DSC 2003) March 20-22, Vienna, Austria ISSN 1609–395X. 2003.

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8
Appendices
Appendix A: Eureka Screenshots 
Appendix B: Patient Facing Materials 
Appendix C:  Baseline Questionnaires
Appendix D: Symptom Trackers (In Eureka App)
Appendix E: Patient Handout Instructions for Stool Collection 
Appendix F: 3-day Diet Diary Questions
Appendix G: N-of-1 Trial Results Display 
Appendix H: Questionnaire about N-of-1 Experience
Appendix I: Study Introduction Flyer: Trifold 
Appendix J: Study Introduction Flyer: Single-Sided
Appendix K: Study Letter
Appendix L: Phone Script 
Appendix M:  DSMB Charter 
Appendix N: Eureka Mobile App Patient Facing Privacy Policy

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Appendix A: Sample Eureka Screenshots

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Appendix B: Patient Facing Materials* 
See Separate documents
*All patient materials will be publicly hosted on the general NiMBAL 
website (www.nimbal.org) and on a study-specific section of the website 
(www.nimbal.org/education/produce-study).  Educational materials of 
broader interest are housed on the general NiMBAL website (e.g., 
recipes, cookbook resources, educational lectures about the SCD, etc.). 
Materials directly relevant to the study will be hosted on the study-
specific section of the website (e.g., study flyer, study information, lists 
of approved food for the study SCD and modified SCD diets, etc.). We 
are also hoping to make a video to recruit the patients. A script for the 
video is attached as an Appendix as well.  
 As this study is pragmatic and minimal risk, we request to use these 
patient-facing materials as templates.  These materials may have minor 
edits to the layout/design and content (e.g., addition/removal of food 
brands due to changes in ingredients that no longer fit the diet regimen), 
which would not require IRB approval.

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Appendix C: Baseline Questionnaires
PROMIS Depression (Child ≥ 14 years)
PROMIS Anxiety (Child ≥ 14 years)

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Parent PROMIS Anxiety

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Parent PROMIS Depression

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Expectation of benefit (Baseline) – Patient Version
1. How helpful do you think the specific carbohydrate diet (SCD) will be for you as part of your treatment 
for IBD?  If you are not sure, please take your best guess. Remember we are only interested in your 
opinion.
Not at all helpful
Not very helpful
Somewhat helpful
Very helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
2. How helpful do you think the modified version of the specific carbohydrate diet (SCD) will be for you 
as part of your treatment for IBD?  If you are not sure, please take your best guess. Remember we 
are only interested in your opinion.
Not at all helpful
Not very helpful
Somewhat helpful
Very helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
3. If you had to choose between the specific carbohydrate diet (SCD) or the modified version right now, 
which one would you select?  
□
Specific Carbohydrate Diet (SCD)
□
Modified Specific Carbohydrate Diet (SCD)
□
Not sure
4. Which symptom(s) are you hoping improves the most with this diet? Check all that apply:
□
Consistency of Stools 
□
Frequency of Stools 
□
Stomach Pain
□
Bloody Stools 
□
Rushing to the Bathroom

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Expectation of benefit (Baseline) - Parent Version
 
1. How helpful do you think the specific carbohydrate diet (SCD) will be for your child as part of his/her treatment 
for IBD?  If you are not sure, please take your best guess. Remember we are only interested in your opinion.
 
 
 
 
 
 
 
 
 
 
 
Not at all helpful
Not very 
helpful
Somewhat 
helpful
Very helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
 
. How helpful do you think the modified version of the specific carbohydrate diet (SCD) will be for your child as part 
of his/her treatment for IBD?  If you are not sure, please take your best guess. Remember we are only interested in 
your opinion.
 
Not at all helpful
Not very helpful
Somewhat helpful
Very helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
 
. If you had to choose between the specific carbohydrate diet (SCD) or the modified version right now, which one 
would you select?  
□
Specific Carbohydrate Diet (SCD)
□
Modified Specific Carbohydrate Diet (SCD)
□
Not sure
. Which symptom(s) are you hoping improves the most with this diet? Check all that apply:
□
Consistency of Stools 
□
Frequency of Stools 
□
Stomach Pain
□
Bloody Stools
□
Rushing to the Bathroom
 

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Appendix D: Symptom Trackers
Daily Symptom Trackers – Patient Version
Stool Consistency
What have most of your stools looked like today?
Stool Frequency
How many stools did you have today? [Enter Integer]
Daily Symptom Trackers - Parent Version
Stool Consistency 
What have most of your child’s stools looked like today?

