Open Label, Randomized, Multicenter, Comparative Effectiveness Trial of Specific Carbohydrate and Mediterranean Diets to Induce Remission in Patients With Crohn's Disease
Phase: NA
Conditions: Crohn Disease
Sponsor: University of Pennsylvania

  
 
V5.4 2019.April.10 
 
  
 
Open Label, Randomized, Multicenter, Comparative Effectiveness Trial of Specific Carbohydrate and Mediterranean 
Diets to Induce Remission in Patients with Crohn’s Disease  
 
 
Principal Investigator  
James D. Lewis, MD, MSCE 
Perelman School of Medicine 
Gastroenterology  
720 Blockley Hall, 423 Guardian Drive 
Philadelphia, PA 19104 
215-573-5137 
lewisjd@mail.med.upenn.edu 
 
Regulatory Sponsor  
Same as above  
  
PCORI Grant Number               10053886 
Investigational Product: 
[If applicable] 
Study Diet  
 
IRB Number: 
 
825907 
IND/ IDE Number: 
[If applicable] 
N/A 
ClinicalTrials.gov Number       NCT03058679 
Initial version 
 
v1.0.20160830 
 
Revised Versions: 
Version 2, October 25, 2016 
 
 
 
Version 3.0, January 23, 2017 
 
 
 
Version 4.0, February 2, 2017 
 
 
 
Version 4.1, February 20, 2017 
 
 
 
Version 4.2, March 24, 2017 
 
 
 
Version 4.3, April 12, 2017 
 
 
 
Version 4.4, April 28, 2017 
 
 
 
Version 4.5, May 25, 2017 
 
 
 
Version 4.6, September 01, 2017 
 
 
 
Version 4.7, December 12, 2017 
 
 
 
Version 4.8, February 27, 2018  
Version 5.0, March 20, 2018 
Version 5.1, August 14, 2018 
Version 5.2, October 24, 2018 
Version 5.3, January 30, 2019Verison 5.4, April 10, 2019 
 

 
Page 2 of 81 
 
 
Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS ....................................................................................................................... 6 
STUDY SUMMARY .................................................................................................................................... 7 
1. BACKGROUND AND STUDY RATIONALE ....................................................................................... 10 
1.1  
INTRODUCTION .......................................................................................................................... 10 
1.2 
BACKGROUND AND RELEVANT LITERATURE ................................................................................ 10 
1.2.1 
Therapeutic strategies for Crohn’s disease ........................................................................ 10 
1.3 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ..................................................... 10 
1.4 
CLINICAL DATA TO DATE IN ADULTS AND CHILDREN .................................................................... 11 
1.5 
PATIENT-CENTEREDNESS (PCORI METHODOLOGY CRITERION 3) ............................................... 12 
1.5.1 
Generation and prioritization of the research question by patients from the CCFA Partners 
Patient-Powered Research Network (PPRN). ................................................................................. 12 
1.5.2 
This research will focus on outcomes of primary interest to patients with CD ................... 13 
1.6 
DOSE RATIONALE ...................................................................................................................... 14 
2 
STUDY OBJECTIVES ..................................................................................................................... 14 
2.2 
PRIMARY OBJECTIVES ............................................................................................................... 14 
2.3 
SECONDARY OBJECTIVES .......................................................................................................... 14 
3 
INVESTIGATIONAL PLAN ............................................................................................................. 14 
3.2 
GENERAL DESIGN ...................................................................................................................... 14 
3.2.1 
Informed Consent and Screening (PCORI Methodology Criterion 3) ................................. 15 
3.2.2 
Study Intervention Phase .................................................................................................... 15 
3.3 
ALLOCATION TO INTERVENTIONAL GROUP ................................................................................... 16 
3.4 
STUDY ENDPOINTS .................................................................................................................... 17 
3.4.1 
PRIMARY STUDY ENDPOINTS ..................................................................................................... 17 
3.4.2 
SECONDARY STUDY ENDPOINTS ................................................................................................ 17 
3.4.2.1 
CLINICAL REMISSION ............................................................................................................. 17 
3.4.2.2 
OTHER PATIENT REPORTED OUTCOME MEASURES ................................................................... 17 
3.5 
PRIMARY SAFETY ENDPOINTS [IF APPLICABLE] ............................................................................ 17 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION .................................................... 17 
4.1 
INCLUSION CRITERIA .................................................................................................................. 17 
4.2 
EXCLUSION CRITERIA ................................................................................................................ 18 
4.3 
PARTICIPANT RECRUITMENT ...................................................................................................... 18 
4.4 
DURATION OF STUDY PARTICIPATION ......................................................................................... 18 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES ................................................................................... 19 
4.6 
VULNERABLE POPULATIONS ....................................................................................................... 19 
5 
STUDY INTERVENTION ................................................................................................................. 19 
5.1 
DESCRIPTION ............................................................................................................................ 19 
5.2 
INTERVENTION REGIMEN ............................................................................................................ 19 
5.3 
RECEIPT ................................................................................................................................... 19 
5.4 
STORAGE .................................................................................................................................. 20 
5.5 
PREPARATION AND PACKAGING .................................................................................................. 20 
5.6 
ADMINISTRATION AND ACCOUNTABILITY ...................................................................................... 20 
5.7 
SUBJECT COMPLIANCE MONITORING .......................................................................................... 20 
5.7.1 
Return or Destruction of Investigational Product ................................................................ 20 
6 
STUDY PROCEDURES .................................................................................................................. 20 

 
Page 3 of 81 
 
 
*VERBAL INFORMED CONSENT MAY BE OBTAINED TO ALLOW FOR SOME SCREENING STEPS TO BEGIN PRIOR TO 
THE IN PERSON VISIT. WRITTEN INFORMED CONSENT MUST STILL BE OBTAINED AT THE IN PERSON SCREENING 
VISIT. ..................................................................................................................................................... 21 
6.2 
STUDY INTERVENTION PHASE AND FOLLOW UP PHASE ................................................................ 21 
6.2.1 
Recruitment and Pre-Screening ......................................................................................... 21 
6.2.2 
Visit 1 .................................................................................................................................. 21 
6.2.3 
Visit 2 (week 6 visit) ............................................................................................................ 23 
6.2.4 
Visit 3 (week 12 visit) .......................................................................................................... 24 
6.2.5 
End of Study Visit ............................................................................................................... 24 
6.3 
RESCUE THERAPY [IF APPLICABLE] ............................................................................................. 24 
6.4 
UNSCHEDULED VISITS ............................................................................................................... 24 
6.5 
SUBJECT WITHDRAWAL ............................................................................................................. 25 
7 
STUDY EVALUATIONS AND MEASUREMENTS ......................................................................... 25 
7.1 
MEDICAL HISTORY ..................................................................................................................... 25 
7.2 
DEMOGRAPHIC INFORMATION ..................................................................................................... 25 
7.3 
CURRENT SYMPTOMS ................................................................................................................ 25 
7.4 
CONCOMITANT MEDICATION ....................................................................................................... 25 
7.5 
VITAL SIGNS .............................................................................................................................. 25 
7.6 
LABORATORY EVALUATIONS ....................................................................................................... 26 
7.7 
PLASMA COLLECTION ................................................................................................................ 26 
7.8 
PREGNANCY TESTING ................................................................................................................ 26 
7.9 
STOOL SAMPLE COLLECTION ..................................................................................................... 26 
7.10 
SAMPLE PREPARATION, PROCESSING, AND STORAGE ................................................................... 26 
7.11 
OTHER EVALUATIONS, MEASURES ............................................................................................. 27 
7.12 
EFFICACY EVALUATIONS ............................................................................................................ 27 
8 
STATISTICAL PLAN ....................................................................................................................... 27 
8.1 
PRIMARY ENDPOINT .................................................................................................................. 27 
8.2 
SECONDARY ENDPOINTS ........................................................................................................... 28 
8.3 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................ 29 
8.4 
STATISTICAL METHODS .............................................................................................................. 29 
8.4.1 
Baseline Data...................................................................................................................... 29 
8.4.2 
Efficacy Analysis ................................................................................................................. 29 
8.4.3 
Safety Analysis ................................................................................................................... 31 
8.5 
SUBJECT POPULATION(S) FOR ANALYSIS .................................................................................... 31 
9 
SAFETY AND ADVERSE EVENTS ................................................................................................ 31 
9.2 
DEFINITIONS .............................................................................................................................. 31 
9.2.1 
Adverse Event..................................................................................................................... 31 
9.2.2 
Serious Adverse Event ....................................................................................................... 31 
9.2.3 
Expected Adverse Events ................................................................................................... 32 
9.3 
RECORDING OF ADVERSE EVENT (AE) ....................................................................................... 32 
9.4 
RELATIONSHIP OF AE TO STUDY ................................................................................................ 32 
9.5 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .............................. 32 
9.5.1 
Follow-up SAE report .......................................................................................................... 33 
9.5.2 
Investigator reporting: notifying the study sponsor (Penn) ................................................. 33 
9.6 
MEDICAL MONITORING ............................................................................................................... 34 
9.6.1 
Data and Safety Monitoring Plan ........................................................................................ 34 
9.6.2 
DATA SAFETY MONITORING BOARD ............................................................................................ 34 
10 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING ................................. 35 
10.2 
CONFIDENTIALITY ...................................................................................................................... 35 
10.3 
DATA COLLECTION, SOURCE AND ACCURACY (PCORI METHODOLOGY STANDARD IR-1) ............. 35 
10.4 
RECORDS RETENTION ............................................................................................................... 36 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 37 

 
Page 4 of 81 
 
 
11.2 
STUDY MONITORING PLAN ......................................................................................................... 37 
11.3 
AUDITING AND INSPECTING ........................................................................................................ 37 
12 
ETHICAL CONSIDERATIONS ........................................................................................................ 37 
12.2 
RISKS ....................................................................................................................................... 37 
12.3 
BENEFITS .................................................................................................................................. 38 
12.4 
RISK BENEFIT ASSESSMENT....................................................................................................... 38 
12.5 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ........................................................... 38 
13 
STUDY FINANCES ......................................................................................................................... 38 
13.1 
FUNDING SOURCE ..................................................................................................................... 38 
13.2 
CONFLICT OF INTEREST ............................................................................................................. 38 
13.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................. 39 
14 
COLLABORATIVE EFFORT (PCORI METHODOLOGY CRITERION 2. TECHNICAL MERIT) ... 39 
15 
PUBLICATION PLAN AND DISSEMINATION OF RESULTS (PCORI METHODOLOGY IR-6) .. 39 
16 
APPENDICES .................................................................................................................................. 39 
17 
REFERENCES ................................................................................................................................ 40 
APPENDIX A ............................................................................................................................................ 45 
PROTOCOL SIGNATURE PAGE ............................................................................................................ 45 
APPENDIX B ............................................................................................................................................ 46 
APPENDIX C ............................................................................................................................................ 47 
1. 
OVERVIEW ...................................................................................................................................... 47 
1.1. 
PURPOSE OF THE STUDY ............................................................................................................ 47 
1.2. 
ADHERENCE STATEMENT. .......................................................................................................... 47 
2. 
ADVERSE EVENTS .......................................................................................................................... 48 
2.1. 
DEFINITIONS .............................................................................................................................. 48 
2.2. 
EXPECTED ADVERSE EVENTS .................................................................................................... 48 
2.3. 
RECORDING OF ADVERSE EVENT (AE) ....................................................................................... 48 
2.4. 
RELATIONSHIP OF AE TO STUDY ................................................................................................ 49 
2.5. 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .............................. 49 
2.5.1. 
FOLLOW-UP REPORT ............................................................................................................. 49 
2.5.2. 
INVESTIGATOR REPORTING: NOTIFYING THE STUDY SPONSOR (PENN) ...................................... 49 
3. 
SAFETY REVIEW PLAN AND MONITORING ........................................................................................ 51 
4. 
INFORMED CONSENT ...................................................................................................................... 51 
5. 
DATA QUALITY AND MANAGEMENT .................................................................................................. 52 
6. 
CONFIDENTIALITY .......................................................................................................................... 53 
APPENDIX D ............................................................................................................................................ 54 
STOOL COLLECTION INSTRUCTIONS ................................................................................................. 56 
STOOL COLLECTION INSTRUCTIONS ................................................................................................. 59 
APPENDIX F ............................................................................................................................................ 61 
APPENDIX G ........................................................................................................................................... 66 
1. 
DEFINITIONS AND ROLES ................................................................................................................ 66 
2. 
OVERVIEW ..................................................................................................................................... 66 
3. 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 67 
3.1. 
SOURCE DOCUMENTS................................................................................................................ 67 
3.2. 
CASE REPORT FORMS ............................................................................................................... 67 
3.3. 
DATA ACCESS ........................................................................................................................... 67 
4. 
DATA COLLECTION ......................................................................................................................... 67 
4.1. 
BEST PRACTICES IN ADMINISTRATION OF PROMIS MEASURES .................................................... 70 

 
Page 5 of 81 
 
 
5. 
ANALYTIC PLAN .............................................................................................................................. 70 
5.1. 
OVERVIEW ................................................................................................................................ 70 
5.2. 
SAMPLE SIZE ............................................................................................................................. 71 
5.3. 
ANALYSES FOR RECRUITMENT, RETENTION AND DATA QUALITY ..................................................... 72 
5.4. 
ANALYSIS OF BASELINE DATA .................................................................................................... 72 
5.5. 
EFFICACY ANALYSIS .................................................................................................................. 72 
5.5.1. 
OUTCOME DEFINITIONS.......................................................................................................... 72 
5.5.1.1. 
SCDAI ................................................................................................................................. 72 
5.5.1.2. 
SECONDARY ENDPOINTS ....................................................................................................... 73 
5.5.1.3. 
REDUCTION IN FECAL CALPROTECTIN ..................................................................................... 73 
5.5.1.3.1. 
REDUCTION IN SYSTEMIC INFLAMMATION ............................................................................ 73 
5.5.1.3.2. 
CROHN’S DISEASE ACTIVITY INDEX (CDAI) ........................................................................ 73 
5.5.1.3.3. 
PRO2 AND PRO3 ............................................................................................................ 74 
5.5.1.4. 
COMBINED PRO AND FCP OUTCOME ..................................................................................... 74 
5.5.1.5. 
PROMIS MEASURES ............................................................................................................. 74 
5.5.1.6. 
PHYSICAL FUNCTION AND JOINT PAIN ...................................................................................... 74 
5.5.2. 
STATISTICAL ANALYSIS FOR PRIMARY AND SECONDARY OUTCOME MEASURES........................... 74 
5.5.3. 
ANALYSIS OF PROMIS AND ARTHRITIS MEASURES ................................................................. 76 
5.5.4. 
SAFETY ANALYSIS ................................................................................................................. 76 
5.6. 
ANCILLARY BIOMARKER DISCOVERY STUDIES: ............................................................................. 76 
 
 
 
 
 
 

 
Page 6 of 81 
 
 
List of Abbreviations 
 
 
 
 
For example: LIST OF ABBREVIATIONS-list alphabetically. 
 
AE: Adverse event 
DCC: Data Coordinating Center 
DMC: Data Management Center 
DM: Diabetes Mellitus 
DMS: Data Management System 
DSMB: Data Safety Monitoring Board 
FCP: Fecal Calprotectin 
SCD: Specific Carbohydrate Diet 
MSD: Mediterranean Style Diet 
PPRN: Patient-Preferred Research Network 
 
 
 
 
 
 
 
 

 
Page 7 of 81 
 
 
Study Summary 
Title 
Randomized, Multicenter, Comparative Effectiveness Trial of Specific Carbohydrate 
and Mediterranean Diets to Induce Remission in Patients with Crohn’s Disease  
 
Short Title 
DINE-CD 
IRB Number 
825907 
Phase 
N/A 
Methodology 
Open Label Randomized Clinical Trial 
Study Duration 
3 years  
Study Center(s) 
Multicenter trial of up to 50 sites 
Objectives 
Primary: 
1. To compare the effectiveness of the Specific Carbohydrate Diet and a 
Mediterranean style diet to induce symptomatic and clinical remission in 
patients with Crohn’s disease. 
2.  
Secondary:  
1. To compare the effectiveness of the Specific Carbohydrate Diet and a 
Mediterranean style diet to reduce mucosal inflammation in patients with 
active Crohn’s disease. Mucosal inflammation will be assessed by 
measuring the concentration of calprotectin in the feces (FCP). 
2. To compare the effectiveness of the Specific Carbohydrate Diet and a 
Mediterranean style diet to reduce systemic inflammation in patients with 
active Crohn’s disease. Systemic inflammation will be assessed by 
measuring the concentration of C reactive protein (CRP). 
3. To compare the effectiveness of the Specific Carbohydrate Diet and a 
Mediterranean style diet to improve the following symptoms in patients 
with Crohn’s disease: a) fatigue, b) pain, c) joint symptoms. 
4. To determine the proportion of patients who continue the study diets when 
prepared food is no longer provided without cost and the reasons for 
discontinuation of the diets.   
Number of Subjects 
194 participants to be enrolled across all sites 

 
Page 8 of 81 
 
 
Main Inclusion and 
Exclusion Criteria 
 
 
Inclusion Criteria: 
◦ 
Age ≥18 
◦ 
Documented diagnosis of Crohn’s disease 
◦ 
sCDAI >175 and <400  
◦ 
Access to a computer with internet and the ability to complete daily online 
surveys 
◦ 
Capable of providing consent to participate 
Exclusion Criteria 
◦ 
Pregnancy 
◦ 
Hospitalized patients or surgery planned within 6 weeks 
◦ 
Ostomy or known symptomatic intestinal stricture 
◦ 
Use of the Specific Carbohydrate Diet within 4 weeks of screening 
◦ 
Start or change* dose of thiopurines, natalizumab, vedolizumab or 
methotrexate(w/in 12 weeks) or anti-TNF or ustekinumab (w/in 8 weeks) of 
screening 
◦ 
Start or change* in dose of any 5-ASA medication within  2 weeks of 
screening 
◦ 
Use of antibiotics within 2 weeks of screening  
◦ 
Start or change* corticosteroids within 1 week of screening or dose >20mg 
prednisone or equivalent 
◦ 
Baseline stool frequency >4 bowel movements/day when well 
◦ 
BMI<16 or ≥40 
◦ 
Celiac disease, recent c diff colitis, or diabetes 
◦ 
Albumin<2.0mg/dl (if measured as part of routine clinical care) 
* Exception for treatment failures: if a subject is determined to fail on 
any of the following standard lines of treatment at the treating 
investigator’s discretion, subjects may screen for study intervention 
based upon the following wash out periods: 4 weeks for thiopurine and 
methotrexate and 8 weeks for natalizumab, vedolizumab, anti-TNF, or 
ustekinumab. 
 
Investigational Product 
(drug, biologic, device, 
etc.) 
 
Specific Carbohydrate Diet – up to 3000 calories provided to the participant 
per day. 
Duration of administration 
(if applicable) 
6 weeks 
Reference therapy 
Mediterranean Diet – up to 3000 calories provided to participant per day 
Statistical Methodology 
The primary analyses for the RCT will use 2-sided tests of statistical 
significance and will be performed using the intention-to-treat principle. The 
primary analysis will compare the proportion of patients who achieve a 
symptomatic remission  at week 6 using the Cochran-Mantel-Haenszel (CMH) 
chi square test . All patients who are withdrawn or lost to follow-up prior to 
week 6 will be considered treatment failures.  The MSD will be considered the 
reference group for all analyses. 
Safety Evaluations  
Not applicable  

 
Page 9 of 81 
 
 
Data and Safety Monitoring 
Plan  
A Data Safety and Monitoring Board (DSMB) will oversee the safety of the 
study.  
 
