Biologic and Immunomodulator Withdrawal in Pediatric Crohn Disease With Deep Clinical Remission Using the Crohn Disease Exclusion Diet
Phase: NA
Conditions: Crohn Disease
Sponsor: Children's Hospital of Philadelphia

 
Monotherapy Withdrawal in Crohn Disease: February 6, 2015 
 
Title: 
Biological and Immunomodulator Monotherapy Withdrawal in 
Pediatric Crohn Disease Patients with Deep Clinical Remission 
Using the Crohn Disease Exclusion Diet 
Short Title 
CEASE 
Sponsor: 
CHOP IBD Center 
eIRB Number: 
IRB 14-011628 
Protocol Date: 
March 30, 2015 
Amendment 1 Date: May 27, 2015 
Amendment 5 Date: February 3, 2017 
Amendment 2 Date: June 15, 2015 
Amendment 6 Date: April 11, 2018 
Amendment 3 Date: May 17, 2016 
Amendment 7 Date: May 10, 2019 
Amendment 4 Date: November 30, 2016 
 
 
PI: Ronen Stein, MD  
Division of Pediatric Gastroenterology 
The Children’s Hospital of Philadelphia 
3401 Civic Center Blvd, Philadelphia, PA 19104 
phone: 215-590-7801 
SteinR2@email.chop.edu 
 
 
 

 
  
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms............................................................................. iv 
Abstract ................................................................................................................................. vi 
Schedule of Study Procedures ............................................................................................. vi 
 
1 BACKGROUND INFORMATION AND RATIONALE ............................................. 1 
1.1 INTRODUCTION ............................................................................................................. 1 
1.2 CROHN'S DISEASE EXCLUSION DIET .................................................................. 2 
1.3 RELEVANT LITERATURE AND DATA .............................................................................. 2 
1.4 COMPLIANCE STATEMENT ............................................................................................ 4 
2 STUDY OBJECTIVES .................................................................................................... 4 
2.1 PRIMARY OBJECTIVE (OR AIM) ..................................................................................... 4 
2.2 SECONDARY OBJECTIVES (OR AIM) .............................................................................. 4 
3 INVESTIGATIONAL PLAN.......................................................................................... 5 
3.1 GENERAL SCHEMA OF STUDY DESIGN .......................................................................... 5 
    3.1.1  Screening Phase ...................................................................................................... 5 
   3.1.2 Study Intervention Phase ......................................................................................... 5 
   3.1.3 Follow-up Phase ...................................................................................................... 5 
3.2 ALLOCATION TO TREATMENT GROUPS AND BLINDING .......... …………………………6  
3.3    STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ............................................ 6 
3. 3.1 Duration of Study Participation ............................................................................ 6 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected ........................ 6 
3.4 STUDY POPULATION ..................................................................................................... 6 
3.4.1 Inclusion Criteria ................................................................................................... 6 
3.4.2 Exclusion Criteria .................................................................................................. 7 
4 STUDY PROCEDURES.................................................................................................. 7 
4.1 SCREENING VISIT .......................................................................................................... 7 
4.2 STUDY TREATMENT PHASE ............................................................................................ 7 
4.2.1  Telephone Call ...................................................................................................... 7 
4.2.2  Email Communication  ......................................................................................... 8 
4.2.3  Study Visit 1 .......................................................................................................... 8 
4.2.4  Telephone Call ...................................................................................................... 8 
4.2.5  Email Communication .......................................................................................... 8 
4.2.6  Study Visit 2  ......................................................................................................... 8 
4.2.7   Telephone Call ...................................................................................................... 9 
4.2.8   Study Visit 3 ........................................................................................................... 9 
4.2.9   Study Visit 4 ........................................................................................................... 9 
4.2.10 Study Visit 5 ........................................................................................................... 9 
4.2.11 Clinical Flare/Relapse Visit l ................................................................................ 9 
 

 
  
 
 
 
 
 
iii
 
4.3 MEDICAL RECORD REVIEW ............................................................................... 10 
4.4 UNSCHEDULED VISITS ................................................................................................ 10 
4.5 SUBJECT COMPLETION/WITHDRAWAL ........................................................................ 10 
4.5.1 Early Termination Study Visit ............................................................................. 10 
   4.6 DATA POOLING…………………………………………………………………...11
 
 
5 STUDY EVALUATIONS AND MEASUREMENTS ................................................. 11 
5.1 SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ......................... 11 
5.1.1 Medical Record Review ....................................................................................... 11 
5.1.2 Pediatric Crohn Disease Activity Index .............................................................. 12 
5.1.3 Modified MARS Questionnaire ............................................................................ 12 
5.1.4 3-day Food Diary ................................................................................................ 12 
5.1.5 24 Hour Dietary Recall ....................................................................................... 12 
5.1.6 Stool  .................................................................................................................... 13 
5.1.7  Oral Swabs  .......................................................................................................... 13 
5.1.8  Rectal Swabs ......................................................................................................... 13 
5.1.9  Environmental Swabs…………………………………………………………………   14 
5.2 EFFICACY EVALUATIONS  ........................................................................................... 14 
5.2.1 Diagnostic Tests, Scales, Measures, etc. ............................................................. 14 
5.3 SAFETY EVALUATION ................................................................................................. 14 
6 STATISTICAL CONSIDERATIONS ......................................................................... 14 
6.1 PRIMARY ENDPOINT ................................................................................................... 14 
6.2 SECONDARY ENDPOINTS ............................................................................................. 14 
6.3 CONTROL OF BIAS AND CONFOUNDING ...................................................................... 14 
6.4 STATISTICAL METHODS .............................................................................................. 15 
6.4.1 Baseline Data ....................................................................................................... 15 
6.4.2 Analysis of Primary Outcome of Interest ............................................................. 15 
6.5 SAMPLE SIZE AND POWER ........................................................................................... 15 
7 SAFETY MANAGEMENT ........................................................................................... 15 
7.1 CLINICAL ADVERSE EVENTS ....................................................................................... 15 
7.2 ADVERSE EVENT REPORTING ..................................................................................... 15 
8 STUDY ADMINISTRATION ....................................................................................... 16 
8.1 DATA COLLECTION AND MANAGEMENT ..................................................................... 16 
8.1.1 Data sources ........................................................................................................ 17 
8.2 CONFIDENTIALITY ...................................................................................................... 17 
8.3 REGULATORY AND ETHICAL CONSIDERATIONS .......................................................... 17 
8.3.1 Data and Safety Monitoring Plan ........................................................................ 17 
8.3.2 Risk Assessment ................................................................................................... 18 
8.3.3 Potential Benefits of Study Participation ............................................................ 18 
8.3.4 Risk-Benefit Assessment ....................................................................................... 18 
8.4 RECRUITMENT STRATEGY ........................................................................................... 19 

 
  
 
 
 
 
 
iv
8.5 INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ..................................... 19 
8.6 PAYMENT TO SUBJECTS/FAMILIES .............................................................................. 19 
9 PUBLICATION ............................................................................................................. 19 
10 REFERENCES ............................................................................................................. 20 

 
  
 
 