U SI N G SI N G L E S U B J E C T ( N- O F- 1) D E SI G N S T O A N S W E R P A TI E N T-I D E N TI FI E D R E S E A R C H 
Q U E S TI O N S – AI M 1
V er si o n: 5. 2, J a n u ar y 2 9, 2 0 2 0
C O N FI D E N TI A L
P a g e 4 5
St o ol Fr e q u e nc y - P ar e nt 
V ersi o n
H o w m a n y st o ols di d y o ur c hil d h a v e t o d a y? [ E nt er 
I nt e g er]
W e e kl y S y m pt o m T r a c k e r s – P ati e nt V e r si o n
W ei g ht ( o pti o n al)
W h at is y o ur c urr e nt w ei g ht t a k e n o n y o ur h o m e sc al e 
i n p o u n d s? [ N u m b er]
P R O MI S P ai n I nt erf er e nc e 
( p ati e nt ≥ 1 4 y e ars)
P R O MI S GI S y m pt o ms
( p ati e nt ≥ 1 4 y e ars)
I n t h e p ast 7 d a ys …
M y p o o p w as l o os e or w at er y
I r us h e d t o t h e b at hr o o m t o a v oi d a n acci d e nt
I h a d bl o o d i n m y p o o p
I h a d a st o m ac h ac h e
E ac h of t h e f o ur it e ms is sc or e d as 1 ( N e v er), 2 ( R ar el y), 
3 ( S o m eti m es), 4 ( Oft e n), a n d 5 ( Al w a ys)
P e di atric Ulc er ati v e C olitis 
Acti vit y I n d e x ( P U C AI) – 
P ati e nt V e r si o n
" T h es e ar e q u esti o ns a b o ut h o w y o ur c hil d h as b e e n f e eli n g 
o v er t h e p ast 2 4 h o urs "
Q u esti o n 1. H o w m uc h h as y o ur st o m ac h b e e n h urti n g i n 
t h e p ast 2 4 h o urs?

N ot at all 

H urti n g s o m e w h at, b ut I c a n i g n or e it

H urti n g v er y m uc h; it is al w a ys o n m y mi n d

U SI N G SI N G L E S U B J E C T ( N- O F- 1) D E SI G N S T O A N S W E R P A TI E N T-I D E N TI FI E D R E S E A R C H 
Q U E S TI O N S – AI M 1
V er si o n: 5. 2, J a n u ar y 2 9, 2 0 2 0
C O N FI D E N TI A L
P a g e 4 6
Q u esti o n 2. Di d y o u h a v e st o ols c o nt ai ni n g bl o o d o v er t h e 
p ast 2 4 h o urs?

N ot at all 

A s m all a m o u nt o nl y, i n l ess t h a n h alf of st o ols

S m all a m o u nt wit h m ost st o ols 

L ar g e a m o u nt, i n m or e t h a n h alf of st o ols
Q u esti o n 3. W hic h of t h e f oll o wi n g b est d escri b es y o ur 
st o ol o v er t h e p ast 2 4 h o urs?

S oli d 

S oft ( p ass es e asil y) 

W at er y
Q u esti o n 4. N u m b er of st o ols p er 2 4 h o urs (fr o m 
y est er d a y t his ti m e u ntil n o w).
Pl e as e r e m e m b er t h at if y o u ar e h a vi n g s m all fr e q u e nt 
st o ols 
o n e aft er a n ot h er 
wit h o ut 
h a vi n g l eft t h e 
b at hr o o m, it c o u nts as o n e st o ol.

0- 2 

3- 5 

6- 8 

M or e t h a n 8
Q u esti o n 5. Di d y o u w a k e u p o v er ni g ht b ec a us e y o u 
n e e d e d t o m o v e y o ur b o w els?