 
 

 
Page 10 of 81 
 
 
1. Background and Study Rationale 
1.1  
Introduction 
This study will be conducted in full accordance with all applicable University of Pennsylvania Research 
Policies and Procedures and all applicable Federal and state laws and regulations.  This protocol is 
designed to compare the effectiveness of two dietary interventions for patients with Crohn’s disease (CD). 
This randomized controlled trial (RCT) will provide the strongest evidence to date as to whether a 
commonly used restriction diet known as the Specific Carbohydrate Diet (SCD) is superior to a 
Mediterranean style diet (MSD) that has been demonstrated to have numerous other health benefits. The 
two diets will be compared in terms of their ability to resolve the symptoms that characterize this 
debilitating disease; and as secondary objectives, we will evaluate the ability of the diets to reduce 
inflammation of the bowel, systemic inflammation and other symptoms of the disease.  
 
1.2 
Background and Relevant Literature  
CD is a chronic, debilitating disease with no cure that affects more than 500,000 Americans, with peak 
incidence in the 2nd and 3rd decades of life1-6. Cardinal symptoms of CD are abdominal pain, diarrhea, and 
weight loss. Most patients with CD will require at least one bowel resection – many require multiple 
resections7,8. The most feared complication of repeated bowel resections is short gut syndrome, causing 
chronic diarrhea, life threatening malnutrition and dehydration. Other complications of CD include mouth 
sores, eye problems (e.g. uveitis and episcleritis), arthritis and arthralgia, erythema nodosum, pyoderma 
gangrenosum, kidney stones, and blood clots. The currently available medical therapies are only effective 
for a fraction of the patients with CD (described below). Furthermore, the medications used to treat CD 
also may increase the risk of life threatening complications such as serious infections or cancer9-17. Sadly, 
despite the advances in medical therapy, patients with CD, particularly those with persistently active 
symptoms, have high rates of disability18-23, reduced quality of life24-27, and reduced life expectancy relative 
to the general population28.  
1.2.1 
Therapeutic strategies for Crohn’s disease  
Numerous medications are efficacious in the treatment of CD, nearly all of which suppress the immune 
system (reviewed in29-31). The most effective of the currently available medications are antibodies directed 
against tumor necrosis factor α (anti-TNF) used in conjunction with a second immunosuppressant 
medication (either a thiopurine or methotrexate). However, even with this approach remission rates are 
<60%32 and substantially wane over time33,34. Moreover, chronic immunosuppression is associated with 
numerous adverse effects including uncommon but potentially fatal adverse reactions, particularly 
lymphoma and serious infections9-17. Concerns about these uncommon but life threatening adverse 
effects strongly influence patients’ choice of medical therapies35-37. As such, there is great interest in and 
need for alternative treatment strategies that are not based on immunosuppression.  
 
Like for many intestinal diseases, it has been suggested for decades that dietary patterns may influence 
the course of CD. Indeed, this is among the most frequently asked question by patients.  Furthermore, 
the majority of patients report intolerance to specific food items38,39 and many follow nutritionally 
compromised diets40, yet less than half have seen a nutritionist41. Thus, understanding the role of diet on 
the natural history of CD is of major public health interest. Unfortunately, there have been few high quality 
studies that specifically addressed this question. 
 
1.3 
Name and Description of the Investigational Product  
The Specific Carbohydrate Diet was popularized by Elaine Gottschall in the book Breaking the Vicious Cycle42. 
The menu created for participants randomized to the SCD will follow the detailed descriptions in the book for 
which foods are allowed and not allowed. The SCD restricts all but simple carbohydrates. The only 
carbohydrates permitted are monosaccharides: glucose, fructose, and galactose.  Fresh fruits and vegetables 
are universally acceptable with the exception of potatoes and yams. Certain legumes (i.e. lentils, split peas) are 
permitted, however others (i.e. chickpeas, soybeans) are not. No grains are permitted in the SCD. Saccharin 
and honey are permitted in addition to moderate use of sorbitol and xylitol. Canned fruits and vegetables are 
not permitted due to possible added sugars and starches. Unprocessed meats are permitted in the SCD without 
limitation. However processed, canned, and most smoked meats are restricted due to possible sugars and 

 
Page 11 of 81 
 
 
starches used in additives. Milk is not permitted in the SCD due to lactose content. However, certain lactose 
free cheeses are permitted as is homemade lactose-free yogurt.  See Appendix K for a detailed description of 
the menu for participants on the SCD. 
1.4 
 Clinical Data to Date in Adults and Children 
Dietary interventions are an attractive adjunct or alternative to immunosuppression therapy for CD. 
Exclusive enteral nutrition (EEN) with elemental, semi-elemental and defined formula diets are commonly 
used in the treatment of pediatric CD, particularly in Canada, Japan and Europe43-45. Commercially 
available formulae have proved efficacious in treating symptoms and intestinal inflammation in CD in 
addition to supporting nutritional needs (Figure 1 adapted from Cochrane review).46-48However, the 
effectiveness is greatest when used as the exclusive source of nutrition.47,49 When compared head to 
head against corticosteroids, both resulted in improved symptoms, but only EEN resulted in healing of the 
mucosal inflammation which characterizes CD46. This approach has the advantage of avoiding the need 
for immunosuppression medications but is difficult to maintain long term. For maintenance of remission, 
a diet in which half of the daily calories were from an elemental supplement resulted in a nearly 50% 
reduction in CD relapse rates compared to a regular diet50, suggesting that less extreme dietary 
interventions may be beneficial as well.  
 
Two recent systematic reviews have addressed this question. The first reviewed 23 RCTs of fiber 
supplementation in IBD51. Although meta-analysis was not possible, the authors concluded that the role 
of fiber is intriguing and merits further investigation in adequately powered clinical trials. The second 
systematic review examined dietary interventions more broadly52.  Although summary measures of 
efficacy were not calculated, the authors concluded that exclusion diets such as the specific carbohydrate 
diet (SCD) and the low FODMAP (fermentable oligo-, di-, and monosaccharides and polyphenols) were 
the most promising. This is consistent with systematic evaluations that show that the majority of patients 
believe diet affects the course of their disease53,54 and the countless testimonials of patients who have 
tried SCD and other restriction diets as treatment for CD. 
 
Fiber supplementation and restriction diets are completely different strategies to manage CD, though 
exclusion diets are more closely related to EEN and are the focus of this proposed study. In our prior 
qualitative review, we documented that most restriction diets had little clinical evidence to support their 
efficacy55. However, several recent small studies have provided important evidence that use of the SCD 
both improves symptoms and reduces bowel inflammation. For example, Suskind et al. reported the 
effectiveness of the SCD in 7 children with CD who were not receiving any immunosuppressive 
therapies56. All had clinical improvement by 3 months and in those whose inflammatory markers were 
measured, there was notable improvement. Cohen et al. completed a more rigorous evaluation of the 
SCD57. Ten children with CD received SCD as primary therapy. Video capsule endoscopy was completed 
at baseline and after 12 weeks of diet therapy; mucosal inflammation was quantified with the Lewis score 
(LS). There was significant improvement overall, with 4 of 10 achieving complete mucosal healing 
(LS<135) and 6 of 10 achieving clinical remission. Thus, like EEN, the SCD demonstrated meaningful 
clinical improvement and mucosal healing in this uncontrolled study. Several other notable small trials of 
restriction diets have also demonstrated improved disease activity and prolonged time to relapse58-64. 
Some of these were either derived from or have similarities to the SCD61,64. For example, Olendzki studied 
a diet that was derived specifically from the SCD and reported clinical improvement in 24 of 27 patients 
(89%) who attempted the diet64. Sigall-Boneh and colleagues noted clinical remission in 33 of 47 (70%) 
children and young adults treated with a restriction diet with or without caloric supplementation with a 
defined formula diet, including 6 of 7 patients who used the diet without supplemental nutrition from a 
defined formula. Of those with baseline elevated CRP, 70% had complete normalization, while 11 of 15 
(73%) with colonoscopy or small bowel imaging demonstrated mucosal healing. The restriction diet 
resembled the SCD as condiments, sauces, gluten, dairy, processed meats and foods, and canned foods 
were all forbidden. Taken together, these small clinical trials have begun to provide evidence to support 
the testimonials of patients regarding the effectiveness of the SCD.  
One might ask why all patients would not at least try the SCD as an adjunctive therapy for CD. The answer 
lies in the challenge associated with following this diet and the lack of strong endorsement by 
guidelines30,31,65 such that many clinicians do not routinely recommend this to their patients. In preparing 
for this proposal, we queried potential participating sites if they made specific dietary recommendations. 
Four of 25 (16%) answered yes – only one routinely recommending the SCD. Rather, in the absence of 

 
Page 12 of 81 
 
 
strong data in favor of a specific elimination diet (such as the SCD), most clinicians recommend that their 
patients with CD follow a generally healthy, balanced diet.   
 
The MSD is a well-balanced diet that is much easier to follow than the SCD and is consistent with the 
United States Department of Agriculture and World Health Organization recommendations. Numerous 
cohort studies, randomized controlled trials, and systematic reviews support the efficacy of this diet to 
reduce inflammation66, cardiovascular disease67,68, cancer69, and mortality70. This is particularly important 
for patients with CD, as a recent meta-analysis linked CD with an increased risk of cardiovascular 
disease71. Notably, the MSD entails higher fiber intake and appreciably lower red meat intake than the 
average American diet, and is associated with higher fecal concentrations of short chain fatty acids72, thus 
supporting its role as an adjunctive therapy for CD. Additional supportive evidence comes from several 
small studies. Rajendran used food specific IgG4 levels guide a personalized exclusion diet62. Eggs and 
beef were the most commonly excluded foods. The 29 patients on the exclusion diet experienced a 
significant reduction in symptoms and reduction in the ESR as compared to pretreatment levels. The 
major limitation of this study was the absence of a control group. Stronger evidence for the MSD comes 
from work by Chiba et al.63, who in a small study (N=22) demonstrated superiority of the semi-vegetarian 
versus an omnivorous diet to maintain clinical remission (94% vs. 33%)63. It should be noted that this was 
not a randomized trial but rather allowed patients to choose whether or not to continue on the diet after 
discharge. Together, these studies lend support to the therapeutic potential of the MSD for CD in addition 
to the overall health benefits associated with this diet. 
 
The MSD was selected as the alternative diet based on 1) the strong evidence of its role in overall health, 
2) the easier implementation in routine life, 3) evidence that characteristics of the diet including higher 
fiber and lower red meat intake may be specifically beneficial for patients with CD, and 4) consistency 
with recommendations to follow a well-balanced diet. The MSD is backed by strong evidence supporting 
improved health outcomes in many other domains, including cardiovascular, neurodegenerative disease 
and cancer. 66-70 
 
1.4.1 
Gaps in Evidence: High quality evidence for the optimal diet once patients are 
diagnosed is lacking (PCORI Methodology Criterion 1)  
As documented in CCFA Partners, patients routinely modify their diets in an attempt to improve 
symptoms42,43. Unfortunately, the current evidence base to guide how patients with CD should modify their 
diet is suboptimal, reflecting a disconnect with patients’ demand for high quality data to inform this 
question. This also results in inconsistent messages being transmitted to patients. We recently 
systematically reviewed the recommendations available to patients on the internet44. We reviewed the top 
30 hits on Google and Bing for the search strings “Crohn’s disease diet” and “ulcerative colitis diet”. There 
was enormous variability in the recommendations across the websites. For example, 24% of websites 
said to include any fruit, while 44% said to avoid any fruits. Thus, patients and their physicians face 
substantial uncertainty about the best diet for CD. The purpose of this study is to fill the evidence gap. 
Here we describe existing evidence that supports the need for comparative effectiveness trials of dietary 
interventions. 
 
 
1.5 
Patient-Centeredness (PCORI Methodology Criterion 3) 
 1.5.1 
Generation and prioritization of the research question by patients from the CCFA Partners 
Patient-Powered Research Network (PPRN).  
Prior to launching CCFA Partners, it was apparent in the medical literature that patients with IBD were 
deeply interested in the role of diet. We previously demonstrated that the benefits of therapy outweigh 
the harms for most patients79,80. Yet fear of these risks is a major deterrent to patients considering such 
therapy35. Rather, if given a choice of an equally effective nutritional intervention versus a medical 
therapy, patients with CD overwhelmingly prefer a nutritionally based therapy81. Indeed, and alternative 
medicine (CAM) has been tried by approximately 50% of patients with IBD, with 5-10% using the 
SCD82. Commonly reported reasons for CAM use are to improve symptoms and provide the patient 
with greater control of the disease82. Beyond what can be measured in a structured scientific 
experiment, our patients demonstrated their demand for nutrition-based therapies with their actions. For 
example, in 2014, 3008 patients registered for a CCF produced live webinar on nutrition and IBD and 

 
Page 13 of 81 
 
 
5360 patients viewed the recording of the webinar. Similarly, in 2014, approximately 6400 patients 
visited the Diet Module of the I’ll Be Determined Website (www.ibdetermined.org), representing 27% of 
all visitors to the website.  
 
Once the PPRN was launched, we began to collect research questions proposed by patient members. 
Our interactive patient portal includes a Research section that engages patients in proposing research 
questions, and discussing and voting upon research questions proposed by others. This process of 
crowdsourcing generates a dynamic set of patient-generated research priorities. By a large margin, diet 
was the patient originated study question that generated the greatest support from the PPRN members 
(Table 1). From the first 69 questions proposed and 900 votes cast to endorse questions, two of the 
three most endorsed questions were directly related to diet (combined 211 votes of support) and the 
third question was on the effectiveness of a probiotic formulation, a topic closely related to diet.  
  
Table 1. Questions receiving the most support from PPRN members (from 69 questions proposed and 
900 votes cast). 
 
Question proposed by PPRN patient member 
Votes in support 
We should compare individuals who manage their disease with medications and those who 
manage their disease with popular diets in the IBD community, such as Specific Carbohydrate 
Diet, FODMAP, Paleo, etc. 
131 
Research the validity of VSL#3 probiotic in controlling flare ups or as a factor in remission 
96 
Compare symptoms of IBD patients who consume dairy and those who avoid dairy 
80 
 
With knowledge of this, we reached out to two patient members of the PPRN, both of whom had actively 
discussed and endorsed the question, to solicit further input that would allow our team of scientists to fully 
understand the aspects of this question that were most important to the patients. (Note, the patient who 
proposed the question is a member of the PPRN Patient Governance Council and suggested the inclusion 
of other network members in this proposal.) The patients clarified that both were successfully using diet 
as their primary therapy for their CD but wanted more evidence to guide what is the most effective diet. 
With their help, through a series of conference calls, we finalized the research question. Our jointly 
established research goal is to determine the comparative effectiveness of two commonly used diets by 
patients with CD, the SCD and the MSD. 
 
1.5.2 
This research will focus on outcomes of primary interest to patients with CD  
The proposed research will focus on two primary outcomes, resolution of the symptoms that 
characterize active CD and interfere with daily activities and reduction of bowel inflammation. Each of 
these is important to patients in their own right. Diarrhea, abdominal pain, and decline in overall 
wellbeing are the most common presenting symptoms for patients with CD83,84 (i.e. presence of these 
symptoms overcomes the inertia to ignore one’s health). In our ongoing PCORI-funded study within 
CCFA Partners, we have confirmed that patients with CD have substantial disutility for these symptoms 
of CD. We surveyed 1250 patients with CD with discrete choice experiments (DCEs) using methods of 
conjoint analysis to estimate patients’ utilities for treatment outcomes. Within the DCE, patients were 
asked to choose between two treatment options, each of which was described in terms of the following 
attributes: duration and severity of symptoms (including diarrhea, abdominal pain and general 
wellbeing), duration of use of steroids, and absolute increase in risk of severe infections, cancer, and 
need for bowel resection surgery. Our preliminary analysis demonstrates the strong negative 
preferences that patients have for active CD symptoms and steroid use and that the disutility is strongly 
tied to duration of symptoms (i.e. short periods of mild to moderate symptoms and/or steroid use are 
tolerable while longer periods or severe symptoms are not). We have considered this in designing our 
study, particularly the inclusion criteria and trial duration.  
 
We will also examine resolution of inflammation as measured with a fecal marker, calprotectin (FCP). 
This biomarker is a strong predictor of another outcome of importance to patients – the duration that 
they will remain free of symptoms of CD. It has been repeatedly demonstrated that patients with IBD 
who have an elevated FCP concentration have earlier relapse of disease85. Thus, we will use this 

 
Page 14 of 81 
 
 
biomarker as a surrogate for future disease course. Importantly, we have demonstrated that patients 
highly value time in remission using similar DCE methodology. In this study, patients are willing to 
accept substantial risks of serious infection (approximately 18% per year) or lymphoma (approximately 
0.75% per year) in exchange for 5-years without symptoms86.  
 
Thus, this study will focus on resolution of clinical symptoms and a biomarker that predicts likelihood of 
relapse of the disease, two outcomes confirmed to be of high importance to patients with CD. Of course, 
we will also measure other patient reported outcomes using tools such as Patient Reported Outcome 
Measurement System (PROMIS) measures. 
 
1.6 
Dose Rationale  
Participants will be asked to exclusively eat the diet to which they are assigned for a total of 12 weeks. 
The primary outcome will be assessed at six weeks.  Six weeks was chosen for two main reasons.  We 
felt it was unlikely that patients would stay on a diet for more than 6 weeks if they did not observe a 
benefit.  Additionally, in Breaking the Vicious Cycle, it is stated that one month is sufficient to know if the 
SCD is working42. 
2 
Study Objectives 
This RCT is designed to address the following primary aim and a number of secondary aims which are 
considered exploratory in nature: 
2.2 
Primary Objectives 
1. To compare the effectiveness of the Specific Carbohydrate Diet and a Mediterranean style diet 
to induce symptomatic and clinical remission in patients with Crohn’s disease. 
 
Hypothesis 1. Patients following the SCD will be more likely to experience resolution of 
CD symptoms than patients following a MSD. 
2.  
2.3 
Secondary Objectives 
1. To compare the effectiveness of the Specific Carbohydrate Diet and a Mediterranean style diet 
to reduce mucosal inflammation in patients with active Crohn’s disease. Mucosal inflammation 
will be assessed by measuring the concentration of calprotectin in the feces (FCP). 
2. To compare the effectiveness of the Specific Carbohydrate Diet and a Mediterranean style diet 
to reduce systemic inflammation in patients with active Crohn’s disease. Systemic inflammation 
will be assessed by measuring the concentration of C reactive protein (CRP). 
 
3. To compare the effectiveness of the Specific Carbohydrate Diet and a Mediterranean style diet 
to improve the following symptoms in patients with Crohn’s disease: a) fatigue, b) pain, c) joint 
symptoms. 
4. To determine the proportion of patients who continue the study diets when prepared food is no 
longer provided without cost and the reasons for discontinuation of the diets.   
3 
Investigational Plan  
3.2 
General Design 
This is a randomized, multicenter, comparative effectiveness trial of SCD and MSD to induce remission 
in patients with Crohn’s Disease.  Participants will be screened for eligibility criteria and if eligible, enrolled 
into the trial.  Participants will continue on the diet to which they are randomized for 6 weeks with all food 
being provided to the participant during this time period. Participants will complete brief daily online 
surveys throughout their entire study participation, from consent to week 12. These will be used to 
calculate scores for the Short Crohn’s Disease Activity Index (sCDAI). The primary outcome will be 
assessed at week 6 at an in-person visit.  From weeks 7 to 12 participants will be asked to adhere to their 
randomized study diet on their own.  At week 12 participants will be evaluated at an in-person visit.   

 
Page 15 of 81 
 
 
3.2.1 
Informed Consent and Screening (PCORI Methodology Criterion 3) 
Participants will be identified through review of clinical appointment schedules and chart review or through 
physician referral. Study participants will also be recruited through the CCFA Partners PPRN, an engaged 
and activated cohort of more than 14,000 adult patients with IBD who contribute to research by providing 
patient-generated health data through online surveys and other modalities and have agreed to be 
contacted to participate in additional observational, interventional, and translational studies.73 Once 
identified as potentially eligible based on self-reported symptoms and medication use, we will be able to 
contact these patients to assess their interest in the study and refer them to a participating center in their 
region to undergo screening and enrollment in this study.  
 