 
 
 
v
ABBREVIATIONS AND DEFINITIONS OF TERMS  
CD 
 
Crohn disease 
PCDAI 
 
Pediatric Crohn Disease Activity Index 
CDED 
PEN 
 
Crohn’s Disease Exclusion Diet 
Partial enteral nutrition 
TNF- α 
CRP 
ESR 
MARS 
   Tumor necrosis factor alpha 
C-reactive protein 
Erythrocyte sedimentation rate 
Medication Adherence Rating Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
 
 
 
 
 
vi
ABSTRACT 
Context:   
Crohn disease (CD) is an idiopathic, chronic, relapsing and remitting inflammatory 
condition of the gastrointestinal tract with a high risk for complications and need for surgical 
interventions.  The incidence rate in the pediatric population is rapidly increasing.  
Immunomodulators and biologic therapies are effective at inducing and maintaining 
remission in pediatric CD, yet there is no proven strategy for reducing exposure to 
medications once sustained remission has been achieved.  Diet has been proven to impact 
disease activity in CD and may allow for sustained drug-free remission.  
Objectives: The primary objective of this study is to determine differences in time-to-relapse 
and the proportion of subjects with sustained relapse-free remission between subjects on the 
Crohn’s Disease Exclusion Diet (CDED) and those on an unrestricted diet.  The secondary 
objective is to determine the proportion of all subjects with sustained relapse-free remission 
52 weeks after withdrawal of biological or immunomodulator monotherapy by the primary 
gastroenterologist as part of clinical care. 
The third objective is to assess the compliance of subjects to the CDED. 
Study Design: This will be an open-label, non-randomized pilot study involving 25 pediatric 
Crohn disease patients in deep clinical remission, who will be withdrawing from biologic or 
immunomodulator monotherapy based on the clinical judgment of their primary 
gastroenterologist.  Subjects will choose whether or not to adhere to the diet.  Subjects who 
do not adhere to the CDED will serve as controls.  
Setting/Participants: Recruit outpatients with CD who will be withdrawing from biologic or 
immunomodulator monotherapy based on the clinical judgment of their primary 
gastroenterologist.  Any patient in deep clinical remission who meets inclusion criteria and 
consents is eligible for this study. 
Study Interventions and Measures: The study intervention is the CDED. Measures will be 
obtained from stool testing, diet logs/adherence questions, and medical record review.  
Main study outcome measures: 1) Differences in time-to-relapse and proportion of subjects 
with sustained relapse-free response among those who do and do not participate in the 
dietary intervention as measured by the Pediatric Crohn’s Disease Activity Index (PCDAI), 
C-Reactive Protein (CRP), microbiome, and stool calprotectin.  2) Compliance with the 
dietary intervention as measured by the modified MARS questionnaire.   
 
 
 
 

 
  
 
 
 
 
 
vii
 
SCHEDULE OF STUDY PROCEDURES 
Parameter 
Week 
0 
Week 
1 
(Phon
e 
Call)0  
Wee
k 3 
(Ema
il) 
Wee
k 6 
Week 
7 
(Phone 
Call)0  
Wee
k 9 
(Em
ail) 
Wee
k 12 
Week 
13 
(Phone 
Call)0  
Wee
k 24  
Week 
36  
Week 
52  
Clinica
l 
Flare00 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
Stool 
Calprotecti
n  
X+ 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
CRP, ESR* 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Weight* 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Modified 
MARS 
questionnai
re 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
3 days food 
diary 
 
 
X 
 
 
X 
 
 
X 
 
 
 
24-Hour 
Recall 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Tolerability 
 
X 
 
 
X 
 
 
X 
 
 
 
 
CDED 
Phase 1 diet 
X 
X 
X 
 
 
 
 
 
 
 
 
 
CDED 
Phase 2 diet 
 
 
 
X 
X 
X 
 
 
 
 
 
 
CDED 
Phase 3 diet 
 
 
 
 
 
 
X 
X 
 
 
 
 
CDED 
Phase 4 diet 
 
 
 
 
 
 
 
 
X 
X 
X 
 
PCDAI* 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Stool 
for 
microbiome 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Swabs 
(Rectal and 
Oral) 
for 
microbiome 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
*From Chart Review  
+From Chart Review (obtained within the previous 3 months) 
 
0Only Subjects on study diet 

 
  
 
 
 
 
 
viii
00 This study visit may occur during the first 52 weeks of the study if the subject is in the 
office for a clinical flare. 

 
  
 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Crohn disease (CD) is an idiopathic, chronic, relapsing and remitting inflammatory 
condition of the gastrointestinal tract with a high risk for complications and need for surgical 
interventions.  The incidence rate of CD is estimated to be 1 in 10,000 children per year and 
is rising [1].  In children, CD tends to have a more aggressive course with more associated 
complications.  The majority of children require an effective maintenance medication 
therapy to prevent relapse and complications.  
To date, there is no proven strategy for reducing exposure to medication once sustained 
remission has been achieved.  It is possible that medications cannot be easily stopped 
because environmental triggers that perpetuate the disease, such as diet, still remain.  Akin 
to the connection between smoking and lung disease, if the environmental exposure 
continues the disease may continue to progress.  In this proposed study, a dietary 
intervention, the Crohn’s Disease Exclusion Diet (CDED) will be investigated.   
1.2 
Crohn’s Disease Exclusion Diet  
The CDED is a diet that excludes food felt to be pro-inflammatory, such as those that contain 
dairy, wheat products, sauces, soft drinks, fruit juice, processed meats dairy, and emulsifiers.  
It has previously been shown to be effective in inducing remission in patients with CD [2].   
The following table details general categories of allowed and restricted foods in the diet: 
Allowed Foods 
Restricted Foods 
Fresh Fish and Chicken Breast (unlimited) 
Processed or smoked meats  
White Rice, Rice Noodles 
Breads, Pastas, Cereals and Baked Goods 
Fresh fruits  
Dried Fruits 
Fresh Vegetables 
Dairy Products  
Fresh Beef (limited amount) 
Canned Food 
Honey, Fresh Herbs, Onion Garlic, Olive and 
canola oil (for cooking). Limited table sugar 
Packaged Snacks and candy 
Water, Seltzer Water, Herbal Teas, Freshly-
squeezed orange juice (limited) 
Soft drinks, fruit juices, sweetened beverages, 
alcoholic beverages, coffee 
 
The diet is most restrictive during the first 6 weeks (CDED Phase I), then becomes less 
restrictive during the subsequent 6 weeks (CDED Phase II).  There is no access to free diet 
during the first 12 weeks, but thereafter, as long as patients are otherwise compliant  1-2 free 
diet meal per week are allowed (CDED Phases III-IV).  This free diet meal does allow a 
regular portion of dairy, wheat products, sauces, soft drinks, fruit juice, cakes, and ice cream, 
but does not allow processed meats such as hot dogs or luncheon meats and does not allow 
binging on non-recommended foods.   
Because the diet does restrict some common foods, patients may need to take a caloric 
supplement of their choosing if they cannot meet nutritional and caloric needs with the diet 

 
  
 
  
 
 