N o

Y es
Q u esti o n 6. H o w h as y o ur acti vit y l e v el b e e n o v er t h e p ast 
2 4 h o urs?

I h a v e b e e n a bl e t o d o m y us u al acti viti es wit h o ut 
a pr o bl e m

S o m eti m es I h a v e h a d t o st o p w h at I w a nt e d t o 
d o b ec a us e I w as n ot f e eli n g w ell

I h a v e n ot b e e n a bl e t o d o m y us u al acti viti es at 
all
S h ort Cr o h n’s Dis e as e 
Acti vit y I n d e x ( S C D AI)  – 
P ati e nt V e r si o n
T h es e q u esti o ns r ef er t o t h e ti m e p eri o d fr o m w h e n y o u 
a w o k e y est er d a y t o w h e n y o u a w o k e t o d a y.  
1.
Pl e as e i n dic at e t h e n u m b er of li q ui d or s oft st o ols 
t h at y o u h a v e h a d ( a ns w er:  o p e n e n d e d fr e q u e nc y)

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2. Please indicate your abdominal pain level (answer 
choice:  0=none; 1=mild; 2=moderate; 3=severe)
3. Please rate your general well-being (answer choice:  
0=generally well; 1= slightly under par; 2=poor; 
3=very poor; 4=terrible)
Weekly Symptom Trackers - Parent Version
Weight (optional) 
What is your child’s current weight taken on your home scale 
in pounds? [Number]
PROMIS 
Pain 
Interference 
Parent 
Proxy
PROMIS GI Symptoms
Parent Proxy
In the past 7 days…
My child’s poop was loose or watery
My child rushed to the bathroom to avoid an accident
My child had blood in his/her poop
My child had a stomachache
Each of the four items is scored as 1 (Never), 2 (Rarely), 3 
(Sometimes), 4 (Often), and 5 (Always)
Pediatric Ulcerative 
Colitis Activity 
Index (PUCAI)
"These are questions about how your child has been feeling over 
the past 24 hours"
 
Question 1. How much has your child’s stomach been hurting in 
the past 24 hours?

Not at all 

Hurting somewhat, but my child can ignore it

Hurting very much; it is always on my child’s mind
 

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Question 2. Did your child have stools containing blood over the 
past 24 hours?

Not at all 

A small amount only, in less than half of stools

Small amount with most stools 

Large amount, in more than half of stools
 
Question 3. Which of the following best describes your child’s 
stool over the past 24 hours?

Solid 

Soft (passes easily) 

Watery
 
Question 4. Number of stools per 24 hours (from yesterday this 
time until now).
Please remember that if your child is having small frequent 
stools one after another without having left the bathroom, it 
counts as one stool.

0-2 

3-5 

6-8 

More than 8
 
Question 5. Did your child wake up overnight because s/he 
needed to move his/her bowels?

No

Yes
 
Question 6. How has your child’s activity level been over the past 
24 hours?

My child has been able to do his/her usual activities 
without a problem

Sometimes my child has had to stop what s/he wanted 
to do because  s/he was not feeling well

My child has not been able to do his/her usual activities 
at all
 
Short Crohn’s 
Disease Activity 
Index (SCDAI)
These questions refer to the time period from when your child 
awoke yesterday to when s/he awoke today.  
1. Please indicate the number of liquid or soft stools that your 
child has had (answer:  open ended frequency)

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2. Please indicate your child’s abdominal pain level  (answer 
choice:  0=none; 1=mild; 2=moderate; 3=severe)
3. Please rate your child’s general well-being (answer 
choice:  0=generally well; 1= slightly under par; 2=poor; 
3=very poor; 4=terrible)
 
 

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Appendix E: Patient Handout Instructions for Stool 
Collection
See Separate Document

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Appendix F: 3-day Diet Recall Questions
See Attached

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Appendix G: N-of-1 Trial Results Display

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Appendix H: Questionnaire about N-of-1 Experience – Patient 
Version
        Patient Experiences: 
1. Now that you have completed your N-of-1 trial, how helpful do you think the Specific Carbohydrate 
Diet (SCD) was for you (your child) as part of your (your child’s) treatment for IBD?  If you are not 
sure, please take your best guess. Remember we are only interested in your opinion.
Not at all helpful
Not very helpful
Somewhat 
helpful
Very helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
2. How helpful do you think the modified version of the Specific Carbohydrate Diet (SCD) was for 
you (your child) as part of your (your child’s) treatment for IBD?  If you are not sure, please take 
your best guess. Remember we are only interested in your opinion
Not at all helpful
Not very helpful
Somewhat 
helpful
Very helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
□
Specific Carbohydrate Diet
□
Modified Version of the SCD
□
Neither
3. Which treatment would you prefer to use 
going forward into the future?
    