No data collection or other study procedures will take place until the participant provides verbal or written 
informed consent to participate in the research study.   
 
The informed consent, screening, and baseline data collection which make up visit 1 can occur on the 
same day or be completed across several days. Participants will be pre-screened for nominal eligibility 
prior to the baseline visit or at the baseline visit. A pre-screening script will be used for determining nominal 
eligibility over the phone prior to the baseline visit.  
 
The following screening and baseline data will be collected: participants’ height, weight and vital signs, 
their medical history, diet history, their symptoms and any medication they may be taking. Their blood will 
be drawn to measure hsCRP and hematocrit levels. At some sites, two additional tubes of blood may be 
drawn for plasma. A physical exam will be done to obtain CDAI score. Participants will collect a stool 
sample no more than 28 days prior to start of the study diet and no more than 28 days after the date of 
initial consent (either in verbal or written form). Female participants will be asked to take a urine pregnancy 
test. Participants’ charts will be reviewed and abstracted to obtain information for eligibility. One 24-hour 
dietary recall will be completed after the screening visit prior to start of the study diet. A dietitian from the 
University of Pennsylvania will contact  the participant to complete this. The participant will complete daily 
online surveys regarding their Crohn’s disease symptoms in order to calculate an sCDAI score. 
Participants will also be instructed about these online surveys they will receive throughout the study and 
when to collect stool samples. 
 
The participant will ship their stool sample to Dr. Gary Wu’s lab at the University of Pennsylvania. Penn 
will send an aliquot of stool to LabCorp to measure FCP. Remaining sample will be aliquoted and stored 
in the biobank managed by the CCF. See section 7.8 Stool Processing for more information.  
 
The participant must complete 5 to 7 days of sCDAI symptom recording (the daily online surveys) before 
randomization and the start of study diet. They should not complete the 5-7 days of sCDAI symptom 
recording more than 14 days prior to start of study diet. Also, the participant must complete 5-7 
consecutive days of sCDAI symptom recording no more than 14 days after nominal eligibility is 
determined.   
 
Medical records may need to be requested for potential participants identified through CCFA Partners 
who are not already a patient at one of the participating clinic sites. Only the medical records necessary 
to determine eligibility should be requested.  The Data Coordinating Center will provide a medical records 
release form for sites to use.    
3.2.2 
Study Intervention Phase  
 
Randomization will occur after eligibility is confirmed AND the baseline stool sample is received at the 
University of Pennsylvania.  
To determine the participant’s randomization, the Site Coordinator must first confirm receipt of the stool 
sample at Penn and then confirm the participant’s eligibility based on Visit 1 data collection and document 
both in the Data Management System (DMS). Upon documentation of both in the DMS, the DMS will 
automatically provide the Site Coordinator with the participant’s assigned diet. 
 
The Site Coordinator will inform the participant of their assigned diet in person or over the phone. 
 

 
Page 16 of 81 
 
 
Participants will be provided instructions about how and when they will receive their study diet meals and 
will be assisted with registering with the vendor that provides the study diet meals. Participants will follow 
the study diet for 6 – 12 weeks. The first 6 weeks the food will be provided from the study meal vendor. 
The second 6 weeks the participant will be responsible for following the study diet on their own.  
 
3.2.3 
Follow-Up Phase 
Participants will receive daily online surveys to complete for up to 16 weeks starting after consent. During 
weeks 1-6 participants will receive all of their meals shipped directly from the food vendor to the 
participant. At week 3 participants will receive an online survey via email or text about their satisfaction 
with the study diet. On Day 42 (+ or – 3 days) participants will come into the clinic for a visit that will 
involve: collection of information about their symptoms which will be used to obtain an sCDAI score, a 
physical exam to obtain CDAI score, one tube of blood drawn to measure hsCRP and one for HCT, 
possibly a third tube of blood drawn for plasma (for applicable sites only), providing information about 
adverse events, medications, joint symptoms, providing health status information (physical, mental and 
social) to obtain a PROMIS score, and being weighed.  They will take a satisfaction survey about the 
study diet. They will collect one stool sample during days 38-40 and will ship it to Dr. Gary Wu’s laboratory 
at the University of Pennsylvania. On a randomly selected day during week 6, participants will be 
interviewed by a dietitian over the phone who will ask them about what they ate on the previous day.   
 
During weeks 7-12, participants will no longer receive prepared meals, but will adhere to their study diet 
on their own. Participants will be given recipes and instructions about how to prepare study diet meals on 
their own. Participants will also receive an online survey about their satisfaction with the study diet during 
week 9. 
 
On Day 84 (+ or – 3 days), participants will come into the clinic for a visit that will involve: collection of 
information about their symptoms which will be used to obtain an sCDAI score, a physical exam to obtain 
CDAI score, one tube of blood drawn to measure hsCRP and one for HCT, providing information about 
adverse events, medications, joint symptoms, providing health status information (physical, mental and 
social) to obtain a PROMIS score and being weighed.  Participants will take a satisfaction survey about 
the study diet online and they will complete a Diet History Questionnaire online.. The participant will collect 
one stool sample during days 80-82 and ship it to Dr. Gary Wu’s lab at the University of Pennsylvania. On 
a randomly selected day during week 12, a dietitian will contact participants by phone to ask them about 
what they ate on the previous day.  Participants complete the study at the end of the week 12 visit. 
 
Site Coordinators may call participants as needed to remind them of their upcoming study visits, sample 
collections, and online surveys.  
3.3 
Allocation to Interventional Group  
Participants who meet all eligibility requirements, provide a baseline stool sample, and complete 5 to 7 
days of sCDAI online surveys, will be randomly assigned to one of the study diets in a 1:1 ratio of 
SCD:MSD. The randomization will be stratified based on whether the participant is currently using a 
biologic therapy for CD. As such, there will be two strata as follows: 
Biologic Therapy 
Yes 
No 
 
 
 
 Randomization will be blocked using variable block sizes ranging from 2 to 4. A study biostatistician at 
the DCC will generate the randomization scheme which will be incorporated into the study data 
management system.  Once the randomization form is completed in the data management system it will 
generate the participants’ study diet assignment. 

 
Page 17 of 81 
 
 
3.4 
Study Endpoints  
3.4.1 
Primary Study Endpoints 
3.4.1.1 
Symptomatic remission  
Symptomatic remission will be assessed at 6 weeks. This is defined by patient reported outcomes (PROs) 
focusing on the cardinal symptoms of CD - diarrhea, abdominal pain, and general wellbeing. These have 
been combined into the Short Crohn’s Disease Activity Index (sCDAI) which provides a composite 
measure of the PROs. Symptomatic remission will be defined as a sCDAI <15074 in the absence of the 
need for increasing corticosteroid dose or initiation of new therapies for CD during the study period. 
Participants who withdraw from the study prior to week 6 will be categorized as failing to achieve 
symptomatic remission and other related outcomes. 
3.4.2 
Secondary Study Endpoints 
3.4.2.1 
Clinical Remission 
As a secondary clinical outcome, we will measure the CDAI at baseline, 6 weeks and 12 weeks. Clinical 
remission will be defined as a CDAI<150 in the absence of the need for increasing corticosteroid dose or 
initiation of new therapies for CD during the study period75.   
3.4.2.2 
 Other patient reported outcome measures 
The same data elements included in the sCDAI have been combined into two item (stool frequency and 
abdominal pain) and three item patient reported outcome measures using the original weights derived 
from the full CDAI. Optimum cut-points for CDAI remission were mean daily stool frequency ≤1.5, 
abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, 
respectively).PRO2 and PRO3 values corresponding to CDAI scores of 150, 220, and 450 points were 8, 
14, and 34 and 13, 22, and 53 respectively, and the corresponding values for CDAI changes of 50, 70, 
and 100 points, were 2, 5, and 8 and 5, 9, and 14, respectively76. We will examine the individual 
components of these PROs to determine the proportion of each group that met the optimum cutpoint for 
remission that met the PRO2 definition of remission. Finally, we will determine the proportion of each 
group with a reduction in the PR02 and PRO3 that corresponds to 100 point reduction in the CDAI. 
 
The Patient Reported Outcome Measurement System (PROMIS) questionnaire contains several 
measures previously shown to correlate with disease activity and to have construct validity in CD27.  These 
include measures of fatigue, pain interference, social aspects, and sleep. See appendix H for a copy of 
this survey. 
 
A subset of core variables found in the Multi-dimensional Health Assessment Questionnaire (MD-HAQ) 
will be used to assess physical function and joint pain77,78, as well as RADAI Arthritis screening questions. 
See appendix I for a copy of these surveys 
 
We will screen for inflammatory back pain using criteria developed by Sieper et al79. and assess symptom 
severity with the Bath AS Functional index80 in those who screen positive. See appendix J for a copy of 
these criteria. 
3.5 
Primary Safety Endpoints [if applicable] 
Not applicable. 
4 
Study Population and Duration of Participation  
4.1 
Inclusion Criteria 
1. Age ≥18 
2. Documented diagnosis of Crohn’s disease 
3. sCDAI score  >175  
4. Documentation of receipt of a baseline stool sample by the data coordinating center and 
hsCRP.  

 
Page 18 of 81 
 
 
5. Access to a computer with internet and the ability to complete daily online surveys 
6. Capable of providing consent to participate 
7. Able to receive weekly food shipments delivered every Friday for 6 weeks 
4.2 
Exclusion Criteria 
1. Pregnancy 
2. sCDAI >400 
3. Hospitalized patients  
4. Anticipated need for surgery within 6 weeks of randomization 
5. Use of the Specific Carbohydrate Diet within 4 weeks of screening 
6. Start or change*** dose of thiopurines (azathioprine and 6-MP), methotrexate, natalizumab, or 
vedolizumab within 12 weeks prior to screening  
7. Start or change*** dose of anti-TNF agents (including infliximab (Remicade), adalimumab 
(Humira), certolizumab pegol (Cimzia), golimumab (Simponi) or ustekinumab within 8 weeks 
prior to screening. 
8. Start or change in dose of any 5-ASA medications within 2 weeks of screening.  
9. Start or change dose of corticosteroids within 1 week of screening or a dose >20mg/day 
prednisone or equivalent* 
10. Use of antibiotics (other than topical formulations) for any reason within 2 weeks prior to 
screening 
11. Known symptomatic intestinal stricture. 
12. Presence of an ostomy 
13. Baseline stool frequency >4 bowel movements/day when well 
14. BMI <16  
15. BMI ≥40 
16. Celiac disease 
17. Documented C difficile colitis within four weeks of screening 
18. Diabetes Mellitus requiring medication 
19. Albumin<2.0mg/dl, within 4 weeks of screening (if tested as part of routine clinical care) 
20. Known allergy to tree nuts or peanuts  
21. Other conditions that would be a contraindication to any of the study diets or preclude the 
participant from completing the study. 
22. Currently participating in another clinical trial of a drug to treat IBD or a dietary therapy for any 
indication. 
 
*Patients may continue these medications at stable dose for the first six weeks and budesonide may be 
used at any dose. After the 6th week in the study, patients may taper their steroid dose. The study will 
provide a recommended taper schedule. 
**Loading/induction doses of biologic type medication will be considered a stable doses.  
***Exception for treatment failures: if a subject is determined to fail on any of the following standard lines 
of treatment at the treating investigator’s discretion, subjects may screen for study intervention based 
upon the following wash out periods: 4 weeks for thiopurine and methotrexate and 8 weeks for 
natalizumab, vedolizumab, anti-TNF, or ustekinumab. 
 
4.3 
Participant Recruitment  
Participants will be recruited at multiple centers around the U.S. Participants will be identified by reviewing 
clinic schedules each week and reviewing charts of likely eligible patients. Patients may be approached 
via telephone or when they come to the clinic for a clinical visit.  Participants may agree to consent at the 
time of their clinic visit or may return to the clinic on another day to be consented. In some cases, a verbal 
consent via telephone may be done prior to an in-person visit where a full in-person consent process will 
be completed. Participants may also be recruited through CCFA Partners and referred to a participating 
clinic. 
4.4 
Duration of Study Participation 
Participation in the study will last a minimum of 13 weeks from the time participants consent and are 
screened, for those who complete the study protocol.  Adherence to the study diet will take place for up 

 
Page 19 of 81 
 
 
to 12 weeks. Participation may last up to 16 weeks if the maximum time between screening and 
randomization is allowed.  
4.5 
Total Number of Subjects and Sites  
It is expected that 230 participants will need to be enrolled (defined as having provided informed consent 
to participate in this research study) to achieve a final sample size of 194 participants.  Recruitment will 
end when approximately 194 participants have been randomized.   
4.6 
Vulnerable Populations 
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study.  
5 
Study Intervention 
5.1 
Description 
The study intervention is the Specific Carbohydrate diet (SCD).  The study diet is based on the detailed 
descriptions of allowable food in the book Breaking the Vicious Cycle42, by Elaine Gottschall. We will use 
this list of allowed foods to create the menu of food items for the participants randomized to receive the 
SCD. The SCD restricts all but simple carbohydrates. The only carbohydrates permitted are 
monosaccharides: glucose, fructose, and galactose. Fresh fruits and vegetables are universally 
acceptable with the exception of potatoes and yams. Certain legumes (i.e. lentils, split peas) are 
permitted, however others (i.e. chickpeas, soybeans) are not. No grains are permitted in the SCD. 
Saccharin and honey are permitted in addition to moderate use of sorbitol and xylitol. Canned fruits and 
vegetables are not permitted due to possible added sugars and starches. Unprocessed meats are 
permitted in the SCD without limitation. However processed, canned, and most smoked meats are 
restricted due to possible sugars and starches used in additives. Milk is not permitted in the SCD due to 
lactose content. However, certain lactose free cheeses are permitted as is homemade lactose-free yogurt. 
 
The control diet is a Mediterranean Style Diet. This is a well-balanced diet that is consistent with the 
United States Department of Agriculture and World Health Organization recommendations. The MSD 
entails higher fiber intake and appreciably lower red meat intake than the average American diet. It 
involves a high intake of olive oil, fruit, nuts, vegetables, and cereals; a moderate intake of legumes, 
fish, seafood, and poultry; a low intake of dairy products, red meat, processed meats, and sweets; and 
wine in moderation, consumed with meals.29 Red and processed meats, soda drinks, bakery goods, 
sweets, pastries, and spreadable fats are not permitted on this diet. Wine is allowed only with meals and 
no more than two 5 oz. glasses per day.69 
5.2 
Intervention Regimen 
Participants will be provided with fully prepared meals from Healthy Chef Creations (HCC) totaling a 
minimum of 2500 calories. Participants do not have to eat all of the food provided. Beverages will not be 
provided, but participants will be provided with a list of recommended beverages. Participants will receive 
these meals for six weeks. Some of the meals will require heating.  
 
During weeks 7 through 12 participants will be asked to adhere to their randomized diet by preparing their 
own meals and snacks or by purchasing the meals from HCC. Participants will be provided with detailed 
instructions and recipes for preparing their food. 
5.3 
Receipt  
Participants will receive shipments of food to their home (or another location, if desired) each week via 
tracked courier from HCC. Shipments will occur on Fridays. These shipments will contain breakfast, lunch, 
dinner and two snacks for each day of the week.  The food will be delivered fresh (not frozen) with 
sufficient ice packs to remain on a door step until later that evening. Each shipment will contain instructions 
on how to reheat the meal (if needed), whether or not the meal can be frozen and how long the meal can 
be kept under refrigeration before consumed.  Additionally, each shipment will contain contact information 
for customer service representatives of HCC. The representatives can be contacted for any questions 
about the food, its ingredients, preparation instructions etc. 

 
Page 20 of 81 
 
 
5.4 
Storage 
Each meal or snack will be labeled with the storage requirements for that meal (freeze, refrigerate, keep 
at room temperature). Proper preparation with regard to reheating will also be included on a label on each 
meal/snack. 
5.5 
Preparation and Packaging 
All of the meals and snacks for this study will be prepared by HCC in a single kitchen.  All participants, 
regardless of the clinical center from which they were recruited, will receive their meals from HCC directly 
to their homes via tracked courier. Food will arrive in a cardboard box with the food inside surrounded by 
freezer packs. The box will have a label reading “Perishable.” 
5.6 
Administration and Accountability    
HCC will provide a monthly report detailing all of the food deliveries including the date they were delivered 
and to whom. This report will include information on whether additional meals needed to be delivered to 
replace damaged shipments or shipments not received. 
5.7 
Subject Compliance Monitoring 
Adherence to the assigned diet will be assessed using three 24-hour dietary recalls administered by 
trained dietitians on randomly selected days.  This assessment will occur once between screening and 
start of study diet, once during week 6 and once during week 12. We will also have participants complete 
a diet history questionnaire (DHQ) at baseline and week 12. The DHQ asks about food eaten in the past 
30 days. Therefore, the week 12 DHQ will be used in addition to the 24 hour dietary recall to assess 
adherence to the assigned diet. 
5.7.1 
Return or Destruction of Investigational Product  
Participants will be allowed to keep all meals that are delivered to their homes.  If meals are past their 
expiration date or if they are unwanted by the participant, the participant will be responsible for disposing 
of the meals. 
 
 
 
 
 
6 
Study Procedures 
6.1 
 
 
 
 
 
 
Study diet provided 
Weeks 1-6 
Self-adherence to 
diet, food not 
provided Weeks 7-12 
Week 
-28 to -1 
0 
1-5 
6 
7-11 
12 
Visit 
1 
 
 
2 
 
3 
 
In-Person 
In-
Person 
Or 
Phone 
Online 
In-
Person 
Online 
In-
Person 
Informed Consent 
X 
X* 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Diet History 
Questionnaire 
*** 
 
 
 
 
X 
Urine Pregnancy 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 

 
Page 21 of 81 
 
 
sCDAI (symptoms 
collected daily 
throughout study)  
X*** 
 
X  
X 
X  
X 
CDAI 
X 
 
 
X 
 
X 
Physical Exam  
X 
 
 
X 
 
X 
Stool Collection 
X 
 
 
X 
 
X 
Fecal Calprotectin 
X 
 
 
X 
 
X 
Blood draw for hsCRP, 
HCT  
X 
 
 
X 
 
X 
Blood draw for plasma** 
X 
 
 
X 
 
 
PROMIS measures 
X 
 
 
X 
 
X 
Joint symptoms 
X 
 
 
X 
 
X 
Adverse events 
X 
 
 
X 
 
X 
Medications 
X 
 
 
X 
 
X 
One dietary recall (over 
the phone) 
X 
 
 
X 
 
X 
Satisfaction with diet 
 
 
X (week 3) 
X 
X (week 9) 
X 
Weight 
X 
 
 
X 
 
X 
Height 
X 
 
 
 
 
 
Vitals 
X 
 
 
 
 
 
*Verbal informed consent may be obtained to allow for some screening steps to begin prior to the in 
person visit. Written informed consent must still be obtained at the in person screening visit. 
 
**Plasma collection may not apply to all clinic sites.  
 
*** These measures will be completed online prior to the first visit.  
 
6.2 
Study Intervention Phase and Follow Up Phase 
6.2.1 
Recruitment and Pre-Screening 
Site Coordinators and/or Investigators will identify potential participants via review of their medical 
record. The Site Coordinator (SC) may contact the participant either in person or over the phone 
to discuss the study, complete a verbal or in-person informed consent, and ask and record pre-
screening questions to determine nominal eligibility. No data will be recorded without at least 
verbal consent. The SC will immediately enter the pre-screening information, including the 
participant’s contact information and mailing information, into the study data management system 
(DMS). The Site Coordinator will either complete the screening visit (Visit 1) at that time if the 
consent was done in person or will schedule a screening visit for a later date (if initial contact and 
consent was over the phone). 
 