 
2
alone.  The intention of any supplement will be to sustain caloric and nutritional balance, not 
to diagnose, mitigate or treat the underlying disease.  The choice of supplementary formula 
will be based on patient preference, and is not part of the research study objectives.  The diet 
does restrict many forms of calcium, so patients will need to take calcium supplementation to 
meet basic dietary requirements while on the CDED.   
Sigall-Boneh et al. showed that the CDED achieved remission in 70% of 47 patients.  Patients 
in remission had a significant improvement in markers of disease activity, including 
erythrocyte sedimentation rate (ESR), CRP, serum albumin, and the Pediatric Crohn Disease 
Activity Index (PCDAI).  Among 18 patients practicing prolonged dietary restriction (range 
6-24 months) with follow up colonoscopies, 14 patients had complete mucosal healing.   
1.3 
Relevant Literature and Data 
The goals of therapy in pediatric CD are to induce and maintain clinical remission with the 
least toxicity, thereby improving quality of life and preventing known complications of CD, 
such as growth failure, bowel stricturing, or fistula formation.  There are several broad 
categories of maintenance therapies in CD.  Anti-inflammatory medications include 5-ASA 
drugs, antibiotics and non-conventional glucocorticoids.  The immunomodulators include 6-
mercaptopurine, azathioprine, and methotrexate.  The biologics form another class of 
medications that more directly target pro-inflammatory cytokines.  Infliximab and 
adalimumab are two commonly used biologics in pediatric CD.  Infliximab is a chimeric 
monoclonal antibody against an important cytokine in the pro-inflammatory cascade, tumor 
necrosis factor alpha (TNF-).  Infliximab has been shown to induce and maintain clinical 
remission in approximately 70% of patients with moderate to severe CD [3].  
Multiple concurrent medications are often used in the treatment of CD.  The use of an 
immunomodulator in conjunction with a biologic is called dual therapy. Historically, 
biologics were added to the treatment regimen only after failure of anti-inflammatory 
medications or immunomodulators, in what has been termed the “step-up” strategy of 
treating CD.  However, given their efficacy, biologics are now being used more often as 
initial, first-line therapies, to induce and maintain remission in pediatric CD.  This is called 
the “top-down” strategy [4].  
There are several known side effects to biologic use, including anaphylaxis, hypersensitivity 
reactions, and increased susceptibility to infections.  However, the long-term effects of the 
biologics are less known.  There have been reports of increased rates of lymphoma among 
patients being treated with a biologic.  This has also been seen in patients taking 
immunomodulators.  The rates of skin cancers are also increased in patients taking 
immunomodulators.  A particularly aggressive type of lymphoma, hepatosplenic T-cell 
lymphoma, has been reported in patients on dual therapy [5-6].  
The question of when to stop biologic therapy in CD patients with long-standing deep 
clinical remission is important because biologic therapy is expensive and has potential long-
term side effects.  However, the data to support a de-escalation strategy is limited.  Previous 
studies have mainly investigated stopping biologic therapy in adult patients receiving dual 
therapy [7].  Nonetheless, the results of these studies provide useful information that can be 
applied to formulating a de-escalation strategy for patients on monotherapy.  A prospective 

 
  
 
  
 
 
 
3
study investigating 115 CD patients in clinical remission on dual therapy found that after 
stopping infliximab, approximately half of the patients relapsed within 2 years.  However, 
upon further analysis, the authors identified several laboratory parameters that significantly 
decreased the risk of relapse, including normal hemoglobin, C-reactive protein (CRP), and 
stool calprotectin levels.  Amongst patients in the deepest remission, the risk of relapse 
decreased to 20%.  Moreover, approximately 90% of the patients who did relapse were able 
to reestablish clinical remission with reintroduction of infliximab [8].  Most recently, 
Molander et al. looked at adult patients with inflammatory bowel disease in deep clinical 
and endoscopic remission being treated with biologics. Of the 52 total patients, 17 patients 
had a diagnosis of CD.  Of these 17 patients, only 4 were on monotherapy with a biologic.  
At 1 year, 12/17 (70%) continued to be in clinical remission [9].      
A recent study has investigated the question of withdrawing immunomodulator 
monotherapy in adult patients with CD in clinical remission.  Kennedy et al. studied 237 
patients with inflammatory bowel disease, including 129 patients with CD, for 12 months 
following withdrawal of immunomodulator monotherapy.  At 12 months, 77% of patients 
continued to be in clinical remission.  Normal CRP was found to significantly associated 
with decreased risk of relapse [10].  
Therefore, the above studies show that within a subset of CD patients in deep clinical 
remission, de-escalation of biologic therapy or immunomodulator monotherapy may be 
effective.    
Dietary therapy provides an alternative therapeutic modality for CD and may allow for de-
escalation from medications.  The exact pathophysiology of CD has not been fully 
elucidated, but genetics, environment, and the immune system each play a role in disease 
development and progression.  In healthy individuals, the intestinal mucosa is regulated by a 
balance of pro-inflammatory and anti-inflammatory cytokines, but this equilibrium is 
disrupted in CD leading to tissue destruction.  The microbiota, or the bacteria that naturally 
live in the human gastrointestinal tract, play a major role in CD [11].  A sequence of events 
involving an imbalance of protective and harmful bacteria (termed dysbiosis), defects in 
innate immunity, and subsequent adherence or translocation of bacteria may lead to an 
adaptive immune response that causes tissue injury and ulceration.  This is termed the 
bacterial penetration cycle [12-13].  Dietary interventions may exert their effect by exclusion 
of dietary components that may generate dysbiosis, affect the mucous layer, increase 
intestinal permeability and/or allow adherence or translocation of harmful bacteria, such as 
adherent-invasive E Coli or diffusely-adherent E Coli.  
There is strong evidence that providing complete nutrition with polymeric formula can 
induce and maintain clinical remission in up to 80% of patients with CD [14].  Although this 
treatment has no known side effects, it can impair quality of life as the diet is restrictive 
(only formula can be consumed) and is administered through a nasogastric tube.  Therefore, 
studies have investigated the efficacy of liberalized dietary therapies.  A diet providing 80-
90% of calories from formula, with the remainder of the calories coming from a regular diet, 
was found to be effective for induction of remission in CD [15]. 
Dietary therapy may also be effective, if not underutilized, as maintenance therapy, but is 
fraught with obstacles.  Longer term therapy with partial enteral nutrition (PEN) involving 

 
  
 
  
 
 