□
Not sure
4. What is your main reason for selecting that treatment?
    
______________________________________________________________________________
    
______________________________________________________________________________

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How helpful was the your N-of-1 
trial in  
Not at 
all 
helpf
ul
Not very 
helpful
Somewhat 
helpful
Very 
helpful
Extremely 
helpful
5. …. helping you understand the 
impact of diet on your (your 
child’s) IBD symptoms?
□
□
□
□
□
6. …..helping you keep track of  your 
(your child’s) IBD symptoms?
□
□
□
□
□
7. …helping you work more closely 
with your (your child’s) clinician 
to achieve your (your child’s) 
treatment goals?
□
□
□
□
□
8. …helping you notice things that 
make your (your child’s) IBD 
symptoms feel better?
□
□
□
□
□
9. 
…helping 
you 
have 
more 
confidence in the treatment 
approach you (your child) will 
follow going forward?
□
□
□
□
□
Questionnaire about N-of-1 Experience - Parent Version
 
 
. Now that your child has completed his/her  N-of-1 trial, how helpful do you think the Specific Carbohydrate Diet 
(SCD) was for your child as part of his/her treatment for IBD?  If you are not sure, please take your best guess. 
Remember we are only interested in your opinion.
 
Not at all helpful
Not very helpful
Somewhat helpful
Very helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
 
. How helpful do you think the modified version of the Specific Carbohydrate Diet (SCD) was for your child as part 
of his/her treatment for IBD?  If you are not sure, please take your best guess. Remember we are only interested in 
your opinion

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Not at all helpful
Not very helpful
Somewhat 
helpful
Very 
helpful
Extremely helpful
□
1
□
2
□
3
□
4
□
5
□
Specific Carbohydrate Diet
□
Modified Version of the SCD
□
Neither
. Which treatment would you prefer to use for your child going 
forward into the future?
□
Not sure
 
4. What is your main reason for selecting that treatment?
   ______________________________________________________________________________
   ______________________________________________________________________________
 
 
How helpful was your child’s N-of-1 
trial in  
Not at 
all 
helpful
Not 
very 
helpful
Somewhat 
helpful
Very 
helpful
Extremely 
helpful
…. helping you understand the impact of diet on 
his/her IBD symptoms?
□
□
□
□
□
 
 
 
 
 
 
…..helping you keep track of his/her IBD 
symptoms?
□
□
□
□
□
 
 
 
 
 
 
 
 
 
 
…helping you work more closely with your 
child’s clinician to achieve his/her  treatment 
goals?
□
□
□
□
□
 
…helping you notice things that make 
his/her  IBD symptoms feel better?
□
□
□
□
□
…helping you have more confidence in the 
treatment approach s/he will follow going 
forward?
□
□
□
□
□
 

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Appendix I: Study Introduction Flyer: Trifold*
See Separate Document
*The Study Introduction Flyer (trifold) may have cosmetic (i.e., 
design) edits to the layout and format of document, which would 
not require IRB approval. No wording/verbiage changes will be 
made without official IRB approval. 

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Appendix J: Study Introduction Flyer: Single-Sided
See Separate Document
 
*The Study Introduction Flyer (single-sided) may have cosmetic 
(i.e., design) edits to the layout and format of document, which 
would not require IRB approval. No wording/verbiage changes will 
be made without official IRB approval. 

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Appendix K: Study Letter
See Separate Document

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Appendix L: Phone Script
See Separate Document

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Appendix M:  DSMB Charter
See Separate Document

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Appendix N: Eureka Mobile App Patient Facing Privacy 
Policy 
See Separate Document

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Appendix O: Study Poster
See separate document

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Appendix O: Parent Letter
See separate document