The DMS will automatically alert the Data Coordinating Center (DCC) of the new nominally eligible 
participant and will ship one stool collection kit to their home for the baseline stool sample 
collection.  The database will begin automatically emailing or texting the daily sCDAI surveys to 
the participant.  
6.2.2 
Visit 1 
The informed consent, screening, and baseline data collection which make up visit 1 can occur on the 
same day or be completed across several days.  

 
Page 22 of 81 
 
 
 
At Visit 1 the Site Coordinator and/or Site Investigator must collect the following: 
 
 
Informed Consent (if not done so already) 
 
Medical History 
 
Urine Pregnancy 
 
Diet History Questionnaire (see below for more information) 
 
24-hour dietary recall (see below for more information) 
 
Medications 
 
Joint Symptoms 
 
PROMIS Measures  
 
Physical Exam 
 
Vitals 
 
Height and weight 
 
Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) 
 
CDAI 
 
sCDAI (see below for more information) 
 
Adverse Events 
 
Blood draw to measure hsCRP, hematocrit, and to collect plasma (see below for more 
information)  
 
Stool Collection (see below and section 7.8 for more information) 
 
Provide study instructions  
 
 
sCDAI: A minimum of 5 and maximum of 7 days of patient reported symptoms will be required to 
compute the sCDAI to determine eligibility. The participant will accomplish this via daily online surveys 
sent to the participant after at least a verbal consent is obtained. The sCDAI is computed using the 
following equation where L is the number of liquid or very soft stools, A is the rating of abdominal pain (0-
3, none to severe), W is the rating of general wellbeing (0-4, generally well to terrible), n is the day of 
follow-up, and d is the number of days of data used to compute the sCDAI82. 
𝑠𝐶𝐷𝐴𝐼= 44 + 7
𝑑∗((2 ∗∑𝐿
𝑑
𝑛=1
) + (5 ∗∑𝐴
𝑑
𝑛=1
) + (7 ∗∑𝑊
𝑑
𝑛=1
)) 
Stool Collection: The participant must collect a stool sample no more than 28 days from the date 
the participant will start the study diet and no more than 28 days after the initial form of consent. 
Participants at the University of Pennsylvania may bring the sample with them to visit 1. All other 
participants must ship the sample to the University of Pennsylvania in materials the DCC ships to the 
participant’s home. See section 7.8 Stool Processing for more information. 
 
Diet History Questionnaire (DHQ): The participant will complete an online Diet History 
Questionnaire at home prior or immediately following the visit in the clinic. Alternatively, the participant 
may complete it at their visit if a computer with internet is available. It will take approximately 30 minutes 
to complete. The DMS will email the participant the link to the questionnaire as well as their username 
and password to access the questionnaire. 
 
24-hr Dietary Recall: A dietitian from the University of Pennsylvania will call the participant at 
home to ask them what they ate the day before. This should be completed on a random day between 
screening and the start of study diet.  
 
FCP: Upon receipt of the stool sample, laboratory staff at the University of Pennsylvania will send 
a small amount of the sample to LabCorp for a baseline measurement of FCP.  LabCorp will report the 
results to the Data Coordinating Center (Penn). 
 
Blood draw: one tube of blood will be drawn for measuring hsCRP and one for hematocrit. Two 
additional tubes may be drawn for plasma collection. Blood tubes and other collection materials will be 

 
Page 23 of 81 
 
 
provided to the sites. After blood is drawn, the Site Coordinator will spin the tubes of blood in a centrifuge 
using instructions provided from the Data Coordinating Center. They will package the spun tubes in 
materials provided and will place the blood sample for hsCRP and hematocrit in a LabCorp lockbox at 
their site. If the site does not currently have a LabCorp lockbox, LabCorp will install one. The Site 
Coordinator must contact LabCorp to inform them there is a sample for them to pick up. A LabCorp driver 
will pick up the sample. The blood samples for plasma will be stored at the site in a -80° C freezer and 
shipped in batch to Biostorage at the end of the study. See the Manual of Procedures for processing 
instructions for plasma. 
 
Steroid Equivalency chart:  
Cortisone 
25mg 
Hydrocortisone 
20mg 
Prednisone or Prednisolone  
5mg 
Methyl prednisone  
4mg 
Dexamethasone  
0.75mg 
  
 
Randomization will occur after eligibility is confirmed and a stool sample is receieved..  
To determine the participant’s randomization, the Site Coordinator must first confirm receipt of the stool 
sample at Penn and then confirm the participant’s eligibility based on Visit 1 data collection and document 
both in the Data Management System (DMS). Upon documentation of both in the DMS, the DMS will 
automatically provide the Site Coordinator with the participant’s randomization. 
 
The Site Coordinator will inform the participant of their randomized diet in person or over the phone. 
 
The DCC will be alerted to the participant’s eligibility and randomization, after which they will ship two 
more stool collection kits to the participant’s home for the remainder of the study. 
6.2.3 
Visit 2 (week 6 visit) 
The following will be conducted at Visit 2 (week 6): 
 
24-hour dietary recall (see below for more info) 
 
Medications 
 
Joint Symptoms 
 
PROMIS Measures  
 
Physical Exam 
 
Weight 
 
CDAI 
 
SIBDQ 
 
sCDAI (same as for visit 1) 
 
Adverse Events 
 
Blood draw to measure hsCRP, hematocrit, and to collect plasma  
 
Stool Collection  
 
Online Diet Satisfaction Survey (completed at home) 
 
FCP: same as for visit 1 
 
24-hr Dietary Recall: A dietitian from the University of Pennsylvania will call the participant at home to ask 
them what they ate the day before. This should be completed on a random day during week 6. 
 
Blood draw: Blood draw: one tube of blood will be drawn for measuring hsCRP and one drawn for 
hematocrit. One additional tube may be drawn for plasma. The samples will be processed in the same 
manner as in Visit 1.  
 
Stool collection: participants must collect one stool sample during days 38-40.  

 
Page 24 of 81 
 
 
 
Recommended Steroid Taper after week 6: participants who are on steroids may taper after week 6. The 
following tapering schedule is to be used but can be modified by the treating physician in response to 
symptoms or in the case of special circumstances (e.g. a slower taper may be used for patients with a 
history of long-term steroid use): 
20mg/day for one week  15mg/day for one week  10 mg/day for one week  5 mg/day for 
one week  2.5 mg/day for one week  off  
 
 
6.2.4 
Visit 3 (week 12 visit) 
The following will be conducted at Visit 3 (week 12): 
 
Diet History Questionnaire (same as for visit 1) 
 
24-hour dietary recall (see below for more info) 
 
Medications 
 
Joint Symptoms 
 
PROMIS Measures  
 
Physical Exam 
 
Weight 
 
CDAI 
 
SIBDQ 
 
sCDAI (same as for visit 1) 
 
Adverse Events 
 
Blood draw to measure hsCRP and hematocrit Stool Collection  
 
Online Diet Satisfaction Survey (completed at home) 
 
FCP: same as for visit 1 
 
24-hr Dietary Recall: A dietitian from the University of Pennsylvania will call the participant at home to ask 
them what they ate the day before. This should be completed on a random day during week 12. 
 
Stool Collection: participants must collect one stool sample during days 80-82. 
6.2.5 
End of Study Visit 
The end of study visit will take place at week 12 or at the visit where the participant withdraws or is 
withdrawn from the study.  This visit will include a physical exam to obtain CDAI score. An sCDAI score 
will also be calculated. Participants will be asked to collect a stool sample at home and ship it to Penn. 
Stool will be shipped from Penn to LabCorp to obtain an FCP result. Participants will be asked to complete 
a DHQ, SIBDQ,a 24-hour dietary recall, and provide information about adverse events, medications, joint 
symptoms and provide health status information (physical, mental and social) to obtain a PROMIS score.  
Participants will also be weighed and have their blood drawn to measure hsCRP and hematocrit. 
6.3 
Rescue Therapy [if applicable] 
Participants will remain under the care of their treating gastroenterologist while in the study.  If their 
symptoms worsen, participants will contact their treating gastroenterologist and follow any 
recommendations with regard to changes in therapy for their Crohn’s disease.  Participants whose 
worsening symptoms require a change in the current treatment for Crohn’s disease will be considered 
study treatment failures and will be withdrawn from the study. See Section 6.5 for subject withdrawal 
information. 
6.4 
Unscheduled Visits 
Unscheduled visits could potentially occur if a participant experiences an Adverse Event that requires 
medical evaluation.  

 
Page 25 of 81 
 
 
6.5 
Subject Withdrawal  
Participants may withdraw from the study at any time.   
 
Participants may be withdrawn at the discretion of the investigator prior to randomization for the following 
reasons: 
.  
 
Failure to provide the baseline stool sample 
 
Failure to complete at least 5 of the 7 baseline sCDAI surveys 
 
 
Participants will be withdrawn from the study if they experience worsening symptoms requiring a change 
in their Crohn’s disease treatment,the initiation of an antibiotic for gastrointestinal symptoms, and/or an 
increases of greater than 10mg/day of prednisone or equivalent for a non-gastrointestinal condition*.  
*Please see section 6.2.2 for equivalency chart  
 
Participants who have been randomized to one of the two diets and withdraw early from the study should 
complete an end of study visit and provide a stool sample at the time of withdrawal as described in section 
6.2.5.  
 
If the participant wishes to discontinue the study diet early for reasons not related to worsening Crohn’s 
Disease (e.g., they don’t like the diet), they will be asked to remain in follow-up and complete the next in-
person visit at the target date of that visit (either week 6 or week 12). This will be the end of study visit. 
 
7 
Study Evaluations and Measurements  
7.1 
Medical History 
The following information may be obtained from a combination of the participant’s medical charts and/or 
self-report: 
 
Medical and surgical history 
 
Crohn’s disease history 
 
Medication use 
 
Hospitalizations 
 
Laboratory test results – albumin and C. difficile colitis 
7.2 
Demographic information 
Gender, date of birth and race will be collected from each participant. Medication use will be collected at 
each visit.    
7.3 
Current Symptoms 
Participants’ current symptoms, both Crohn’s disease-related and otherwise, will be collected at each 
visit. Crohn’s symptoms will also be collected through daily online surveys. Patient reported outcomes 
using PROMIS and other measures will be assessed at each visit. 
7.4 
Concomitant Medication 
Medication use will be collected at each visit. Participants will be permitted to taper their steroid dose after 
week 6 following the recommended tapering schedule in section 6.2.4. 
7.5 
Vital Signs 
Participants will be weighed on a scale in the clinic at each visit. Participant’s height will be measured at 
Visit 1 using a stadiometer. Participants’ seated temperature, heart rate, and blood pressure will be 
measured at Visit 1.  

 
Page 26 of 81 
 
 
7.6 
Laboratory Evaluations 
Fecal Calprotectin - This biomarker is a strong predictor of an outcome of importance to patients, the 
duration that they will remain free of symptoms of CD. It has been repeatedly demonstrated that patients 
with IBD who have an elevated FCP concentration have earlier relapse of disease83. Thus, we will use 
this biomarker as a surrogate for future disease course. FCP assays will be completed by LabCorp at 
baseline, 6 weeks, and 12 weeks.  
The DCC will provide the Site Investigators with their participants’ FCP results from LabCorp after all of 
the participants have completed the last study visit upon request.  
 
High Sensitivity C-Reactive Protein (hsCRP) – this is a biomarker in the blood that is a measure of 
inflammation in the body. Participants will have their blood drawn at baseline, week 6, and week 12. The 
Site Coordinator will spin the blood according to lab instructions, place the blood sample in the LabCorp 
lockbox at their site and inform LabCorp via phone of the blood sample. LabCorp will then pick up the 
sample for transport to their laboratory. Coordinators will be provided with detailed instructions for this. 
 
Hematocrit will be measured by LabCorp at each visit as part of calculating a Crohn’s Disease Activity 
Index (CDAI) score. 
7.7 
Plasma Collection 
Two tubes (4 tsp) of blood will be drawn and centrifuged at baseline and week 6 for plasma separation 
and collection. . The plasma samples will be stored for future research use related to this study and other 
relevant health related questions. Possible use of the plasma samples include testing for serological 
markers or metabolites. Further blood sample processing, storage, and shipping information for the local 
sites can be found in the DINE-CD Study Manual of Procedures.  
7.8 
Pregnancy Testing 
Female participants will take a urine pregnancy test at screening if they have not yet reached menopause 
or if they have not had a hysterectomy. 
7.9 
Stool Sample Collection 
Stool samples will be collected on the days described above in sections 3.2.1 and 3.2.3. We will ask 
participants to categorize their samples on the Bristol Stool Chart scale. Stool collection kits, including 
pre-paid shipping labels, will be prepared by the DCC in advance and shipped to the participant (or given 
in person for participants at the University of Pennsylvania). Participants should collect a baseline sample 
within 28 days prior to the start of study diet and no more than 28 days from the initial form of consent. 
Participants should collect a sample for visit 6 during days 38-40 and for week 12 during days 80-82. They 
will ship the samples  to Dr. Gary Wu’s lab at the University of Pennsylvania. Shipping will be pre-paid by 
the Data Coordinating Center. 
 
7.10 Sample preparation, processing, and storage 
Stool sample collection kits will be prepared at the DCC and sent directly to the participants’ homes from 
the DCC. Participants will collect their samples at home, put a sample amount of stool into one 10 ml 
Sarstedt spoon-top vial with 5mL of 100% ethanol, and ship back the ethanol aliquot and remaining 
sample to the DCC. At all visits the lab will also aliquot some sample into a container provided from 
LabCorp labeled with participant ID and Date of Birth and send to LabCorp for FCP testing. Remaining 
de-identifiied sample labeled with the unique study ID number will be aliquoted into 4 empty 10mL 
Sarstedt spoon-top vials and one stock tube. The four frozen aliquots, one ethanol aliquot and one stock 
tube will be  stored in a -80°C freezer. Once the lab has enough to create a batch shipment, they will ship 
aliquots in batch to Biostorage Technologies, a biobank who contracts with CCF to store CCF study 
samples. Samples from this study will be stored there for later use. 
 
Four tubes of blood will be collected at baseline, three tubes will be drawn at week 6, and two tubes will 
be drawn week 12. All will be centrifuged according to instructions from the DCC. Two tubes will be 
packaged and placed in the site’s LabCorp lock box for pick-up by LabCorp staff (applicable at all visits). 
These sample will be tested by LabCorp for hsCRP and HCT. The third and fourth tubes at baseline and 

 
Page 27 of 81 
 
 
week 6 will be for plasma separation. Plasma will be aliquoted and frozen within one hour of collection in 
a -80°C freezer at the site. Plasma samples will be stored locally in a -80 freezer and shipped in batch to 
Biostorage at the end of the study. Processing, storage, and shipping instructions can be found in the 
DINE-CD Manual of Operating Procedures. 
7.11 Other Evaluations, Measures 
24-hour dietary recalls will be used to assure adherence with the study diet.  A trained dietitian will 
administer a phone interview to determine what participants have eaten on the randomly selected days 
(described above in Section 3.2.3).   
 
An online, confidential, Diet History Questionnaire (DHQ) will be used to assure adherence with the study 
diet and will be completed at baseline and week 12. Patients will complete the online questionnaire at 
home immediately prior to or immediately following their baseline and week 12 visit. Alternatively, they 
may be able to complete it in the clinic if a computer with internet access is available. We will use the 
National Cancer Institute’s web-based DHQ II questionnaire that asks about food eaten in the past 30 
days. There is no patient identifying information in the DHQ. Patients log into the questionnaire with a 
unique code and password. The DCC will download an Excel file containing study participants’ 
questionnaire responses from a secure https website accessible only by certain study staff at the DCC.  
 
Study diet satisfaction surveys will be administered via an online questionnaire at the time points 
described in section 3.2.3. This will be a brief survey that will allow for free text comments from participants 
about their satisfaction and overall experience with the assigned diet. 
 
The Patient Reported Outcome Measurement System (PROMIS) questionnaire contains several 
measures previously shown to correlate with disease activity and to have construct validity in CD27.  These 
include measures of fatigue, pain interference, social aspects, and sleep.  
 
A subset of core variables found in the Multi-dimensional Health Assessment Questionnaire (MD-HAQ) 
will be used to assess physical function and joint pain77,78.  
 
We will screen for inflammatory back pain using criteria developed by Sieper et al.79 and assess symptom 
severity with the Bath AS Functional index80 in those who screen positive. 
 
We will assess quality of life using a Short Quality of Life in Inflammatory Bowel Disease Questionnaire 
(SIBDQ) at all visits.  
 
Patient’s most recent colonoscopy results prior to the time of randomization will also be collected for those 
subjects with accessible records. Additionally, any colonoscopies conducted during the study or within 6 
weeks of the termination visit may be requested at the opinion of the Principle Investigator.  
 
7.12 Efficacy Evaluations 
Crohn’s Disease Activity Index(CDAI), PRO2 and PRO3 measures85, and Short Crohn’s Disease Activity 
Index (sCDAI)74 will be used to determine if participants’ symptoms have improved or worsened with the 
intervention. The sCDAI assesses clinical remission as defined by patient reported outcomes focusing on 
the cardinal symptoms of CD - diarrhea, abdominal pain, and general wellbeing. The CDAI uses patient 
reported measures, similar to the sCDAI, but also uses findings from a physical exam and laboratory 
measures.   
 
8 
Statistical Plan 
8.1 
Primary Endpoint 
The primary outcome will be measured at 6 weeks after the start of the study diets. Specific aim 1 will 
focus on the outcomes that are most important to patients, specifically the control of the cardinal 
symptoms of CD. We will assess clinical remission as defined by patient reported outcomes (PROs) 
focusing on the cardinal symptoms of CD - diarrhea, abdominal pain, and general wellbeing. These have 

 
Page 28 of 81 
 
 
been combined into the Short Crohn’s Disease Activity Index (sCDAI) which provides a composite 
measure of the PROs. Symptomatic remission will be defined as a sCDAI <15074 in the absence of the 
need for increasing corticosteroid dose or initiation of new therapies for CD during the study period. 
Participants who withdraw from the study prior to week 6 will be categorized as failing to achieve 
symptomatic remission and other related outcomes.  
 
The sCDAI was derived from the Crohn’s Disease Activity Index86 , the standard disease activity index for 
CD clinical trials in adults for the last several decades87. The original index includes the number of liquid 
stools per day, abdominal pain, general wellbeing, extraintestinal complications of CD, use of Lomotil or 
opiates for diarrhea, anemia, weight loss, and the presence of an abdominal mass on physical exam. The 
CDAI has increasingly fallen out of favor as it combines PROs with physical exam, medication use, and 
laboratory data88. As such, investigators validated the sCDAI which patients can complete using a simple 
web-based survey tool without an office visit or blood draw74,82. The sCDAI uses the same scale as the 
full CDAI, such that scores <150 define remission, 150-219 mild activity, 220-450 moderate activity, >450 
severe activity. The correlation between the full CDAI and sCDAI for baseline scores and score change 
was 0.90 and 0.96, respectively74. Our research team has subsequently demonstrated that the sCDAI 
can be accurately measured with less than 7 days of data, thereby reducing participant burden82 (IR-1). 
Indeed, we have utilized this abbreviated version of the sCDAI as part of the CCFA Partners PPRN since 
its inception and in our ongoing RCT of a high vs. low red meat diet for patients with quiescent CD that is 
being conducted within the CCFA Partners PPRN. 
 