 
4
50% of calories applied by nasogastric tube along with a low fat diet was shown to reduce 
relapse and reduce endoscopic recurrence compared with patients on a free diet [16-17]. PEN 
was also found to be as effective 6-mercaptopurine in another study [18].  However, long-
term use of PEN, particularly if administered via feeding tube, may not be feasible for large 
segments of the population over prolonged periods of time.  While sustained use of an 
elemental or polymeric formula is difficult, it is unclear if the formula itself provides a 
protective effect or rather the use of formula simply reduces the amount harmful foods 
consumed in a free diet.  A recent study compared two groups of CD patients on enteral 
nutrition and showed that the group with higher intake of table foods had worse clinical 
outcomes [19]. This suggests that enteral nutrition is successful due to the restriction of 
harmful components of the diet rather than due to a protective effect of formula.   
The findings from Sigall-Boneh et al. also support that it is diet rather than formula that may 
be most effective.  Although subjects in that study did take 50% of their calories from formula, 
there were 7 patients who refused formula but still adhered to CDED.  Of these, 6 still achieved 
remission with the CDED, alone, suggesting that the diet itself, rather than the formula, 
accounted for the clinical remission seen in the study [2].   
Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, and the HIPAA Privacy Rule.  All episodes of 
noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent and assent, and will report unanticipated problems involving risks to subjects or 
others in accordance with The Children’s Hospital of Philadelphia IRB Policies and 
Procedures and all federal requirements.  Collection, recording, and reporting of data will be 
accurate and will ensure the privacy, health, and welfare of research subjects during and 
after the study. 
2 
STUDY OBJECTIVES 
The purpose of this pilot study is to determine clinical outcomes in a subset of pediatric CD 
patients in long-standing deep clinical remission following withdrawal of biologic or 
immunomodulator monotherapy based on the clinical judgment of their primary 
gastroenterologist and placement on either the CDED or an unrestricted diet. 
2.1 
Primary Objective (or Aim) 
 To determine differences in time-to-relapse and the proportion of subjects with 
sustained relapse-free remission between subjects on the CDED and those on an 
unrestricted diet. 
2.2 
Secondary Objectives (or Aim) 
The secondary objectives are to: 

 
  
 
  
 
 
 
5
 To determine the proportion of all subjects with sustained relapse-free remission 52 
weeks after withdrawal of biological or immunomodulator monotherapy (as part of 
clinical care) 
 To assess the compliance of patients to the CDED over 52 weeks. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
This will be an open-label, non-randomized pilot study involving 25 pediatric CD patients in 
deep clinical remission, who will be withdrawing from biologic or immunomodulator 
monotherapy based on the clinical judgment of their primary gastroenterologist. The study 
team will educate participants about the CDED.  Participants who choose not to follow the 
diet will serve as controls. The study will include clinical and laboratory measures of disease 
activity obtained from chart review.  Dietary compliance data will be collected 
prospectively.  The study will be performed at one site – The Children’s Hospital of 
Philadelphia.  However, the research will also include outcome data from collaborators at 
Wolfson Medical Center in Israel running an independent study on medication withdrawal 
and the CDED in Crohn disease patients in deep remission.  This data will come from 
individuals whose identity the investigators cannot readily ascertain, as the data will be de-
identified. Additionally, data from protocols #15-011817 and #09-007286 will be used for 
data analysis for comparison. Data from these individuals will not be included in the 
enrollment numbers for this study and research activities using this will not be reported as 
part of the continuing review.   
The cohort will be followed for 104 weeks (52 weeks of study participation with an 
additional 52 weeks of chart review).  
3.1.1 Screening Phase  
Potential subjects will be screened using the protocol inclusion and exclusion criteria.  
Parental/guardian permission (informed consent) and, if applicable, child assent, will be 
obtained prior to any study related procedures being performed.   
3.1.2 Study Treatment Phase 
Subjects who choose to follow the diet will attend a mandatory teaching session to learn 
more about the CDED.    Subjects who do not wish to follow the CDED will serve as 
controls and will not attend the teaching session.  During the treatment phase adherence to 
the diet will be determined based on 3-day food diaries, 24-hour dietary recalls, and 
questionnaires.  Clinical response will be determined based stool samples for measurement 
of stool calprotectin and by calculation of Pediatric Crohn’s Disease Activity Index 
(PCDAI) scores from medical record.  Subjects will be followed for 52 weeks. 
3.1.3 Follow-up Phase 

 
  
 
  
 
 
 
6
The follow-up phase will occur during the subsequent 52 weeks and will consist of 
extraction of data from the medical chart.  
3.2 
Allocation to Treatment Groups and Blinding 
This is an open-label, non-randomized, study.  Therefore, this study is not blinded.  
Allocation to the treatment group (CDED) versus the control will be determined by whether 
the subject wishes to adhere to the CDED.  Subjects who do not wish to adhere to the diet 
will serve as controls.   
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The study duration per subject will be a maximum of 104 weeks from enrollment.  It is 
standard-of-care for CD patients withdrawing from therapy to follow-up in clinic every 6-8 
weeks for the first year after withdrawal.  The study will involve a baseline visit and follow-
ups at outpatient GI visits during the first 52 weeks after withdrawal of therapy.  For the 
subsequent 52 weeks, data will be collected from chart review, only, and there will be no 
study visits.  There will be open communication via telephone calls to assess compliance 
and to answer any follow-up questions regarding the diet.    A CHOP email address will also 
be provided to allow participants to ask follow-up questions regarding the diet and for 
participants to submit 3-day food diaries. In-person study visits will last approximately 10 
minutes and will occur during regularly-scheduled GI appointments.   
  
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be performed at The Children’s Hospital of Philadelphia. The research will 
also include de-identified outcome data and samples from collaborators at Wolfson Medical 
Center in Israel running an independent study on medication withdrawal and the CDED in 
Crohn disease patients in deep remission. The data and samples from Wolfson Medical 
Center will come from individuals whose identity the investigators cannot readily ascertain, 
as the data will be de-identified.  Data and samples from these individuals will not be 
included in the enrollment numbers for this study and research activities using this will not 
be reported as part of the continuing review. Additionally, data from protocols #15-011817 
and #09-007286 will be used for data analysis for comparison.  
The cohort will be followed for 104 weeks.  Recruitment will stop when approximately 35 
subjects are enrolled. Our goal is 25 evaluable subjects, of whom 10 will participate in the 
dietary intervention. We anticipate that recruitment will last 2 years from study initiation. 
3.4 
Study Population 
3.4.1 Inclusion Criteria 
1) Males or females ages 10 to 21 years old with a diagnosis of CD using the Revised Porto 
criteria who will be withdrawing from biologic or immunomodulator monotherapy as 
part of clinical care.  
2) Normal Growth Velocity, or Tanner 5  

 
  
 
  
 
 
 
7
3) Steroid-free Remission (PCDAI <10  without the height component) for at least 6 months 
prior to enrollment 
4) Colonoscopy during the preceding 3 months with complete mucosal healing or only few 
apthous ulcerations located in one segment 
5) Stool calprotectin <250µg/g during the preceding 3 months  
6) Parental/guardian permission (informed consent) and, if appropriate, child assent. 
3.4.2 Exclusion Criteria 
1) Discontinuation of biologic or immunomodulator therapy by the subject without the 
approval of the primary gastroenterologist.  
2) Those subjects who in the judgment of the investigative team are unable to complete the 
study endpoints. 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria will be reported in accordance with IRB Policies and Procedures.  
4 
STUDY PROCEDURES 
4.1 
Screening Visit 
Subjects being withdrawn from immunomodulator or biologic therapy will be approached to 
participate in this study once it is determined that they meet inclusion criteria.  We will 
ascertain these subjects through a number of methods including electronic medical record 
query of patients in clinical remission and through GI physician referral.  Subjects will be 
approached before or after a CHOP clinic visit or contacted by phone.  
Those subjects who will not be at CHOP prior to the screening visit, a verbal screening 
consent form will be obtained before collecting any screening information.  The screening 
consent will allow us to review their medical record to confirm eligibility and allow the 
subject to bring in a stool sample to the first visit.  When consent is obtained initially by 
telephone, the person obtaining consent will document the participant’s agreement to 
participate on the verbal consent form.  All participants must provide written consent, and 
assent when appropriate, before undergoing any other study procedures.  The study will be 
explained to each participant and their legal guardian when they come to the study site.  If 
the subject and/or guardian agrees to participate, they will sign the written consent form.  
After informed consent is obtained, the patient will be enrolled.  
The following will also be performed at the screening visit:    
 Medical record review for extraction of clinical and laboratory data to allow 
for calculation of PCDAI 
  24 hour dietary recall for baseline diet information 
 Stool, as well as oral and rectal swabs for microbiome analysis 
 Information will be provided about the study diet. Subjects who choose to 
participate in the diet will be invited to a mandatory teaching session to learn 