 
The primary outcome will be measured at 6 weeks. The 6 week study duration was selected for the 
following reasons:  
a. Our stakeholders informed us that they would be unlikely to continue trying a dietary therapy if 
they did not observe a benefit within 6 weeks. 
b. In Breaking the Vicious Cycle, it is stated that one month is sufficient to know if the SCD is 
working. 
c. The practical implications of not allowing changes to the medical therapy for patients with active 
CD for much longer than 6 weeks could be a major disincentive to enrollment. 
8.2 
Secondary Endpoints  
Markers of inflammation 
We will compare the proportion of patients who achieve reduction in FCP to less than 250ug/g and by 
greater than 50% from baseline. Fecal concentration of calprotectin, a calcium binding protein found in 
neutrophilic granulocytes, will be measured by LabCorp. FCP concentration is correlated with endoscopic 
findings of mucosal inflammation and decreases following initiation of medications in active CD90,91. There 
is no single standard to define mucosal healing with FCP92-94; a recent meta-analysis identified 250 µg/g 
as the optimal cut point for endoscopically defined inflammation among patient with IBD95,96.  There are a 
number of important reasons to measure FCP in this study. From the patient’s perspective, FCP predicts 
the risk of recurrence of symptoms for those who have achieved clinical remission through medical or 
surgical therapy90,97,98.  Equally as important, to achieve optimal adoption of dietary strategies into the 
management of CD will require convincing treating physicians of the effectiveness of the diet. Increasingly, 
physicians are demanding evidence that CD treatments improve inflammation in addition to symptoms88. 
Thus, FCP is a biomarker that predicts an important outcome for patients and for physicians it can be 
used to document reduction in mucosal inflammation.   
We will use hsCRP as a marker of systemic inflammation. We can compare the proportion of patients 
who have hsCRP below the upper limit of normal and mean levels of hsCRP as outcome measures.  
Secondary clinical outcomes and combined outcomes 
As a secondary outcome, we will assess the proportion of patients achieving combined clinical remission 
and reduction in FCP using the same criteria described above.  
 
As a secondary clinical outcome, we will measure the Crohn’s Disease Activity Index (CDAI) at baseline, 
6 weeks and 12 weeks. Clinical remission will be defined as a CDAI<150 in the absence of the need for 
increasing corticosteroid dose or initiation of new therapies for CD during the study period. 
 

 
Page 29 of 81 
 
 
The same data elements included in the sCDAI have been combined into two item (stool frequency and 
abdominal pain) and three item patient reported outcome measures using the original weights derived 
from the full CDAI referred to as PRO2 and PRO376. Optimum cut-points for CDAI remission were mean 
daily stool frequency ≤1.5, abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC 
curve 0.79, 0.91 and 0.89, respectively).PRO2 and PRO3 values corresponding to CDAI scores of 150, 
220, and 450 points were 8, 14, and 34 and 13, 22, and 53 respectively, and the corresponding values 
for CDAI changes of 50, 70, and 100 points, were 2, 5, and 8 and 5, 9, and 14, respectively76. We will 
examine the individual components of these PROs to determine the proportion of each group that met the 
optimum cutpoint for remission that met the PRO2 definition of remission. Finally, we will determine the 
proportion of each group with a reduction in the PR02 and PRO3 that corresponds to 100 point reduction 
in the CDAI. 
 
The Patient Reported Outcome Measurement System (PROMIS) questionnaire contains several 
measures previously shown to correlate with disease activity and to have construct validity in CD27.  These 
include measures of fatigue, pain interference, social aspects, and sleep. 
 
A subset of core variables found in the Multi-dimensional Health Assessment Questionnaire (MD-HAQ) 
will be used to assess physical function and joint pain77,78 as well as a RADAI Arthritis screening 
questionnaire. 
 
We will screen for inflammatory back pain using criteria developed by Sieper et al.79 and assess symptom 
severity with the Bath AS Functional index80 in those who screen positive. 
 
8.3 
Sample Size and Power Determination 
The study is designed to enroll 97 patients into each of the treatment arms. With 97 participants per group, 
the study will have 80% to 90% power with a type 1 error of 5% to detect a difference of 20% in 
effectiveness of the two diets depending on the success rate in the reference arm. Our PPRN Patient 
Governance Council met and determined that a smaller difference is unlikely to justify the challenges of 
following a strict restriction diet. 
8.4 
Statistical Methods 
A formal data analysis plan will be prepared as a separate document. The following sections summarize 
the planned analyses. 
8.4.1 
Baseline Data 
The initial analyses will utilize descriptive statistics to define the characteristics of the study cohort. 
Continuous variables will be described as medians and interquartile ranges. Categorical variables will be 
defined as proportions. Formal statistical comparisons of these descriptive variables will be performed 
comparing the two arms of the study using the Wilcoxon rank sum test for continuous variables and the 
chi squared or Fisher’s exact test for categorical variables 99. Because any unbalance in the two groups 
is by definition a chance occurrence, these analyses will be used to highlight areas of substantial 
unbalance between the study arms.  
 
8.4.2 
Efficacy Analysis  
Analysis of the primary outcome: The primary analyses for the RCT will use 2-sided tests of statistical 
significance and will be performed using the intention-to-treat principle.100 Thus, patients will be classified 
according to the study arm that they were assigned, regardless of the amount of food from the assigned 
diet consumed. The primary analysis will compare the proportion of patients who achieve a symptomatic 
remission (aim 1) at week 6 using the Cochran-Mantel-Haenszel (CMH) chi square test, which is 
equivalent to the score test derived from the conditional logistic regression. 99 All patients who are 
withdrawn or lost to follow-up prior to week 6 will be considered treatment failures.  The MSD will be 
considered the reference group for all analyses. Although randomization should minimize unbalance 
between the groups, it is still possible that unbalance may occur. As such, we will use stratified analyses 
and logistic regression analysis to adjust for potential unbalance between the two groups as observed in 

 
Page 30 of 81 
 
 
the descriptive analyses.101 Age, sex, smoking status, duration of CD, presence of disease involving the 
colon and/or rectum, use of corticosteroids during the trial, current use of biologic therapy, and current 
use of immunomodulator therapy will be examined individually for potential confounding of the main 
outcome using logistic regression analysis. All variables that affect the crude estimate of the relative risk 
of effectiveness by 10% or greater will be included in the final model102.  
Stratified analyses will be used to assess for treatment effect heterogeneity based on the following 
variables: presence of documented inflammation at baseline (defined as FCP>250 mcg/g, hsCRP >5 
mg/L.Although pre-specified, we have not powered the study for these subgroup analyses and as such 
they will be considered hypothesis generating. Therefore, we will report the overall results as well as 
results for each subgroup. We note that the strongest a priori hypothesis for treatment effect heterogeneity 
is with the presence or absence of inflammation. We hypothesize that the SCD may appear relatively 
more effective among those patients without active inflammation than among those with confirmed active 
inflammation at baseline.  
 
 
Analysis of secondary outcomes (Secondary Aim 2): 
The secondary outcomes of clinical remission as assessed by the CDAI, PRO2, PRO3 reduction of 
hsCRP by >50% and to <5 mg/L, reduction of FCP by >50% and to a value of <250mcg/g and combined 
clinical remission and resolution of inflammation will be analyzed using the same methods described for 
the primary outcomes.  
 
The secondary outcomes of fatigue, sleep quality, social aspects and pain interference will be measured 
using PROMIS short forms using the same methods as previously employed within CCFA Partners27,103. 
PROMIS items are calibrated using a T score such that 50 is the mean for the general US population with 
a standard deviation of 10. Higher scores reflect greater level of the domain. We will compare PROMIS 
scores at baseline and at the end of the trial using a t-test. If there are meaningful differences in baseline 
scores between the treatment arms, comparison of the PROMIS measures at the end of follow-up will be 
adjusted for the baseline value using linear regression.  
 
Analysis of data from weeks 7 – 12 (Secondary Aim 3): After week 6, participants will need to provide for 
the meals on their own if they choose to remain on the diet. This provides an opportunity to further assess 
the combined feasibility of the diets in the real world and patients’ satisfaction with following the diet. 
Utilizing results from 24-hour dietary recalls, we will determine the proportion of patients assigned to each 
arm who elect to remain on the diet through week 12. We will also determine the proportion of patients 
who were able to discontinue steroid use by week 12 among the subgroup who were taking steroids in 
weeks 1-6. Finally, we will assess reasons for discontinuation of the diet among those who did not 
continue. Comparisons will be made using the CMH  test following the principle of intention to treat. The 
analysis will be repeated among the subgroup of participants who achieved remission by week 6. These 
results will be qualitatively compared to the free text data on satisfaction and personal experience with 
the diets. 
 
Change from baseline stratified by treatment arm: For continuous outcome measures, such as sCDAI, 
PRO2, PRO3, and FCP, we will compare the week 6 and week 12 values to the baseline value using the 
Wilcoxon sign rank test, a nonparametric paired test. These analyses will be conducted separately for 
each treatment group. Imputation of missing data for this analysis will assume the worst case scenario 
that the outcome measure was worse during follow-up than at baseline. (Note that approach to missing 
data for other analyses are described below). 
 
 
 
 
Approach to missing data (PCORI Methodology Standard MD1-5): Our study design will minimize 
missing data by requiring participants to continue to provide data and samples in order to continue to 
receive the study diets without cost. In addition, we will employ reminder methods that were developed in 
our current CCFA Partners RCT and will collect symptoms daily, but have documented that less frequent 
data collection is adequate82. It is possible that missing follow-up data will be more common among 
participants who did not have reduced symptoms, particularly those whose symptoms worsened. There 
are several approaches to missing data in clinical trials. Complete case analysis violates the principle of 

 
Page 31 of 81 
 
 
intention to treat and as such will not be employed. For continuous measures, last observation carried 
forward (LOCF) is the most commonly used, but it is not necessarily the most conservative104.  Baseline 
observation carried forward (BOCF) may be more appropriate, particularly in circumstances where the 
outcome would be expected to return to the baseline level if the treatment is discontinued104. The 
European Medicines Agency recommends picking the most conservative approach depending on the 
individual trial, favoring a responder analysis (i.e. converting continuous variables to dichotomous 
variables) and categorizing all dropouts as treatment failures104. We will use this approach in analyses for 
aims 1 and 2. For the continuous variables in the secondary outcomes, we will use BOCF as the most 
conservative approach. Sensitivity analyses will compare results of our BOCF analysis with that obtained 
using LOCF or multiple imputation methods.  All results will be interpreted and reported after taking into 
account the results of the sensitivity analyses, applying the principle put forth by the EMA to not favor the 
“experimental” arm, which in this RCT would be the SCD. 
 
8.4.3 
Safety Analysis  
All subjects entered into the study and randomized at the baseline visit will have detailed information 
collected on adverse events for the overall study safety analysis. 
8.5 
Subject Population(s) for Analysis 
As a comparative effectiveness study, the primary efficacy and safety analysis will use the principle of 
intention to treat such that all randomized patients will be included in the group that they were 
randomized to, regardless of the level of adherence with the assigned diet.   
9 
Safety and Adverse Events 
9.2 
Definitions 
9.2.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should 
be recorded as an adverse event if the frequency, intensity, or the character of the condition worsens 
during the study period. 
9.2.2 
Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event (not life threatening but may require intervention; for example drug 
overdose, drug abuse, a seizure not resulting in hospitalization) 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  

 
Page 32 of 81 
 
 
9.2.3 
Expected Adverse Events 
As a short term study of two diets, there are few expected risks of the two interventions. These include 
allergic reaction to a component of the food, intolerance of the food other than as an allergic reaction, 
and worsening of Crohn’s disease manifested as any of the following: worsened abdominal pain, 
worsened diarrhea, bowel obstruction, penetrating complications such as fistula or abscess. In addition, 
worsening of extraintestinal manifestations of Crohn’s disease is possible, such as worsening 
arthropathy, mouth sores, skin rashes including pyoderma gangrenosum and erythema nodosum, and 
ocular manifestations such as episcleritis or uveitis. The Crohn’s disease related adverse events would 
not be considered to be caused by the diets, but rather as a consequence of failure of the diet based 
therapy to induce disease remission. Some exacerbations of Crohn’s Disease may result in 
hospitalization and/or the need for surgery. In rare circumstances, exacerbations of Crohn’s disease may 
be life-threatening.  
9.3 
Recording of Adverse Event (AE) 
At each contact with the subject from the screening visit to the end of study visit, the Site Investigator or 
Site Coordinator will seek information on adverse events by specific questioning and, as appropriate, by 
examination.  Information on all adverse events will be recorded immediately on the AE case report form 
(CRF). The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study intervention or participation is not the cause.   
 
Related, treatment-emergent serious and severe adverse events that are still ongoing at the end of the 
study period will be followed up to determine the final outcome, which may include resolution or stable 
outcome.   
 
9.4 
Relationship of AE to Study  
The relationship of each adverse event to the study procedures should be characterized by the Site 
Investigator and recorded on the case report form. The relationship to the study intervention will be 
classified as definitely related, possibly related, not related, or unknown.  For reporting purposes, an 
Adverse Event is considered “related to participation in the research” if the cause of the event is deemed 
possibly related or definitely related to the investigational product or a procedure that was performed for 
the purposes of the research.  
 
9.5 
Reporting of Serious Adverse Events and Unanticipated Problems  
A Serious Adverse Event or Unanticipated Problem (see definition below) is required to be reported to the 
relying IRB within 10 days. If the adverse event involved a death and indicates that participants or others 
are at increased risk of harm the investigators are required to submit a report to the relying IRB within 3 
days. 
 
Non-medical Unanticipated Problems that should be reported to the IRB may include complaint of a 
participant when the complaint indicates unexpected risks or the complaint cannot be resolved by the 
research team, breach of confidentiality, incarceration of a participant when the research was not 
previously approved under Subpart C and the investigator believes it is in the best interest of the subject 
to remain on the study, or premature completion of the entire study for any reason. 
 
Serious Adverse Events or Unanticipated Problems will be reported to the relying IRB using either a 
Reportable Event form from the relying IRB, or by writing a narrative including the minimum necessary 
information listed below.  If not all information is known within the reporting timeframe, the site investigator 
should still complete a Reportable Event form or narrative within the timeframe with the information 
available and inform the relying IRB that a follow-up report will be provided when all information is known. 
 

 
Page 33 of 81 
 
 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study intervention was discontinued 
 
The reason why the event is classified as serious 
 
Investigator 
assessment 
of 
the 
association 
between the event and study intervention 
 
 
If an event does not meet the definition above of a Serious Adverse Event or Unanticipated Problem, a 
narrative summary of events that occurred should be submitted to the relying IRB at the time of Continuing 
Review, including a rational for why the event(s) was not reportable within 10 days.  
 
Any known serious adverse event that occurs after the study period and is considered to be possibly or 
definitely related to the study intervention or study participation will be recorded and reported to the PI, 
the sponsor, and the relying IRB immediately. 
 
9.5.1 
Follow-up SAE report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) should be submitted to the relying IRB. The 
site investigator is responsible for ensuring that all SAEs are followed until either resolved or stable. 
9.5.2 
Investigator reporting: notifying the study sponsor (Penn) 
Site investigators should report serious adverse events and unanticipated problems meeting the 3 day 
reporting requirement (as defined in section 9.5) to the University of Pennsylvania Sponsor by phone and 
via the data management system. Phone notification should be within 24 hours of the site investigator 
becoming aware of the serious adverse event. Notification via the DMS should be done within 72 hours. 
In the case where the DMS form cannot be fully completed with 72 hours, a partially completed form 
should be entered into the DMS within 72 hours, and a completed form should be entered as soon as is 
possible. Report SAE’s by phone to: 
 
James D. Lewis, MD   
Phone: (215) 573-5137 
 
In the event Dr. Lewis cannot be reached, report SAEs to 
Meenakshi Bewtra, MD 
Phone: (215) 746-4922 
 
Or  
Adam Hawkins (215) 746-4218 or Lisa Nessel (215) 573-6003 
 
 
SAE’s that do not meet the 3 day reporting requirement (i.e., do not involve death or indicate that 
participants are at increased risk) should be reported to the sponsor within 10 days via the data 
management system only. No phone call will be required. 
 
For a flow chart outlining SAE reporting to the sponsor, please see Image 1 below. 
 
 
Image 1. SAE Flow Chart 

 
Page 34 of 81 
 
 
 
9.6 
Medical Monitoring 
9.6.1 
Data and Safety Monitoring Plan 
To identify and mitigate potential risks to research subjects, we will inquire with participants at each 
contact if they are experiencing any adverse events. We do not expect that there will be many as the 
intervention is normal, healthy food.  
 
As mentioned above, SAE’s will be reported to the Principal Investigator at the University of Pennsylvania. 
Additionally, we will employ a Data Safety and Monitoring Board (DSMB). Please see the section below 
for details about the DSMB..   
9.6.2 
Data Safety Monitoring Board  
We will convene a DSMB prior to the initiation of the study. The DSMB membership will include 3 total 
members consisting of: 1 biostatistician, 1 experienced clinical investigator with knowledge of CD, and 1 
patient representative. The DSMB will have full authority to recommend suspending the study at any 
time if concerns arise about the safety of the study. Formal meetings of the DSMB will be planned to 
occur prior to the enrollment of the first patient, after one-third of patients are enrolled, after two-thirds of 
patients are enrolled, and at the conclusion of the trial. DSMB meetings will follow the standard format of 
an open session including the DSMB members and the investigators, followed by a closed session of 
the DSMB at which unblinded data can be reviewed, followed by another open session if required. The 
DSMB will render a decision to continue the trial as is, continue the trial with modifications, suspend the 
trial until modifications can be implemented, or to permanently suspend the trial. The study team will 
provide support to the DSMB to generate meeting minutes.  The meeting minutes will be provided to the 
IRB and to PCORI.  
 

 
Page 35 of 81 
 
 
SAE reports will be sent as they occur to the chair of the DSMB for review. 
10 Study Administration, Data Handling and Record Keeping 
10.2 Confidentiality 
Information about study subjects 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 subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects 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 subject is alive) at the end of their scheduled study 
period. 
10.3 Data Collection, Source and Accuracy (PCORI Methodology Standard IR-1) 
Clinical data will be captured through a combination of means. Baseline characteristics of the participants 
and follow-up data on adverse events and physician derived components of the CDAI will be collected by 
the local investigator and recorded in the study database using double data entry by the clinical sites. We 
will use double data entry to minimize data entry errors. Baseline and follow-up data on symptoms and 
medication use will be collected directly from patients through the CCFA Partners PPRN web portal. 
Symptom data will be collected daily via surveys emailed or texted directly to the patients. Diet satisfaction 
and diet history will be collected via online surveys emailed to the participant at certain time points. Patient-
reported medication use will be confirmed with the local investigator. Adherence to the diet will be 
assessed using 24 hour dietary recall data collected by trained dietitians. 
 
10.3.1 Data Coordinating Center (DCC) 
The University of Pennsylvania will serve as the Data Coordinating Center for this study. The DCC will 
develop all data collection instruments in collaboration with the steering committee and the DMC. The 
DCC will be charged with assuring data is entered and that data are complete and accurate. The DCC 
will also be charged with data and safety monitoring and coordinating all meetings of the DSMB.  
 
10.3.2 Data Management Center(DMC) 
The Biostatistics Core of the Center for Gastrointestinal Biology and Disease at the University of North 
Carolina Chapel Hill will serve as the Data Management Center. The DMC will be charged with creating, 
managing, and housing the data management system. 
 
Site Coordinators will collect data on source documents and will complete double data entry onto 
electronic CRFs in the data management system created by the DMC Participants will collect data via 
direct data capture. All of the data will be maintained, archived, retrieved and distributed (except for the 
source documents completed by the Site Coordinators), by a computer system. The use of electronic 
records will increase the speed of data collection and exchange. Electronic records permit economical 
storage of study data and ease of accessibility and analysis. Data management and data quality 
systems will be built into the system. The DCC will have password-required access to the data 
management system where they can export data. The local sites will have password-required access to 
the data management system as well but they will only have access to their site’s data and they will not 
be permitted to export the data.  
 
The Data Management Center (DMC) at the CGIBD at the University of North Carolina will track the data 
collection, provide data security, control for confidentiality of study data, maintain computer backups to 
protect data until study closure and archive study data according to FDA requirements (21 CFR 11). 
Electronic signatures will be linked to each entry. 
 

 
Page 36 of 81 
 
 
All computer systems and programs will be password protected, and all electronic communications of 
study and other confidential information will be encrypted. Personnel at the CGIBD have extensive 
training and experience using electronic data systems. Good computer security practice (restricting 
physical access to machines, prohibition of password sharing, and logging off computers after work 
hours or when away from the machine) will be required of all study personnel.  
 
Standard Operating Procedures exist for users of the DMS. The DMS will be housed on an https secure 
website in order to protect the study participants’ information. Only authorized persons are authorized for 
data entry and access. Data security systems require password protected identification codes for data 
entry and provide protection against data manipulation. The database is located on a server protected by 
firewalls. Access to the database server will not be allowed by users on computers outside of the firewall-
protected zone. Virus protection software is installed on each study machine. System access to computer 
systems will be audited. Redundant backups and off-site backup storage will allow for quick restoration 
of data in the unlikely event that a hardware failure, disaster, or security breach should occur. Servers 
and backups will be located in a secured location with access limited to authorized personnel. 
 
Standardized study management reports will be generated monthly during the recruitment phase of the 
study. These reports will be used to track study progress including patient enrollment, randomization, 
compliance, patient status changes, and study events. The data will be reported for each Study Center 
individually and summarized for the study as a whole. Every six months, a standardized report will also 
be generated for the DSMB meeting. This report will include additional information on clinical events and 
adverse events that is coded by treatment group. Other than the DSMB, the study statistician and 
statistical analyst, no study personnel will see this report. 
 
10.3.3 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, subject files, and records kept at the food dispensing company, and at the 
laboratories.  Any forms or documents with participants’ identifying information placed in the participant’s 
study file will be kept locked using a double lock system (for example, a locked filing cabinet in a locked 
office) and only certain members of the study team will have access to those forms.  
 
Study staff at the local sites will have access to their participants’ PHI. They will not have access to other 
sites’ participant PHI or participant data, with the exception that the research team at the University of 
Pennsylvania may see other sites’ participant PHI and data to facilitate participants’ receipt of study food 
and problem solving. 
 
10.3.4 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained. 
 
Data on CRFs will be collected via double data entry using a secure web-based database designed by 
and housed in the University of North Carolina. The eCRFs will be the source document in some cases. 
These eCRFs will not include PHI or participants’ identifiable information. Instead, eCRFs will be labeled 
with a unique study identification number and PHI will be kept separate.  
 
 If a space on the CRF is left blank because the procedure was not done or the question was not asked, 
type “N/D”.  If the item is not applicable to the individual case, type “N/A”.  
10.4 Records Retention  
Study documents and records will be retained for 7 years after the last participant has completed the 
last visit, unless otherwise notified by the DCC. 

 
Page 37 of 81 
 
 
11 Study Monitoring, Auditing, and Inspecting 
11.2 Study Monitoring Plan 
Most of the data to be collected in this study will be collected directly from participants through our web-
based data entry system. For specific aim 1, the primary outcome is derived from patient reported data. 
For specific aim 2, the primary outcome is derived from the measurement of the concentration of fecal 
calprotectin, which will be done by a commercial laboratory LabCorp. Such data are not subject to 
monitoring other than for completeness. This will be done by the data analysts.  
 
We will monitor the sites for compliance with regulatory documentation and for compliance with the 
study protocol, particularly as it relates to inclusion criteria. We will utilize a system whereby the local 
investigator team prints, redacts if needed, and uploads into our data management system source 
documents that demonstrate the eligibility of the participants. Study monitors will then remotely review 
these documents for compliance with the study protocol, send queries to the local sites, resolve 
outstanding queries, and document the level of adherence with the study protocol. Any findings that 
demonstrate a protocol deviation will be reported to the Penn IRB or local IRB, as appropriate.  Similar 
methods will be employed for reviewing the participating sites regulatory binder. We will provide each 
site with an electronic storage area where their regulatory documents can be stored and then reviewed 
by the monitors. Data quality monitoring will be implemented after the second patient is enrolled at the 
site. Eligibility criteria and consent process will be monitored for all participants. If deemed necessary, 
on site monitoring will be employed. 
11.3 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities. 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
12 Ethical Considerations 
This study will be conducted in accordance with applicable US Government regulations and international 
standards of Good Clinical Practice.  This protocol, any amendments and any study instructions and data 
collection instruments will be submitted to a properly constituted Ethics Committee or Institutional Review 
Board, in agreement with local legal prescriptions for formal approval of the study conduct.  The decision 
of the Ethics Committee or Institutional Review Board concerning the conduct of the study will be made 
in writing to the investigator and a copy of the decision will be provided to the Penn Data Coordinating 
Center before commencement of the study. Continuing review will be required through the Penn 
Institutional Review Board or other local reviewing entities at the recruiting centers.  
12.2 Risks 
The intervention in this trial poses little risk to participants. The prescribed diets are consistent with many 
dietary recommendations to minimize consumption of “processed” foods. There is a theoretical risk of 
delaying a change in the patient’s medication regimen while trying the study diets. However, the duration 
of the primary intervention period is only 6 weeks and we will exclude patients who are hospitalized for 
their CD, require in excess of 20mg per day of prednisone or the equivalent, or for whom the treating 
physician believes that surgery will be required within 6 weeks.  There is minimal risk of phlebotomy, 
including bruising or fainting. However, nearly all of these patients would be expected to undergo 
phlebotomy for clinical reasons at the same time.  
 
As with all research, there is the risk of loss of confidentiality of the data. Within the clinical trial, all data 
collected will be collected in a manner consistent with Good Clinical Practice. The case report forms 
(CRFs) will be electronic, avoiding the risk of paper forms. Access to the data will be limited to the research 
team, including the investigators, the research coordinator, and the data analysts. Electronic data will be 

 
Page 38 of 81 
 
 
stored on servers within the University of North Carolina. Access to the server is password protected.  
The servers are backed-up nightly to prevent loss of information.  
 
No vulnerable populations are included in this study. 
12.3 Benefits 
Participants may benefit from participation in this trial if the dietary intervention reduces their symptoms 
of CD and the related inflammation. If either study diet is demonstrated to be superior to the other, it is 
anticipated that many patients with CD would elect to follow a similar diet. 
12.4 Risk Benefit Assessment 
The leading unanswered question for patients with IBD is what diet to eat. Ultimately, regardless of the 
results, we will provide an answer to the question, “What should I eat?” If either of the diets is 
demonstrated to be superior, then we can confidently recommend that diet to patients with active CD. If 
neither diet is found to be superior, the default recommendation will be to follow a “healthy” and well-
rounded diet such as the MSD. This is a low risk study, so the risks to subjects are reasonable in the 
context of the information to be gained.  
12.5 Informed Consent Process / HIPAA Authorization  
The Informed Consent and HIPAA Authorization will be combined into one form. The Research 
Coordinator or Investigators at the local site will obtain informed consent. The consent process will take 
place in a private space in the clinic where the patient sees their gastroenterologist. Participants will be 
permitted to provide consent at the time of the consent discussion or they will be required to come back 
to provide written informed consent at the screening visit. They may be initially verbally consented over 
the phone prior to collection of pre-screening information, with a later date scheduled to complete the in-
person consent. During the consent process, participants will be encouraged to ask questions. Ample 
time will be dedicated to answering all of the participants’ questions to make sure they understand the 
study. They will be permitted to think about whether they want to participate, review the consent form on 
their own and discuss it with whomever they like and sign the consent form at a later visit. Potential 
participants will be reminded that the study is voluntary and they are not required to participate. Both the 
participant and the person obtaining consent will sign the consent form. A copy of the consent will be 
provided to the participant.  
 
To participate in this study, participants will be required to join the Crohn’s and Colitis Foundation’s (CCF) 
online patient research network called CCFA Partners. This research network is an online group of adult 
patients with Inflammatory Bowel Disease (IBD) who agree to contribute to IBD-related research. It does 
not cost anything to join. By signing up to be a member of CCFA Partners, participants agree to be 
contacted for potential participation in other IBD research studies, and to provide information regarding 
their health through online questionnaires. Completion of online questionnaires and participation in other 
research studies is voluntary and not required for participation in DINE-CD. They can opt out of any 
questionnaire and can decline any research study. They can also withdraw at any time from CCFA 
Partners. 
13 Study Finances 
13.1 
Funding Source 
This study is funded through the Crohn’s and Colitis Foundation and the Patient Centered Outcomes 
Research Institute (PCORI). 
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts 
of Interest Related to Research. Only sites with a Conflict of Interest Policy will be permitted to participate. 
Exceptions to this may be made on a case by case basis and only with permission from the University of 
Pennsylvania’s Conflict of Interest Standing Committee and other applicable regulatory bodies. Each local 
site will be required to follow their institution’s Conflict of Interest Policy Related to Research. 

 
Page 39 of 81 
 
 
13.3 Subject Stipends or Payments 
Participants will not be compensated for their participation in this research study. 
 
14 Collaborative Effort (PCORI Methodology Criterion 2. Technical Merit) 
The proposed study is a unique collaboration between CCFA Partners, AR-PoWER, and 
ImproveCareNow (ICN) and will also leverage the infrastructure of the Mid-South CDRN. 
We will invite interested ICN centers to participate in the trial through the recruitment and follow-up of their 
young adult patients (who will simultaneously be co-enrolled into the CCFA Partners PPRN). We will also 
work with ICN to disseminate study findings. ICN is submitting a related proposal to use n-of-1 
methodology to study the impact of the SCD in pediatric CD. If both proposals are funded, this will offer a 
unique opportunity to compare two different study designs to answer related questions in related 
populations (adult and pediatric CD). 
 
Our partnership with the AR-PoWER PPRN takes advantage of the fact that many patients with CD have 
co-morbid arthritis and related conditions and studies to evaluate the impact of diet on arthritis have been 
prioritized by patients in the AR-PoWER network. Our partnership with AR-PoWER will enable us to study 
the effects of our dietary interventions on joint symptoms using a series of PROs selected in collaboration 
with AR-PoWER patients and scientists. This will provide important preliminary data of both the 
effectiveness and feasibility of future dietary studies in rheumatology patients. We will also partner with 
the AR-Power PPRN to disseminate our study findings, as appropriate.  
The Mid-South CDRN will provide informatics, administrative, and regulatory support for this study at two 
of CDRN sites: Vanderbilt and the University of North Carolina at Chapel Hill.  
15 Publication Plan and Dissemination of Results (PCORI Methodology IR-6)  
The results will be submitted to PCORI for review according to their guidelines for final reports. In addition, 
the results will be submitted for publication as a full length manuscript to a peer reviewed journal, allowing 
for complete description of the key methodology and results. The results will also be made available 
through the clinicaltrials.gov website. We will also utilize the PPRN infrastructure as all 3 PPRNs have 
developed dissemination strategies through their Phase I efforts, and will be refining and expanding such 
strategies over the course of Phase II.  
 
We also have the support of the CCF to assist in the dissemination of our study results across multiple 
stakeholders-- nurses, dietitians, physicians and other allied health professionals. The CCF routinely 
hosts local, regional, and national patient and provider educational events. Additionally, the CCF hosts 
live webinars, publishes multiple brochures and newsletters, and maintains an active website. Total 
contacts are estimated at over 500,000 individuals each year (personal contact, Laura Wingate, CCF 
September 13, 2015).  
Finally, we will work with our patient collaborator and active IBD blogger (thegreatbowelmovement.org), 
Ms. Meyer, to further disseminate the findings to patients and healthcare practitioners. 
 
16 Appendices 
 Appendix A: Protocol Signature Page 
 Appendix B: Study Procedures Flowchart/Table 
 Appendix C: Data Safety Monitoring Plan  
 Appendix D: Stool Kit Preparation SOP   
 Appendix E: Stool collection instructions for Patients 
 Appendix F: DSMB Charter 
 Appendix G: Analytic and Statistical Plan  
 Appendix H: PROMIS Measures 
 Appendix I: RADAI Arthritis screening and RAPID 3 Questionnaire 
 Appendix J: Inflammatory back pain screening questions and Bath AS Functional index 
 Appendix K: Menu Samples 
 

 
Page 40 of 81 
 
 
17 References 
 
1. 
Herrinton LJ, Liu L, Lafata JE, et al. Estimation of the period prevalence of inflammatory bowel 
disease among nine health plans using computerized diagnoses and outpatient pharmacy 
dispensings. Inflamm. Bowel Dis. Apr 2007;13(4):451-461. 
2. 
Herrinton LJ, Liu L, Lewis JD, Griffin PM, Allison J. Incidence and prevalence of inflammatory 
bowel disease in a Northern California managed care organization, 1996-2002. Am. J. 
Gastroenterol. 2008;103(8):1998-2006. 
3. 
Loftus EV, Jr., Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn's 
disease in population-based patient cohorts from North America: a systematic review. . Aliment. 
Pharmacol. Ther. 2002;16(1):51-60. 
4. 
Loftus EV, Jr., Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. 
Crohn's disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. 
Gastroenterology. 1998;114(6):1161-1168. 
5. 
Loftus EV, Jr., Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. 
Ulcerative colitis in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival. 
Gut. 2000;46(3):336-343. 
6. 
Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic distribution 
of Crohn's disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol. Dec 
2007;5(12):1424-1429. 
7. 
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of 
inflammatory bowel diseases. Gastroenterology. May 2011;140(6):1785-1794. 
8. 
Peyrin-Biroulet L, Loftus EV, Jr., Colombel JF, Sandborn WJ. The natural history of adult Crohn's 
disease in population-based cohorts. Am. J. Gastroenterol. Feb 2010;105(2):289-297. 
9. 
Lewis JD. How safe are the safest IBD drugs?[comment]. Gastroenterology. 1986;124(7):1986-
1987. 
10. 
Lewis JD, Abramson O, Pascua M, et al. Timing of myelosuppression during thiopurine therapy 
for inflammatory bowel disease: implications for monitoring recommendations. Clin Gastroenterol 
Hepatol. Nov 2009;7(11):1195-1201; quiz 1141-1192. 
11. 
Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of lymphoma among 
inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.[see 
comment]. Gut. 2005;54(8):1121-1125. 
12. 
Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the 
management of inflammatory bowel disease: short- and long-term toxicity. Ann. Intern. Med. 
1989;111(8):641-649. 
13. 
Siegel C, Marden S, Persing S, Larson R, Sands B. Risk of Lymphoma Associated with Anti-TNF 
Agents for the Treatment of Crohn's Disease: A Meta-Analysis. Gastroenterology. 2008;134(4):A-
144. 
14. 
Gupta G, Lautenbach E, Lewis JD. Incidence and risk factors for herpes zoster among patients 
with inflammatory bowel disease. Clinical Gastroenterology & Hepatology. 2006;4(12):1483-
1490. 
15. 
Toruner M, Loftus EV, Jr., Harmsen WS, et al. Risk factors for opportunistic infections in patients 
with inflammatory bowel disease. Gastroenterology. 2008;134(4):929-936. 
16. 
Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving 
thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 
Nov 7 2009;374(9701):1617-1625. 
17. 
Strangfeld A, Listing J, Herzer P, et al. Risk of herpes zoster in patients with rheumatoid arthritis 
treated with anti-TNF-alpha agents.[see comment]. JAMA. Feb 18 2009;301(7):737-744. 
18. 
van der Have M, Fidder HH, Leenders M, et al. Self-reported disability in patients with 
inflammatory bowel disease largely determined by disease activity and illness perceptions. 
Inflamm Bowel Dis. Feb 2015;21(2):369-377. 
19. 
Busch K, da Silva SA, Holton M, Rabacow FM, Khalili H, Ludvigsson JF. Sick leave and disability 
pension in inflammatory bowel disease: a systematic review. J Crohns Colitis. Nov 
2014;8(11):1362-1377. 
20. 
van der Valk ME, Mangen MJ, Leenders M, et al. Risk factors of work disability in patients with 
inflammatory bowel disease--a Dutch nationwide web-based survey: work disability in 
inflammatory bowel disease. J Crohns Colitis. Jul 2014;8(7):590-597. 

 
Page 41 of 81 
 
 
21. 
Hoivik ML, Moum B, Solberg IC, Henriksen M, Cvancarova M, Bernklev T. Work disability in 
inflammatory bowel disease patients 10 years after disease onset: results from the IBSEN Study. 
Gut. Mar 2013;62(3):368-375. 
22. 
Ananthakrishnan AN, Weber LR, Knox JF, et al. Permanent work disability in Crohn's disease. 
Am J Gastroenterol. Jan 2008;103(1):154-161. 
23. 
Feagan BG, Bala M, Yan S, Olson A, Hanauer S. Unemployment and disability in patients with 
moderately to severely active Crohn's disease. Journal of clinical gastroenterology. May-Jun 
2005;39(5):390-395. 
24. 
Cohen RD. The quality of life in patients with Crohn's disease. Aliment. Pharmacol. Ther. Sep 
2002;16(9):1603-1609. 
25. 
Graff LA, Walker JR, Lix L, et al. The relationship of inflammatory bowel disease type and activity 
to psychological functioning and quality of life. Clin. Gastroenterol. Hepatol. Dec 2006;4(12):1491-
1501. 
26. 
Lichtenstein GR, Yan SK, Bala M, Hanauer S. Remission in patients with Crohn's disease is 
associated with improvement in employment and quality of life and a decrease in hospitalizations 
and surgeries. American Journal of Gastroenterology. Jan 2004;99(1):91-96. 
27. 
Kappelman MD, Long MD, Martin C, et al. Evaluation of the patient-reported outcomes 
measurement information system in a large cohort of patients with inflammatory bowel diseases. 
Clinical gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association. Aug 2014;12(8):1315-1323 e1312. 
28. 
Bewtra M, Kaiser LM, TenHave T, Lewis JD. Crohn's disease and ulcerative colitis are associated 
with elevated standardized mortality ratios: a meta-analysis. Inflamm Bowel Dis. Mar 
2013;19(3):599-613. 
29. 
Sandborn WJ, Feagan BG, Lichtenstein GR. Medical management of mild to moderate Crohn's 
disease: evidence-based treatment algorithms for induction and maintenance of remission. 
Aliment. Pharmacol. Ther. 2007;26(7):987-1003. 
30. 
Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults. Am. J. 
Gastroenterol. Feb 2009;104(2):465-483; quiz 464, 484. 
31. 
Dignass A, Van Assche G, Lindsay JO, et al. The second European evidence-based Consensus 
on the diagnosis and management of Crohn's disease: Current management. J Crohns Colitis. 
Feb 2010;4(1):28-62. 
32. 
Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy 
for Crohn's disease. N. Engl. J. Med. Apr 15 2010;362(15):1383-1395. 
33. 
Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response 
and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. Jan 
2007;132(1):52-65. 
34. 
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the 
ACCENT I randomised trial. Lancet. May 4 2002;359(9317):1541-1549. 
35. 
Johnson FR, Ozdemir S, Mansfield C, et al. Crohn's disease patients' risk-benefit preferences: 
serious adverse event risks versus treatment efficacy. Gastroenterology. Sep 2007;133(3):769-
779. 
36. 
Peppercom MA. 6-mercaptopurine for the management of ulcerative colitis: a concept whose time 
has come [editorial; comment]. Am. J. Gastroenterol. 1996;91(9):1689-1690. 
37. 
Sands BE, Siegel C, Ozdeir S. Gastroenterologists' tolerance for Crohn's disease treatment risks. 
Am. J. Gastroenterol. 2007;102(Suppl 2):S492. 
38. 
Ballegaard M, Bjergstrom A, Brondum S, Hylander E, Jensen L, Ladefoged K. Self-reported food 
intolerance in chronic inflammatory bowel disease. Scand. J. Gastroenterol. Jun 1997;32(6):569-
571. 
39. 
Limdi JK, Aggarwal D, McLaughlin JT. Dietary Practices and Beliefs in Patients with Inflammatory 
Bowel Disease. Inflamm Bowel Dis. Sep 16 2015. 
40. 
Vagianos K, Bector S, McConnell J, Bernstein CN. Nutrition assessment of patients with 
inflammatory bowel disease. JPEN. J. Parenter. Enteral Nutr. Jul-Aug 2007;31(4):311-319. 
41. 
Prince A, Whelan K, Moosa A, Lomer MC, Reidlinger DP. Nutritional problems in inflammatory 
bowel disease: The patient perspective. J Crohns Colitis. Oct 2011;5(5):443-450. 
42. 
Gottschall E. Breaking the Vicious Cycle. Baltimore, ON: Kirkton Press, Limited; 1994. 
43. 
Lochs H, Dejong C, Hammarqvist F, et al. ESPEN Guidelines on Enteral Nutrition: 
Gastroenterology. Clin. Nutr. Apr 2006;25(2):260-274. 