 
  
 
  
 
 
 
8
about the CDED. The teaching will be led by a study dietician and will involve 
detailed instruction regarding the use of the CDED and how to complete a food 
diary. These sessions will be held 1-2 times per month based on demand.  
4.2 
Study Treatment Phase 
At the end of the teaching session subjects will identify a start date for the diet which 
will fall within 1 week of the teaching session.  
4.2.1 Telephone Call (Week 1 +/- 3 days), Subjects on CDED only 
 General questions to assess tolerability of CDED 
 Modified MARS questionnaire to assess diet compliance 
 
24 hour dietary recall 
 
Answer any follow-up questions about the diet 
4.2.2 Email Communication (Week 3 +/- 3 days)  
 3-day Food Diary submitted via email 
 
If subjects are non-compliant with the diet at Week 3 then they will be moved 
to the control group. 
4.2.3 Study Visit 1 (Week 6 +/- 10 days) 
 Medical record review for extraction of clinical and laboratory data to allow 
for calculation of PCDAI 
 Submission of stool samples for measurements of stool calprotectin and 
microbiome 
 Oral and rectal swabs for microbiome analysis 
 
 Modified MARS questionnaire to assess diet compliance (subjects on CDED 
only) 
 24 hour dietary recall 
4.2.4 Telephone Call (Week 7 +/- 3 days), Subjects on CDED only 
 General questions to assess tolerability of CDED 
 Modified MARS questionnaire to assess diet compliance 
 
Answer any follow-up questions about the diet 

 
  
 
  
 
 
 
9
4.2.5 Email Communication (Week 9 +/- 3 days)  
 3-day Food Diary submitted via email 
4.2.6 Study Visit 2 (Week 12 +/- 10 days) 
 Medical record review for extraction of clinical and laboratory data to allow 
for calculation of PCDAI 
 Submission of stool samples for measurements of stool calprotectin  
 Modified MARS questionnaire to assess diet compliance (subjects on CDED 
only) 
 24 hour dietary recall 
4.2.7 Telephone Call (Week 13 +/- 3 days),  (Subjects on CDED only) 
 Questions to assess tolerability of CDED 
 Modified MARS questionnaire to assess diet compliance 
 
Answer any follow-up questions about the diet 
4.2.8 Study Visit 3 (Week 24 +/- 10 days) 
 Medical record review for extraction of clinical and laboratory data to allow 
for calculation of PCDAI 
 Submission of stool samples for measurement of stool calprotectin 
 Modified MARS questionnaire to assess diet compliance (subjects on CDED 
only) 
 3-day Food Diary (to be completed before appointment) 
4.2.9 Study Visit 4 (Week 36 +/- 10 days) 
 Medical record review for extraction of clinical and laboratory data to allow 
for calculation of PCDAI 
 Submission of stool samples for measurement of stool calprotectin 
 Modified MARS questionnaire to assess diet compliance (subjects on CDED 
only) 
 24 hour dietary recall 

 
  
 
  
 
 
 
10
4.2.10 Study Visit 5 (Week 52) 
 Medical record review for extraction of clinical and laboratory data to allow 
for calculation of PCDAI 
 Submission of stool samples for measurements of stool calprotectin and 
microbiome 
 Oral and rectal swabs for microbiome analysis  
 Modified MARS questionnaire to assess diet compliance (subjects CDED 
only) 
 24 hour dietary recall 
4.2.11 Clinical Flare/Relapse Visit 
 Clinical relapse will be determined by the primary gastroenterologist   
 Modified MARS questionnaire to assess diet compliance (subjects CDED 
only) 
 24 hour dietary recall 
 Submission of stool samples for measurement of stool calprotectin and 
microbiome 
 Oral and rectal swabs for microbiome analysis 
4.3 
Medical record review after the first 52 weeks of therapy withdrawal 
 Medical record review only 
 The following data will be extracted from the medical record: 
(1) Sustained relapse-free remission/time to relapse 
(2) Concurrent medications 
(3) Growth parameters, including height, weight, DEXA scans 
(4) Endoscopy, imaging pathology reports, if applicable 
(5) Surgery or hospitalizations after the first 52 weeks of therapy, if applicable 
(6) Laboratory data, including hematocrit, serum albumin, C-reactive protein, 
sedimentation rate, and stool calprotectin 

 
  
 
  
 
 
 
11
4.4 
Unscheduled Visits 
Subjects may have a clinical flare of Crohn disease (as determined by the primary 
gastroenterologist) during the study.  If the subject is in the office for a clinical flare 
appointment, a 24 hour dietary recall, stool for calprotectin microbiome, oral and rectal 
swabs for microbiome analysis, as well as a modified MARS questionnaire will be 
performed, as well as a medical record review.   
4.5 
Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules or AEs.  The Investigator may also withdraw 
subjects who violate the study plan, or to protect the subject for reasons of safety or for 
administrative reasons.  It will be documented whether or not each subject completes the 
clinical study.  If the Investigator becomes aware of any serious, related adverse events after 
the subject completes or withdraws from the study, they will be recorded in the source 
documents. 
4.5.1 Early Termination Study Visit 
Subjects who withdraw from the study will have all procedures enumerated for the last visit 
as the early termination visit.  
4.6 
Data Pooling 
The study population for this study includes individuals who have been receiving ongoing 
care at The Children’s Hospital of Philadelphia. Many subjects are currently, previously, or 
will be enrolled in other research studies within the Division of Gastroenterology.  Some 
members of this study team also serve as study team members on the other studies.  
Data and samples that have previously, or will be collected as part of participation in other 
studies may be helpful for the current protocol. By signing the consent form, subjects will 
grant access to their data and biospecimens from other studies. Doing so may avoid the 
necessity of repeating tests and procedures. This may minimize the risks to subjects and will 
reduce duplication. Subjects will only have their data and biospecimens from other studies 
used if they consent to sharing the results as part of this study.  
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 
Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
The following data and dates of service will be abstracted from the medical chart (paper or 
electronic) for all subjects. 
 Date of birth 

 
  
 
  
 
 