 
Page 42 of 81 
 
 
44. 
Sandhu BK, Fell JM, Beattie RM, Mitton SG, Wilson DC, Jenkins H. Guidelines for the 
Management of Inflammatory Bowel Disease in Children in the United Kingdom. J. Pediatr. 
Gastroenterol. Nutr. Jan 13 2010. 
45. 
Caprilli R, Gassull MA, Escher JC, et al. European evidence based consensus on the diagnosis 
and management of Crohn's disease: special situations. Gut. Mar 2006;55 Suppl 1:i36-58. 
46. 
Borrelli O, Cordischi L, Cirulli M, et al. Polymeric diet alone versus corticosteroids in the treatment 
of active pediatric Crohn's disease: a randomized controlled open-label trial. Clinical 
gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association. Jun 2006;4(6):744-753. 
47. 
Grover Z, Muir R, Lewindon P. Exclusive enteral nutrition induces early clinical, mucosal and 
transmural remission in paediatric Crohn's disease. Journal of gastroenterology. Apr 
2014;49(4):638-645. 
48. 
Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for induction of remission in 
Crohn's disease.[update of Cochrane Database Syst Rev. 2001;(3):CD000542; PMID: 
11686966]. Cochrane Database of Systematic Reviews. 2007;1. 
49. 
Lee D, Baldassano RN, Otley AR, et al. Comparative Effectiveness of Nutritional and Biological 
Therapy in North American Children with Active Crohn's Disease. Inflamm Bowel Dis. Aug 
2015;21(8):1786-1793. 
50. 
Takagi S, Utsunomiya K, Kuriyama S, et al. Effectiveness of an 'half elemental diet' as 
maintenance therapy for Crohn's disease: A randomized-controlled trial. Aliment. Pharmacol. 
Ther. Nov 1 2006;24(9):1333-1340. 
51. 
Wedlake L, Slack N, Andreyev HJ, Whelan K. Fiber in the treatment and maintenance of 
inflammatory bowel disease: a systematic review of randomized controlled trials. Inflamm Bowel 
Dis. Mar 2014;20(3):576-586. 
52. 
Charlebois A, Rosenfeld G, Bressler B. The Impact of Dietary Interventions on the Symptoms of 
Inflammatory Bowel Disease: A Systematic Review. Critical reviews in food science and nutrition. 
Jan 8 2015:0. 
53. 
Cohen AB, Lee D, Long MD, et al. Dietary patterns and self-reported associations of diet with 
symptoms of inflammatory bowel disease. Digestive diseases and sciences. May 
2013;58(5):1322-1328. 
54. 
Zallot C, Quilliot D, Chevaux JB, et al. Dietary beliefs and behavior among inflammatory bowel 
disease patients. Inflamm Bowel Dis. Mar 29 2012. 
55. 
Lee D, Albenberg L, Compher C, et al. Diet in the pathogenesis and treatment of inflammatory 
bowel diseases. Gastroenterology. May 2015;148(6):1087-1106. 
56. 
Suskind DL, Wahbeh G, Gregory N, Vendettuoli H, Christie D. Nutritional therapy in pediatric 
Crohn disease: the specific carbohydrate diet. Journal of pediatric gastroenterology and nutrition. 
Jan 2014;58(1):87-91. 
57. 
Cohen SA, Gold BD, Oliva S, et al. Clinical and mucosal improvement with specific carbohydrate 
diet in pediatric Crohn disease. Journal of pediatric gastroenterology and nutrition. Oct 
2014;59(4):516-521. 
58. 
Riordan AM, Hunter JO, Cowan RE, et al. Treatment of active Crohn's disease by exclusion diet: 
East Anglian multicentre controlled trial. Lancet. Nov 6 1993;342(8880):1131-1134. 
59. 
Bartel G, Weiss I, Turetschek K, et al. Ingested matter affects intestinal lesions in Crohn's disease. 
Inflamm. Bowel Dis. Mar 2008;14(3):374-382. 
60. 
Jones VA, Dickinson RJ, Workman E, Wilson AJ, Freeman AH, Hunter JO. Crohn's disease: 
maintenance of remission by diet. Lancet. Jul 27 1985;2(8448):177-180. 
61. 
Sigall-Boneh R, Pfeffer-Gik T, Segal I, Zangen T, Boaz M, Levine A. Partial enteral 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. Aug 2014;20(8):1353-1360. 
62. 
Rajendran N, Kumar D. Food-specific IgG4-guided exclusion diets improve symptoms in Crohn's 
disease: a pilot study. Colorectal Dis. Sep 2011;13(9):1009-1013. 
63. 
Chiba M, Abe T, Tsuda H, et al. Lifestyle-related disease in Crohn's disease: relapse prevention 
by a semi-vegetarian diet. World J Gastroenterol. May 28 2010;16(20):2484-2495. 
64. 
Olendzki BC, Silverstein TD, Persuitte GM, Ma Y, Baldwin KR, Cave D. An anti-inflammatory diet 
as treatment for inflammatory bowel disease: a case series report. Nutrition journal. 2014;13:5. 
65. 
Sandborn WJ. Crohn's disease evaluation and treatment: clinical decision tool. Gastroenterology. 
Sep 2014;147(3):702-705. 

 
Page 43 of 81 
 
 
66. 
Schwingshackl L, Hoffmann G. Mediterranean dietary pattern, inflammation and endothelial 
function: a systematic review and meta-analysis of intervention trials. Nutrition, metabolism, and 
cardiovascular diseases : NMCD. Sep 2014;24(9):929-939. 
67. 
Hoevenaar-Blom MP, Nooyens AC, Kromhout D, et al. Mediterranean style diet and 12-year 
incidence of cardiovascular diseases: the EPIC-NL cohort study. PloS one. 2012;7(9):e45458. 
68. 
Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a 
Mediterranean diet. The New England journal of medicine. Apr 4 2013;368(14):1279-1290. 
69. 
Schwingshackl L, Hoffmann G. Adherence to Mediterranean diet and risk of cancer: a systematic 
review and meta-analysis of observational studies. International journal of cancer. Journal 
international du cancer. Oct 15 2014;135(8):1884-1897. 
70. 
Sofi F, Cesari F, Abbate R, Gensini GF, Casini A. Adherence to Mediterranean diet and health 
status: meta-analysis. BMJ. 2008;337:a1344. 
71. 
Fumery M, Xiaocang C, Dauchet L, Gower-Rousseau C, Peyrin-Biroulet L, Colombel JF. 
Thromboembolic events and cardiovascular mortality in inflammatory bowel diseases: a meta-
analysis of observational studies. J Crohns Colitis. Jun 2014;8(6):469-479. 
72. 
De Filippis F, Pellgrini N, Vannini L, et al. High-level adherence to a Mediterranean diet 
beneficially impacts the gut microbiota and associated metabolome. Gut. 2015:In press. 
73. 
Long MD, Kappelman MD, Martin CF, et al. Development of an internet-based cohort of patients 
with inflammatory bowel diseases (CCFA Partners): Methodology and initial results. Inflamm. 
Bowel Dis. Nov 2012;18(11):2099-2106. 
74. 
Thia K, Faubion WA, Jr., Loftus EV, Jr., Persson T, Persson A, Sandborn WJ. Short CDAI: 
development and validation of a shortened and simplified Crohn's disease activity index. Inflamm. 
Bowel Dis. Jan 2011;17(1):105-111. 
75. 
Vermeire S, Schreiber S, Sandborn WJ, Dubois C, Rutgeerts P. Correlation between the Crohn's 
disease activity and Harvey-Bradshaw indices in assessing Crohn's disease severity. Clin 
Gastroenterol Hepatol. Apr 2010;8(4):357-363. 
76. 
Khanna R, Zou G, D'Haens G, et al. A retrospective analysis: the development of patient reported 
outcome measures for the assessment of Crohn's disease activity. Aliment Pharmacol Ther. Jan 
2015;41(1):77-86. 
77. 
Pincus T, Swearingen CJ, Bergman MJ, et al. RAPID3 (Routine Assessment of Patient Index 
Data) on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with 
DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, 
scored in five versus more than ninety seconds. Arthritis Care Res (Hoboken). Feb 
2010;62(2):181-189. 
78. 
Pincus T, Yazici Y, Bergman M. A practical guide to scoring a Multi-Dimensional Health 
Assessment Questionnaire (MDHAQ) and Routine Assessment of Patient Index Data (RAPID) 
scores in 10-20 seconds for use in standard clinical care, without rulers, calculators, websites or 
computers. Best Pract Res Clin Rheumatol. Aug 2007;21(4):755-787. 
79. 
Sieper J, van der Heijde D, Landewe R, et al. New criteria for inflammatory back pain in patients 
with chronic back pain: a real patient exercise by experts from the Assessment of 
SpondyloArthritis international Society (ASAS). Ann. Rheum. Dis. Jun 2009;68(6):784-788. 
80. 
Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing 
spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J. Rheumatol. 
Dec 1994;21(12):2281-2285. 
81. 
Daperno M, D'Haens G, Van Assche G, et al. Development and validation of a new, simplified 
endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest. Endosc. Oct 
2004;60(4):505-512. 
82. 
Henao MP, Bewtra M, Osterman MT, et al. Measurement of Inflammatory Bowel Disease 
Symptoms: Reliability of an Abbreviated Approach to Data Collection. Inflamm Bowel Dis. Jul 17 
2015. 
83. 
Mao R, Xiao YL, Gao X, et al. Fecal calprotectin in predicting relapse of inflammatory bowel 
diseases: a meta-analysis of prospective studies. Inflamm. Bowel Dis. Oct 2012;18(10):1894-
1899. 
84. 
Harvey RF, Bradshaw JM. A simple index of Crohn's-disease activity. Lancet. 1980;1(8167):514. 
85. 
Khanna R, Zou G, D'Haens G, et al. A retrospective analysis: the development of patient reported 
outcome measures for the assessment of Crohn's disease activity. Aliment. Pharmacol. Ther. Jan 
2015;41(1):77-86. 

 
Page 44 of 81 
 
 
86. 
Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn's disease activity index. 
National Cooperative Crohn's Disease Study. Gastroenterology. 1976;70(3):439-444. 
87. 
Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints 
for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology. Feb 
2002;122(2):512-530. 
88. 
Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory 
Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Am. J. 
Gastroenterol. Aug 25 2015. 
89. 
Osterman MT, Aberra FN, Cross R, et al. Mesalamine dose escalation reduces fecal calprotectin 
in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol. Nov 2014;12(11):1887-
1893 e1883. 
90. 
Lewis JD. The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. 
Gastroenterology. May 2011;140(6):1817-1826 e1812. 
91. 
Summerton CB, Longlands MG, Wiener K, Shreeve DR. Faecal calprotectin: a marker of 
inflammation throughout the intestinal tract. Eur J Gastroenterol Hepatol. Aug 2002;14(8):841-
845. 
92. 
D'Haens G, Ferrante M, Vermeire S, et al. Fecal calprotectin is a surrogate marker for endoscopic 
lesions in inflammatory bowel disease. Inflammatory bowel diseases. Dec 2012;18(12):2218-
2224. 
93. 
Sipponen T, Karkkainen P, Savilahti E, et al. Correlation of faecal calprotectin and lactoferrin with 
an endoscopic score for Crohn's disease and histological findings. Aliment. Pharmacol. Ther. Nov 
15 2008;28(10):1221-1229. 
94. 
Schoepfer AM, Beglinger C, Straumann A, et al. Fecal calprotectin correlates more closely with 
the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and 
the CDAI. The American journal of gastroenterology. Jan 2010;105(1):162-169. 
95. 
Waugh N, Cummins E, Royle P, et al. Faecal calprotectin testing for differentiating amongst 
inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation. 
Health technology assessment. Nov 2013;17(55):xv-xix, 1-211. 
96. 
Lin JF, Chen JM, Zuo JH, et al. Meta-analysis: fecal calprotectin for assessment of inflammatory 
bowel disease activity. Inflammatory bowel diseases. Aug 2014;20(8):1407-1415. 
97. 
Schoepfer AM, Lewis JD. Serial fecal calprotectin measurements to detect endoscopic recurrence 
in postoperative Crohn's disease: is colonoscopic surveillance no longer needed? 
Gastroenterology. May 2015;148(5):889-892. 
98. 
Wright EK, Kamm MA, De Cruz P, et al. Measurement of fecal calprotectin improves monitoring 
and detection of recurrence of Crohn's disease after surgery. Gastroenterology. May 
2015;148(5):938-947 e931. 
99. 
Armitage P, Berry G. Statistical Methods in Medical Research. 2nd ed. Oxford: Blackwell 
Scientific Publications; 1987. 
100. 
Piantadosi S. Clinical trials: A methodological perspective. New York: John Wiley & Sons, Inc.; 
1997. 
101. 
Meinert C, Tonascia S. Clinical Trials: Design, Conduct, and Analysis. Oxford: Oxford university 
Press; 1986. 
102. 
Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation 
[published erratum appears in Am J Epidemiol 1989 Nov;130(5):1066]. Am. J. Epidemiol. 
1989;129(1):125-137. 
103. 
Ananthakrishnan AN, Long MD, Martin CF, Sandler RS, Kappelman MD. Sleep disturbance and 
risk of active disease in patients with Crohn's disease and ulcerative colitis. Clinical 
gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association. Aug 2013;11(8):965-971. 
104. 
Agency EM. Guideline on Missing Data in Confirmatory Clinical Trials 10 July 2010. 2010. 
 
 
 
 

 
Page 45 of 81 
 
 
Appendix A 
 
 
Protocol Signature Page 
I will provide copies of the DINE-CD Study protocol (v5.4 2019.Apr.10), any subsequent protocol 
amendments and access to all information furnished by the sponsor to study personnel under my 
supervision.  I will discuss this material with them to ensure that they are fully informed about the 
investigational drug and the study protocol. 
 
I agree to conduct this clinical trial according to the protocol described herein.   I also agree to conduct 
this study in compliance with applicable federal, state and local regulations, Guidelines for Good Clinical 
Practice (GCP), and with the requirements of my Institutional Review Board.  I understand that I may not 
implement this protocol without first receiving written IRB approval.  
 
Furthermore, I understand that I cannot make any changes to this protocol.  (The only exception being an 
action needed to remove a subject from immediate harm, with subsequent notification to the study PI and 
IRB.) 
 
 
 
CLINICAL SITE INVESTIGATOR:___________________________________                ___________ 
 
 
 
 
 
 
(Signature) 
 
 
 
 
(Date) 
 
 
NAME: (Please Print) 
 
 
 
INSTITUTION: 
 
 
Instructions: Upon signature, please upload a copy of this form to the DMS. 
 
 
 

 
Page 46 of 81 
 
 
Appendix B 
 
 

 
Page 47 of 81 
 
 
Appendix C 
Data and Safety Monitoring Plan 
 
Randomized, Multicenter, Comparative Effectiveness Trial of Specific 
Carbohydrate and Mediterranean Diets to Induce Remission in 
Patients with Crohn’s Disease 
James Lewis, M.D., M.S.C.E., Principal Investigator 
Perelman School of Medicine at the University of Pennsylvania 
 
1. Overview 
1.1. Purpose of the study 
This is a randomized, multicenter, comparative effectiveness trial of SCD and MSD to induce remission 
in patients with Crohn’s Disease.  The primary study objectives are  
 
1. To compare the effectiveness of the specific carbohydrate diet and a Mediterranean style diet to 
induce symptomatic and clinical remission in patients with Crohn’s disease. 
2.  
 
Secondary objectives include:  
1. To compare the effectiveness of the specific carbohydrate diet and a Mediterranean style diet to 
reduce mucosal inflammation in patients with active Crohn’s disease. Mucosal inflammation will be 
assessed by measuring the concentration of calprotectin in the feces (FCP). 
2. To compare the effectiveness of the Specific Carbohydrate Diet and a Mediterranean style diet to 
reduce systemic inflammation in patients with active Crohn’s disease. Systemic inflammation will be 
assessed by measuring the concentration of C reactive protein (CRP). 
 
3. To compare the effectiveness of the specific carbohydrate diet and a Mediterranean style diet to 
improve the following symptoms in patients with Crohn’s disease: a) fatigue, b) pain, c) joint 
symptoms. 
4. To determine the proportion of patients who continue the study diets when prepared food is no 
longer provided without cost and the reasons for discontinuation of the diets.   
 
Participants will be screened for eligibility criteria and if eligible, enrolled into the trial.  Participants will 
continue on the diet to which they are randomized for 6 weeks with all food being provided to the 
participant during this time period. Participants will complete daily online surveys throughout their entire 
participation. From consent to the last study visit, participants may complete up to 15 weeks of daily online 
surveys. The primary outcome will be assessed at week 6 at an in-person visit.  From weeks 7 to 12 
participants will be asked to adhere to their randomized study diet on their own. At week 12 participants 
will be evaluated at an in-person visit.   
 
The study is designed to enroll 97 patients into each of the treatment arms. Specific aims 1 and 2 will be 
considered separately and no reduction in type 1 error will be applied for multiple testing. With 97 
participants per group, the study will have 80% to 90% power with a type 1 error of 5% to detect a 
difference of 20% in effectiveness of the two diets depending on the success rate in the reference arm. 
Our PPRN Patient Governance Council met and determined that a smaller difference is unlikely to justify 
the challenges of following a strict restriction diet. 
1.2. Adherence statement.  
The Data and Safety Monitoring Plan (DSMP) outlined below will adhere to the protocol approved by the 
University of Pennsylvania IRB. 
 

 
Page 48 of 81 
 
 
2. Adverse Events 
2.1. Definitions 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event (not life threatening but may require intervention; for example drug 
overdose, drug abuse, a seizure not resulting in hospitalization) 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
2.2. Expected Adverse Events 
As a short term study of two diets, there are few expected risks of the two interventions. These include 
allergic reaction to a component of the food, intolerance of the food other than as an allergic reaction, 
and worsening of Crohn’s disease manifest as any of the following: worsened abdominal pain, worsened 
diarrhea, bowel obstruction, penetrating complications such as fistula or abscess. In addition, worsening 
of extraintestinal manifestations of Crohn’s disease is possible, such as worsening arthropathy, mouth 
sores, skin rashes including pyoderma gangrenosum and erythema nodosum, and ocular manifestations 
such as episcleritis or uveitis. The Crohn’s disease related adverse events would not be considered to 
be caused by the diets, but rather as  consequence of failure of the diet based therapy to induce disease 
remission.  
 