 
12
 NIH ethnicity 
 Diagnosis 
 Date of diagnosis 
 Disease location 
 Weight 
 Height 
 Body mass index 
 Laboratory values 
 History of previous abdominal and perianal surgeries 
 List of current and historical medications 
 Reports from any previous endoscopies or radiological tests, including 
pathology biopsy results 
 Extraintestinal manifestations such as frank arthritis, primary sclerosing 
cholangitis, and/or uveitis 
 PCDAI 
 Environmental history 
 Surgical History 
5.1.2 Pediatric Crohn Disease Activity Index (PCDAI) 
A PCDAI will be extracted from the medical chart at baseline and at every visit for every 
subject.  The PCDAI is a validated measure of disease severity [20].  It includes subjective 
patient reporting of symptoms, physical examination, growth parameters, and several 
laboratory tests (hematocrit, erythrocyte sedimentation rate, and serum albumin).  Scores 
range from 0 to 100.  Scores of 0-10 correspond to no disease activity, 11 – 30 represents 
mild disease, and a score greater than 30 is defined as moderate to severe disease activity. It 
is standard-of-care for the PCDAI to be calculated at each office visit by the primary 
gastroenterologist, so this information will be obtained from chart review.  
5.1.3 MARS Questionnaire 
The modified MARS Questionnaire is a validated measure of medication adherence. It will 
be administered by a study member during each study visit, but only to subjects on the 
CDED.  

 
  
 
  
 
 
 
13
5.1.4 3-day Food Diary 
A 3-day food diary will be filled out by all subjects, including those on an unrestricted diet, 
prior to several study visits. At weeks 3 and 9 subjects will email the completed 3-day food 
diary to the CHOP IBD Research Center email address, accessible only to study team 
members. Subjects will receive detailed instructions regarding how to complete a food diary 
during the mandatory informational diet session.  The food diary will document all food and 
drink intake, including estimated portion sizes, during a 3-day period, and will be helpful in 
determining caloric intake and adherence to the diet, if applicable.  Food Processor Nutrition 
Analysis Software will be used to analyze the food diary.  This program is currently used 
clinically within the Division of Gastroenterology and provides all the features needed to 
accurately analyze a 3-day food diary for the purposes of this study.   
5.1.5 24 Hour Dietary Recall 
A 24 hour dietary recall will be conducted by a study member during several study visits. 
All subjects, including those on an unrestricted diet, will recall their food/drink intake during 
the previous 24 hours.  This will be helpful in determining caloric intake and adherence to 
the diet, if applicable. Food Processor Nutrition Analysis Software will be used to analyze 
the dietary recall.  This program is currently used clinically within the Division of 
Gastroenterology and provides all the features needed to accurately analyze a 24 hour 
dietary recall for the purposes of this study.  In general, recall of dietary intake can be very 
subjective and is prone to potential inaccuracies. By using two different methods of 
capturing dietary intake (the recall and the food diary) analyzed by experienced members of 
the study team (registered dieticians and gastroenterologists) the investigators will be able to 
accurately measure caloric intake in our participants. 
If a subject fails to meet 100% of his/her estimated nutritional needs during analysis of a 24 
hour dietary recall or a 3-day food diary (based on established World Health Organization or 
Recommended Daily Allowance guidelines), then the subject will be instructed to modify 
his/her intake within the confines of the diet, including the use of a nutritional supplement of 
the subject’s choosing.      
5.1.6 Stool 
Stool for measurement of stool calprotectin will be collected and analyzed at the CHOP 
central lab.  The results of each stool calprotectin will be entered into the electronic medical 
record.  Stool calprotectin is used as a marker of intestinal inflammation.  It is standard-of-
care at the CHOP Inflammatory Bowel Center to consider any stool calprotectin value above 
250µg/g as significantly elevated.  If a study participant has a stool calprotectin above 
250µg/g during the course of the study, the primary gastroenterologist will be notified of the 
lab value either in person or via email.  The study will cover the costs of measuring the stool 
calprotectin, unless already being ordered for clinical care.  All other laboratory data will be 
obtained from chart review only. 
Additionally, some of the stool sample will be used to sample the luminal contents of the 
intestine. If the stool is collected at home prior to arrival at the study visit then the subject 
will store the stool in the refrigerator prior to submitting it to a study team member. Stool 

 
  
 
  
 
 
 
14
samples will be returned to CHOP using pre-paid mailers, by dropping it off at the main 
hospital or a satellite location, or by submitting it to a study team member at a study visit. 
Samples will be refrigerated and then stored at -80˚C or in a liquid nitrogen freezer. For 
DNA isolation, DNA extraction kits will be used.    
5.1.7 Rectal Swabs 
Two rectal swab samples will be obtained by research staff or clinical team members. Each 
sterile swab will be inserted 2-3 cm into the rectum, turned 360 degrees, removed, placed 
into the original tubes and sealed tightly and stored frozen at -80°C or in a liquid nitrogen 
freezer until analysis.  DNA will be purified from swabs in 96-well plates using the Mo-Bio 
PowerSoil® kits and utilizing Eppendorf epMotion® automated liquid handling. 
5.1.8 Oral Swabs 
Two oral swab samples will be obtained using sterile swabs. A study team member will 
instruct subjects on how to obtain oral swab samples. Samples will be stored at at -80°C or 
in a liquid nitrogen freezer until analysis.  DNA will be purified from swabs in 96-well 
plates using the Mo-Bio PowerSoil® kits and utilizing Eppendorf epMotion® automated 
liquid handling. 
5.1.9 Environmental Swab 
At the time of the rectal or oral swab collection, an environmental control sample will 
be obtained from the room air. If subjects are collecting samples at home, they will be 
provided instructions for collecting the environmental swab.  
5.2 
Efficacy Evaluations  
The efficacy of the study intervention will be determined by comparing the differences in 
time-to-relapse and the proportion of subjects with sustained relapse-free remission between 
subjects on the CDED and those who choose not to follow the CDED.  Remission will be 
assessed using PCDAI, CRP, and stool calprotectin.   
 
 Diagnostic Tests, Scales, Measures, etc. 
The results of each stool calprotectin will be entered into CHOP’s electronic medical record 
and shared with the participant’s primary gastroenterologist.  Stool calprotectin is used as a 
marker of intestinal inflammation.  It is standard-of-care at the CHOP Inflammatory Bowel 
Center to consider any stool calprotectin value above 250µg/g as significantly elevated.  If a 
study participant has a stool calprotectin above 250µg/g during the course of the study, the 
primary gastroenterologist will be notified of the lab value either in person or via email.  The 
modified MARS questionnaire, 3-day calorie count, and 24-hour dietary recall will be used 
to measure dietary adherence.  
5.3 
Safety Evaluation 
All adverse events will be documented. All decisions related to restarting biological of 
immunomodulator therapy will be made by the primary gastroenterologist.   

 
  
 
  
 
 
 
15
6 
STATISTICAL CONSIDERATIONS 
6.1 
Primary Endpoint 
The primary endpoint will be differences in time-to-relapse and sustained relapse-free 
remission at 52 weeks, as assessed using PCDAI, CRP, microbiome, and stool calprotectin, 
between subjects on the CDED and subjects on a free diet.  
6.2 
 Secondary Endpoints 
Secondary endpoints will include the following: 
 Time-to-relapse and sustained relapse-free remission at 52 weeks, as assessed using 
PCDAI, CRP, microbiome, and stool calprotectin, in all subjects. 
 Compliance with the dietary intervention as measured by the modified MARS 
questionnaire 
 
6.3 
Control of Bias and Confounding 
Subjects being withdrawn from immunomodulator or biologic therapy will be approached to 
participate in this study.  We will ascertain these subjects through a number of methods 
including query of the electronic medical record for patients in clinical remission and 
through GI physician referral.  With these measures, we believe we will capture all subjects 
eligible and avoid bias. 
6.4 
Statistical Methods 
6.4.1 Baseline Data  
Standard descriptive statistics will be used to describe subject characteristics, which will 
include information such as the distribution of age, race/ethnicity, and disease 
characteristics.   Summary statistics such as means, standard deviations, medians, and ranges 
will be compiled for all measured variables.  Frequencies will be computed for all 
categorical and ordinal variables.  Box plots will be used to examine distributions, identify 
potential influential points, and guide in the choice of transforming if warranted. 
Additionally, data from protocols #15-011817 and #09-007286 will be used for data analysis 
for comparison.  
 
6.4.2 Analysis of Primary Outcomes of Interest 
The primary analysis will include all subjects meeting all inclusion and exclusion criteria 
and completing the first study visit.  The primary endpoint will be sustained relapse-free 
remission at 52 weeks and will be expressed as a percentage with a 95% confidence interval.  
Time-to-relapse analysis comparing free diet and the CDED will be performed using a Cox 
regression model. 

 
  
 
  
 
 
 
16
6.5 
Sample Size and Power 
There is no pediatric literature on withdrawing immunomodulator or biological 
monotherapy in CD patients in deep clinical remission.  Therefore, this pilot study is needed 
to determine effect size for a larger randomized controlled study.  We have approximately 
120 patients in clinical remission on biological monotherapy.  This does not include patients 
on immunomodulator monotherapy.  Unfortunately, the number of patients in remission who 
have already undergone immunomodulator/biologic withdrawal by their primary 
gastroenterologists at this center is not available. However, even if this data were available it 
would not truly reflect the feasibility of recruitment at the current moment as medication 
withdrawal has been receiving more attention within the pediatric gastroenterology 
community over the last several months.  The target sample size will be to enroll 35 subjects 
to yield 25 eligible subjects, 10 of whom would participate in the CDED, which is a 
reasonable number of patients to recruit over the two years of expected recruitment and 
should provide sufficient data regarding an effect size for future, larger, studies.  This study 
will also be helpful in determining how many subjects will elect to adhere to the CDED 
versus staying on the regular diet. 
7 
SAFETY MANAGEMENT 
7.1 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
7.2 
Adverse Event Reporting 
The majority of this study is observational in nature.  The dietary intervention is not 
expected to pose a risk greater than minimal risk.  Therefore, SAEs are not expected.  If any 
unanticipated problems related to the research involving risks to subjects or others happen 
during the course of this study (including SAEs) these will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. 
AEs that are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review.  
8 
STUDY ADMINISTRATION 
8.1 
Data Collection and Management 
1. Confidentiality of Data.  In order to ensure confidentiality, each subject will be given 
a study ID number.  There will be a master list saved on a secure CHOP password-
protected drive that will link the personal health information used to identify the 
patient with their study ID number.  Data will be entered into a password protected 
REDCap database and maintained on a secure CHOP server.  The study team will 
collect the information and will be responsible for data management and accuracy of 
records.  Only the study team on this protocol will have access to the data.  Data and 
backups will be stored in the CHOP Research Information Systems Storage Area 
Network (SAN).  Access to the SAN directories where data are stored will be limited 
to study personnel, with authentication performed using CHOP’s enterprise Active 

 
  
 
  
 
 
 
17
Directory service.  All information collected in this study will be kept confidential as 
required by law. 
2.  Security/Recovery of Data.  The password-protected REDCap database will be 
maintained on a secure CHOP server, and it will also be saved on a secure CHOP 
password-protected drive. 
3. In addition to REDCap, the study will use an electronic honest broker developed and 
managed by CHOP’s Department of Biomedical and Health Informatics (DBHi) 
(f.k.a. Center for Biomedical Informatics).  
The Electronic Honest Broker (eHB):  The eHB is a software service that 
interconnects research systems and the research portal (described below) by 
escrowing and securely storing Protected Health Information (PHI) and the variable 
associations with research systems.  The eHB encrypts this information on the client 
side before storing this sensitive information.  Persons or organizations who are 
named as the actual keepers of the honest broker can call the eHB Application 
Programming Interface (API) to re-identify and supplement subject data and/or 
specimens for predefined reasons.  Research staff on the study can request re-
identification of subject records from the eHB by written request to the DBHi for 
quality assurance and quality control purposes only.   
Subject information will be entered into the Biorepository Portal (BRP) and stored in 
the eHB encrypted database.  These PHI elements include: 
 Medical Record Number or Other Unique Identifier 
 Last Name 
 First Name 
 Date Of Birth 
Holding these identifiers in the eHB allows for creation of a unique subject list that 
can be linked to research data and specimen records on demand as data is entered. 
The BRP is a federated web application used to support longitudinal biospecimen 
collection activities. Using HTTP protocols, it interfaces with downstream data 
systems, including REDCap and Thermo Scientific's Nautilus LIMS, to provide a 
single unified interface for data collection and update activities. Data backup is 
performed nightly via a dedicated backup system.  The backup environment is 
maintained by a dedicated staff using dedicated resources.  Access to the backup 
environment is restricted to Research Information Systems staff. 
8.1.1 Data sources  
Data will be collected from the medical records at CHOP (EPIC, ChartMaxx, paper records, 
etc).  If the subject is not a CHOP patient, we will request the subject to sign an 
Authorization to Release/Obtain Patient Information form so we can obtain the medical 
records from the primary gastroenterologist.  Additionally, using the honest broker clinical 

 
  
 
  
 
 
 
18
information can be pulled from the clinical data warehouse, surescripts, and clarity.  Data 
will be entered into a CHOP REDCap database and the BRP that will only be accessible to 
members of the research team.  The research will also include de-identified data and samples 
from a collaborator (Dr. Arie Levine) at the Wolfson Medical Center in Israel running a 
study with a similar protocol. And coded data from IRB #15-011817 and #09-007286 
obtained through an honest broker. The data and samples will come from individuals whose 
identity the investigators cannot readily ascertain, as the data will be de-identified to the 
CEASE study team. Data and samples from these individuals will not be included in the 
enrollment numbers for this study and research activities using this will not be reported as 
part of the continuing review, but may be included in data analysis. The data for these 
protocols is stored within CHOP’s secure research drives. There is limited access to these 
drives with required approval to gain access. If data is shared outside of CHOP, the send 
secure CHOP email will be utilized.  
8.2 
Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy.  The investigators and other site 
personnel will not use such data and records for any purpose other than conducting the 
study.  Safeguards to maintain subject confidentiality are described under Data Collection 
and Management – Confidentiality.   No identifiable data will be used for future study 
without first obtaining IRB approval. The investigators and other site personnel will not use 
such data and records for any purpose other than conducting the study, and the protected 
health information collected will not be reused or disclosed to any other person or entity, 
except as required by law or for authorized oversight of the research project.  The following 
groups of people at CHOP may have access to this information: the study team and the 
Hospital’s Institutional Review Board and compliance office. 
8.3 
Regulatory and Ethical Considerations 
8.3.1 Data and Safety Monitoring Plan 
The safety and monitoring plan for this project will focus on safeguards to ensure 
confidentiality as described in Section 8.1. Unanticipated problems involving risks to 
subjects will be monitored over the course of the study by the Principal Investigator.    
8.3.2 Risk Assessment 
The only additional procedures will be collection of stool, rectal swabs, and oral swabs. 
Additionally, subjects will have the option to receive the dietary intervention. Therefore, 
participation in this study is minimal risk. Collecting stool may contain germs that spread 
disease. Subjects will be reminded to carefully wash their hands and use careful handling 
techniques to avoid spreading infection. Subjects may experience small physical discomfort 
while having the swab samples taken.  However, once the swab is removed, the discomfort 
will be alleviated.    
The intervention diet restricts potentially unhealthy components of diet, such dairy, wheat 
products, sauces, soft drinks, fruit juice, and processed meats. Therefore, the diet may 
restrict foods that the patient may enjoy and may limit necessary nutrients.  Routine detailed 

 
  
 
  
 
 
 
19
dietary recall recorded by study members (who are registered dieticians or physicians) at 
study visits will assess the caloric and nutrient intake of the subjects’ diet.  If a subject does 
not meet 100% of estimated nutritional needs (based on standard World Health Organization 
equations for resting energy expenditure or Recommended Daily Allowance guidelines) 
when assessed during any 24 hour dietary recall or 3-day calorie count then study members 
may suggest modification of a subject’s intake within the confines of the diet, including the 
use of a nutritional supplement of the subject’s choosing.  If at the time of the next visit the 
subject continues to not meet at least 75% his/her caloric needs then the subject will be 
removed from the dietary intervention.    
While in this study a subject may have a Crohn disease flare.  This will be determined by the 
primary gastroenterologist.  The decision to take subjects off of Crohn disease medications 
will be made by the primary gastroenterologist and any decision to go back on medication 
will also be made by the primary gastroenterologist, as part of clinical care.  Healthier diets 
have never been shown to induce a Crohn flare.  Therefore participation in this study should 
not put subjects at increased risk for a flare.   
8.3.3 Potential Benefits of Study Participation 
The direct benefit to a subject’s participation in this study may include improved clinical 
outcomes after withdrawal of medical therapy while on the intervention diet.  For patients 
who do not choose to participate in the dietary intervention there are no direct benefits.  
There are, however, positive, indirect benefits to society to be gained from this study since 
the study will allow for a better understanding of de-escalation strategies in pediatric 
patients with Crohn disease. 
8.3.4 Risk-Benefit Assessment 
The potential benefits of the patients who participate in the dietary intervention outweigh 
any potential risks in this study, as the diet may potentially increase their chances of staying 
in remission.  For patients not involved in the diet there are no direct individual benefits.  
However, the risks of participating in this study are minimal, and these risks are outweighed 
by the benefits to society to be gained from new knowledge about de-escalation strategies in 
pediatric patients with CD. 
8.4 
Recruitment Strategy 
Subjects being withdrawn from immunomodulator or biologic therapy will be approached to 
participate in this study.  We will ascertain these subjects through a number of methods 
including query of the electronic medical record for patients in clinical remission and 
through GI physician referral.  Study team members will make contact with potential 
subjects to describe the study and enroll patients who are interested in participating.  No 
advertising will be used.  We expect to enroll sufficient number of subjects to achieve our 
study aims.   
8.5 
Informed Consent/Assent and HIPAA Authorization 
Study personnel will obtain consent and assent for the study.  Discussion about participation 
will occur with a study team member. Subjects may make a decision about study 
participation at that time, or may decide to enroll at a later visit.   

 
  
 
  
 
 
 
20
The study will be thoroughly explained by study personnel, including the study rationale and 
goals.   Potential participants will be given the opportunity to ask questions about the study, 
risks, benefits, and confidentiality.  A member of the research team will explain each section 
of the consent form and questions will be encouraged.  Written consent will be obtained 
after all the questions and discussions have been completed.  For the subjects under 18 years 
of age, assent will be obtained by explaining briefly the study while the parent/guardian is 
present.  Assent will be documented in writing on the consent form.  Participation in all 
areas of the study will be completely voluntary.  Should the subjects become intolerant of 
any aspect of the study, their participation will be discontinued.  Subjects who turn 18 
during the course of the study will be re-consented. 
8.5.1 Waiver of Documentation of Consent 
For potential subjects who are not at CHOP prior to enrollment, they may be contacted by 
phone.  A verbal screening informed consent form will be obtained before collecting any 
screening information.  If there are questions regarding eligibility, relevant information from 
the patient’s medical record will be sought from their treating physician.  In addition, 
subjects may be asked to provide a stool sample before coming to the study site.  When 
consent is obtained initially by telephone, the person obtaining consent will document the 
participant’s agreement to participate on the verbal screening informed consent form. All 
participants must provide written consent, and assent when appropriate, before undergoing 
any other study procedures.  
8.5.2 Waiver of Assent 
A full waiver of assent is requested only for the verbal screening consent form which can be 
done over the telephone with parents/guardian and children may not be available. At the 
enrollment visit, the study will be reviewed in its entirety with the participant and the 
participant’s parents/guardian. Written assent will be obtained at this in-person visit and 
documented on the main consent form 
8.5.3 Waiver of HIPAA Authorization 
A partial waiver of HIPAA authorization to obtain verbal authorization is requested for 
subjects enrolled who will need to provide research samples prior to being seen at CHOP.  
8.6 
Payment to Subjects/Families  
Subjects will receive a $10 prepaid bankcard each time rectal and oral swabs are obtained 
(up to 3 times during the 1-year study period) and each time a stool sample is completed (up 
to 6 times during the study period). The maximum amount that a subject will receive during 
this study is $90 in gift cards.  The cost of measuring the stool calprotectin will be covered 
by the investigators and the families will not be charged. All other lab measures will be 
ordered by the primary gastroenterologist per standard of care. 

 
  
 
  
 
 
 
21
9 
PUBLICATION 
Data from this study, including preliminary data analyses, will be presented at national 
meetings and submitted for publication.  Confidentiality will be maintained during 
publication.   
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nutrition with a crohn's disease exclusion diet is effective for induction of remission in 
children and young adults with crohn's disease. Inflamm Bowel Dis. 2014 
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3. Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, et al. Induction 
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4. Antunes O, Filippi J, Hebuterne X, Peyrin-Biroulet L. Treatment algorithms in crohn's - 
up, down or something else? Best Pract Res Clin Gastroenterol. 2014 Jun;28(3):473-83.  
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antagonist therapy and lymphoma development: Twenty-six cases reported to the food 
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