These risks are specified in the protocol and informed consent form.  
2.3. Recording of Adverse Event (AE) 
At each contact with the subject from the screening visit to the end of study visit, the Site Investigator or 
Site Coordinator will seek information on adverse events by specific questioning and, as appropriate, by 
examination. Every event that is reported to either the principal investigator or the designated research 
associates by the subject or medical staff caring for the subject and which meets the criteria will be 
documented. Information on all adverse events will be recorded immediately on the AE case report form 
(CRF). We will document a description of the event, the date the event occurred, its relation to the 
investigational product or study procedures (not related, possibly related, definitely related, unknown), the 
grade of severity (normal, mild, moderate, severe), whether it is resolved or ongoing, and if resolved, the 
resolution date. The site investigator will be required to review each AE and initial on the AE form that 
they have reviewed it. The clinical course of each event will be followed until resolution, stabilization, or 
until it has been determined that the study intervention or participation is not the cause.   
 

 
Page 49 of 81 
 
 
Related, treatment-emergent serious and severe adverse events that are still ongoing at the end of the 
study period will be followed up to determine the final outcome, which may include resolution or stable 
outcome.   
2.4. Relationship of AE to Study  
The relationship of each adverse event to the study procedures should be characterized by the Site 
Investigator and recorded on the case report form. The relationship to the study intervention will be 
classified as definitely related, possibly related, not related, or unknown.  For reporting purposes, an 
Adverse Event is considered “related to participation in the research” if the cause of the event is deemed 
possibly related or definitely related to the investigational product or a procedure that was performed for 
the purposes of the research.  
2.5. Reporting of Serious Adverse Events and Unanticipated Problems  
A Serious Adverse Event or Unanticipated Problem (see definition below) is required to be reported to the 
relying IRB within 10 days. If the adverse event involved a death and indicates that participants or others 
are at increased risk of harm the investigators are required to submit a report to the relying IRB within 3 
days. 
 
Non-medical Unanticipated Problems that should be reported to the IRB may include complaint of a 
participant when the complaint indicates unexpected risks or the complaint cannot be resolved by the 
research team, breach of confidentiality, incarceration of a participant when the research was not 
previously approved under Subpart C and the investigator believes it is in the best interest of the subject 
to remain on the study, or premature completion of the entire study for any reason. 
 
Serious Adverse Events or Unanticipated Problems will be reported to the relying IRB using either a 
Reportable Event form from the relying IRB, or by writing a narrative including the minimum necessary 
information listed below.  If not all information is known within the reporting timeframe, the site investigator 
should still complete a Reportable Event form or narrative within the timeframe with the information 
available and inform the relying IRB that a follow-up report will be provided when all information is known. 
 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study intervention was discontinued 
 
The reason why the event is classified as serious 
 
Investigator 
assessment 
of 
the 
association 
between the event and study intervention 
 
 
If an event does not meet the definition above of a Serious Adverse Event or Unanticipated Problem, a 
narrative summary of events that occurred should be submitted to the relying IRB at the time of Continuing 
Review, including a rational for why the event(s) was not reportable within 10 days.  
 
Any known serious adverse event that occurs after the study period and is considered to be possibly or 
definitely related to the study intervention or study participation will be recorded and reported to the PI, 
the sponsor, and the relying IRB immediately. 
2.5.1. Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) should be submitted to the relying IRB. The 
site investigator is responsible for ensuring that all SAEs are followed until either resolved or stable. 
2.5.2. Investigator reporting: notifying the study sponsor (Penn) 
Site investigators should report serious adverse events and unanticipated problems meeting the 3 day 
reporting requirement (as defined in section 9.5) to the University of Pennsylvania Sponsor by phone and 
via the data management system. Phone notification should be within 24 hours of the site investigator 

 
Page 50 of 81 
 
 
becoming aware of the serious adverse event. Notification via the DMS should be done within 72 hours. 
In the case where the DMS form cannot be fully completed with 72 hours, a partially completed form 
should be entered into the DMS within 72 hours, and a completed form should be entered as soon as is 
possible. Report SAE’s by phone to: 
 
James D. Lewis, MD   
Phone: (215) 573-5137 
 
 
In the event Dr. Lewis cannot be reached, report SAEs to 
Meenakshi Bewtra, MD 
Phone: (215) 746-4922 
 
Or  
Adam Hawkins 215-746-4218 or Lisa Nessel (215) 573-6003  
 
 
SAE’s that do not meet the 3 day reporting requirement (i.e., do not involve death or indicate that 
participants are at increased risk) should be reported to the sponsor within 10 days via the data 
management system only. No phone call will be required. 
 
For a flow chart outlining SAE reporting to the sponsor, please see Figure 1 below. 
 
 
Figure1. SAE Flow Chart 
 
 

 
Page 51 of 81 
 
 
 
3. Safety Review Plan and Monitoring 
Principal Investigator (PI): Adverse events will be reviewed by the PI and the members of the 
DSMB. As described above, the PI will review all SAE reports in real time. Every quarter, 
reports of adverse events will be tabulated for review by the PI. The adverse events will be 
categorized by MedDRA categories at increasingly levels of granularity. The PI is also 
responsible for overall monitoring of the progress of the study, including enrollment, retention, 
data completeness, and site monitoring. 
 
A Data and Safety Monitoring Board (DSMB) will be assembled prior to enrolment of the first 
participant in the trial. The DSMB will consist of at least 5 members. Three members will 
constitute a quorum.  Members of the DSMB shall have no financial, scientific, or other conflict 
of interest with the study. Collaborators or associates of the investigators in this trial are not 
eligible to serve on the DSMB. Written documentation attesting to absence of conflict of interest 
is required. Please see the DSMB charter for further details.  
 
The DSMB will meet once prior to the start of recruitment.  Subsequently, the DSMB will meet 
annually  with the first meeting occurring no later than once 50% of the total accrual goal has 
been met. . The DSMB may request an emergency meeting at any time and for any reason. At 
each DSMB meeting, review of progress will include updates on enrollment, retention, data 
completeness, and site monitoring. The DSMB members will also review all reported adverse 
events, including SAEs.  
 
Overall progress of the trial will be reported to PCORI according to the standard PCORI 
progress report template. 
 
The study investigators will obtain a renewal of the IRB approval for all participating sites at 
least once each year. Were the IRB approval to lapse at any site, no further research activity 
shall take place at that study site until approval renewal is obtained.  
 
4. Informed Consent 
 
Informed consent will be obtained from each subject at entry into the study. No study activities 
will occur until Informed Consent occurs. The participants may be verbally consented initially, 
with a formal in-person consent process completed in person. At both the verbal and in-person 
consent the entire study, study procedures, and intervention will be explained to the participant 
as well as the risks involved to the participant in participating. They will be given time to read 
over the study information and discuss it with their doctor, family, or friends, if they would like. 
They will also be given the opportunity to ask any questions to the study team and they will be 
provided with the contact number for the Office of Research Affairs if they have questions 
about their rights as a research participant. They will be made duly aware that participation in 
the research study is voluntary and they do not lose any of their rights by participating. If the 
participant would like to participate in the study, they will be asked to sign and date the consent 
form. The study staff obtaining consent will also sign and date the consent form and provide a 
copy to the participant.  
 
Verbal Informed consent may occur if a potential participant is identified via chart review prior 
to their upcoming clinic visit. In this case, the Research Coordinator will ask the potential 
participant’s gastroenterologist if he or she may contact the potential participant about the 
study. If permission is granted, the Coordinator will call the potential participant and gain their 
interest in the trial. If they are interested and would like to provide a stool sample, complete 
surveys about their current Crohn’s disease symptoms and complete a screening visit at the 
time of their upcoming clinic visit, then the Coordinator will complete a verbal consent process 
with the potential participant. Upon coming into the clinic, the Coordinator will complete an in-
person informed consent process with the participant.  
 

 
Page 52 of 81 
 
 
5. Data Quality and Management 
 
A. 
Describe measures taken to insure data integrity and protection of databases.  
 
The Biostatistics Core of the Center for Gastrointestinal Biology and Disease at the University of 
North Carolina Chapel Hill will serve as the Data Management Center. The DMC will be charged 
with creating, managing, and housing the data management.  The DCC will be charged with 
assuring data is entered and are complete and accurate. The DCC will also be charged with data 
and safety monitoring and coordinating all meetings of the DSMB.  
 
Site Coordinators will complete minimal data entry immediately after each participant’s visit, 
utilizing a double data entry system to minimize error and ensure data quality. 
 
With the exception of the minimal visit data, most of the data to be collected in this study will be 
collected directly from participants through our web-based data entry system. For specific aim 1, 
the primary outcome is derived from patient reported data. For specific aim 2, the primary 
outcome is derived from the measurement of the concentration of fecal calprotectin, which will 
be done by a commercial laboratory LabCorp. Such data are not subject to monitoring other 
than for completeness. This will be done by the data analysts.  
 
We will monitor the sites for compliance with regulatory documentation and for compliance with 
the study protocol, particularly as it relates to inclusion criteria. We will utilize a system whereby 
the local investigator team prints, redacts, and uploads into our data management system source 
documents that demonstrate the eligibility of the participants. Study monitors will then remotely 
review these documents for compliance with the study protocol, send queries to the local sites, 
resolve outstanding queries, and document the level of adherence with the study protocol. See 
the table below for the list of source documents that the monitors will review for each 
inclusion/exclusion criteria. Any findings that demonstrate a protocol deviation will be reported to 
the Penn IRB or local IRB, as appropriate. The first remote monitoring visit will occur after a site 
enrolls its first 4 participants. After that, remote monitoring visits will occur each time 6 more 
participants are enrolled (for example, visits will occur after the 4th, 10th, 16th, 22nd participant, etc). 
 
Similar methods will be employed for reviewing the participating sites regulatory binder. We will 
provide each site with an electronic storage area where their regulatory documents can be stored 
and then reviewed by the monitors. Eligibility criteria and consent process will be monitored for 
all participants. If deemed necessary, on site monitoring will be employed. 
 
Source Documents that will be reviewed by the study monitors for protocol compliance are 
outlined in the following table. 
Data type 
Source Document to review 
Age 
Demographics from medical record 
Medications 
Office notes from 16 weeks prior to randomization 
and medication list up to 16 weeks prior to 
randomization 
Clostridium Difficile 
Any stool sample testing in medical record within 
4 weeks prior to the screening visit 
Diabetes 
Mellitus 
requiring 
medication 
Medication list and problem list/diagnosis list in 
medical record 
hsCRP 
Blood draw results done by the study at the 
screening visit, at week 6 and week 12 
Albumin 
Blood draw results in medical record within 4 
weeks prior to the screening visit 
BMI 
Physical exam source document done at the 
screening visit 
FCP 
FCP result done by the study at baseline (stool 

 
Page 53 of 81 
 
 
must be collected within 28 days prior to start of 
study diet), at week 6 and week 12 
sCDAI score 
sCDAI score in the DMS at baseline from at least 
5 days of symptom recording 
Intestinal Stricture 
Imaging in the last year and two office notes – the 
office note closest to the screening visit and the 
office note immediately preceding that visit 
 
 
Data quality checks will be built into the DMS, such that nonsensical data will prompt the Site 
Coordinators to check for accuracy, certain questions will be required for form completion, 
and skip patterns will be in place. We will also implement a data quality monitoring system 
after the second patient is enrolled that will report on form completeness and on the 
timeliness of form completion. Data quality checks will continue monthly throughout the study 
by the Data Coordinating Center. Data queries will be sent from the DCC to the local sites.  
 
Reports on form completion, missing data reports so that we are aware of patterns of missing 
data early on in the study, logic checks will be completed throughout the study. Reminders 
will be automatically sent to the sites from the DMS for upcoming visit target dates 14 days 
prior to the visit target date. Another reminder will be sent in advance of visit window closing 
dates. Not only are we going to check for missing data we are going to proactively manage 
the data to avoid missing data.  
 
B. 
Describe measures taken to insure data integrity and protection of databases. 
All computer systems and programs will be password protected, and all electronic 
communications of study and other confidential information will be encrypted. Personnel at the 
CGIBD have extensive training and experience using electronic data systems. Good computer 
security practice (restricting physical access to machines, prohibition of password sharing, and 
logging off computers after work hours or when away from the machine) will be required of all 
study personnel.  
 
Standard Operating Procedures exist for users of the DMS. Only authorized persons are 
authorized for data entry and access. Data security systems require password protected 
identification codes for data entry and provide protection against data manipulation. The database 
is located on a server protected by firewalls. Access to the database server will not be allowed by 
users on computers outside of the firewall-protected zone. Virus protection software is installed 
on each study machine. System access to computer systems will be audited. Redundant backups 
and off-site backup storage will allow for quick restoration of data in the unlikely event that a 
hardware failure, disaster, or security breach should occur. Servers and backups will be located 
in a secured location with access limited to authorized personnel. 
6. Confidentiality 
 
As mentioned in the section above, participant information will be kept on secure servers and 
electronic communication of information will be encrypted. Samples and CRFs will be labeled 
with a unique study identifier to protect participants’ confidentiality. Only members of the study 
team will have access to the web application. Source documents will be kept separately from 
CRFs.  Paper forms with participants’ identifiers will be kept secure in a double lock system 
such as a locked filing cabinet in a locked office.  
 
 

 
Page 54 of 81 
 
 
Appendix D 
DINE-CD SOP: Assembly of Stool Sample Collection Kits  
Version: 1 
Date: August 19, 2016 
 
This SOP outlines the assembly of stool sample collection kits at the Data Coordinating Center. 
 
If you have any questions, please contact Adam Hawkins ahawkeye@upenn.edu or 215-746-
4218 
 
To be done in advance, or on a continuous basis, by lData Coordinating Center 
Materials for ONE Specimen Collection kit:  
 
A. (1) White stool collection bucket + lid + frame 
B. (1) Therapak Styrofoam shipper 
C. (1) Gallon-size Ziploc bag 
D. (1) Biohazard label 
E. (1) Exempt Human Specimen label 
F. (1) Study label  
G. (1) Stool Collection form 
H. (1) Stool Collection Instructions for participants 
I. (1) UPS/FedEX Shipping label to ship to the participant’s home (if applicable) 
J. (1) UPS/FedEX Shipping label for the participant to ship the sample to the University of 
Pennsylvania 
K. (1) Black canvas bag (for Penn participants) 
L. (1) Additional Black canvas bag (for Penn participants who will bring the stool sample with them to 
their visit) 
*You will also need mailing tape 
 
1. Print and obtain a study label with the participant’s study ID number on it 
2. Get a white stool collection bucket and place a study label on it. 
3. Print a Stool Collection form and record the participant’s ID number on it and date of birth. 
4. Place the white bucket with the lid on it, the Ziploc bag, the Stool Collection form and Stool 
Collection instructions for participants into the Styrofoam shipper.  
5. Obtain a UPS/FedEx Shipping label with the following name and address as the sender and 
recipient: 
Name: Lillian Chau 
Address: 421 Curie Blvd 
 
 936 BRB II/III 
 
Philadelphia, PA 19104 
 
6. Insert the shipping label into a plastic sleeve  
 
7. Place the shipping label and sleeve from step 6 inside the Styrofoam cooler so that the 
participant can use it after they receive the kit. Close the lid. Place the frame in the box and 
gently fold it over the lid of the Styrofoam cooler, making sure it doesn’t break. 
8. Seal the box with mailing tape. 
9. You need to print/obtain another shipping label that will have your address as the sender and 
the participant as the recipient.  

 
Page 55 of 81 
 
 
10. Place this label on the outside of the box (either in a sleeve or not; if you use a sleeve, you can 
instruct the participant to use this same sleeve when it is their turn to ship. Taking the sleeve 
off may damage the integrity of the box making it unacceptable to ship).  
11.  Place the Biohazard Label and Exempt Human Specimen label on the outside of the shipper 
cardboard box on a different side than the shipping label. 
12. Arrange for courier pick-up or drop off the box at a courier pick-up location or store. 
 
 
 

 
Page 56 of 81 
 
 
STOOL COLLECTION INSTRUCTIONS 
 
Please collect your first stool sample as soon as possible on a Sunday, Monday, Tuesday, or 
Wednesday following the instructions below. Do not collect a sample on Thursday, Friday, 
or Saturday. You will need to schedule your sample to be picked up by UPS as soon as 
possible after you collect it so that it is shipped soon after collection (see step 16 on page 3 
below).  
 
Contact your study coordinator if you notice any of the pieces of the kit below are missing 
or if you have any questions as you complete the stool collection.  
 
Each stool collection kit contains: 
 
One stool collection bucket with a frame, a lid, and a label on the 
outside. 
One gallon-size plastic storage bag 
Four gel ice packs 
One Therapak Shipper: a Styrofoam cooler and lid inside a cardboard 
box, equipped with a Biohazard label, an Exempt Human Specimen 
label, an Excepted Quantities label and a plastic specimen bag.  
One spoon-top labeled vial filled with 5mL ethanol  
 
One Stool Collection form to document date and time of collection and 
date of birth (further instructions for filling out the form are located on 
the form) 

 
Page 57 of 81 
 
 
 
STEP 1. Put the gel ice packs in your freezer at home as soon as 
you get your kit so they are already frozen when you are ready to 
collect your sample(s).   
 
 
 
 
STEP 2. When you are ready to collect the sample, raise the toilet 
seat.  Pass urine into the toilet first, if necessary. Do not let urine 
or water from the toilet get into the collection bucket. Place 
the stool collection frame on the back of the toilet bowl.  All four 
corners of the collection frame should be supported by the toilet 
bowl.  Place collection bucket in the frame.  
 
 
 
 
 
 
STEP 3. Place the toilet seat down.  Do not urinate into the 
collection bucket and do not let urine or water touch the stool 
sample.  Deposit your stool directly into the collection bucket. 
 
STEP 4. After collecting your sample, remove the collection bucket 
from the frame.  Discard the frame.   
 
 
STEP 5. Take the lid off of the spoon-top vial. Scoop a small 
amount of stool from the sample and place this into the vial. Only 
scoop enough to fill the scoop. It does not need to be a heaping 
scoop. Screw the tap on the vial tightly. Shake the vial to make 
sure the sample comes off the spoon.  
 
 
STEP 6.  Write the date on the label on the outside of the vial. Place 
the vial in the plastic bag labeled, “Biohazard” and seal the bag. 

 
Page 58 of 81 
 
 
STEP 7. Put the lid on the stool collection bucket and write the date 
of collection on the label on the outside. Place it in the gallon size 
Ziploc plastic bag and seal the bag. 
 
 
 
 
 
 
 
STEP 8.  Complete the Stool Collection form. Record the date and 
time of collection on the Stool Collection Form. Also record your 
Date of Birth if it is not already recorded there by the Study 
Coordinator. Lastly, choose the type on the Bristol Stool scale that 
most represents your sample and record it in the space provided. 
 
 
 
 
 
STEP 9. Put the frozen gel ice packs in the Styrofoam cooler.  
 
STEP 10. Put the two plastic bags containing your samples into the 
cooler. 
 
 
 
 
 
STEP 11. Fold the Stool Collection form and place it on top of the 
samples. Put the lid of the cooler on top. 
 
STEP 12. Close the flaps on the box. The sample is ready to be 
provided to study staff.  
 
***The next steps are for shipping the sample to the study lab 
at the University of Pennsylvania *** 
 
STEP 13: Seal the box with tape to prepare for shipping 
 
STEP 14: Place the shipping label that was included in the cooler in 
the label pouch on the outside of the box, replacing the used label. 
 
STEP 15: Make sure the Biohazard sticker, the “Exempt Human 
Specimen,” sticker and the sticker with a red capital letter “E” are on 
the box.  
 
STEP 16: Call 1-800-PICK-UPS to arrange a pick-up of the sample. 
Place the sample outside your home for the courier to pick up. You 
will not need to be there when they pick it up. All pick up fees will be 
paid for by the study. If you collect a sample at night, have it picked 
up the next morning. 
 
 
 

 
Page 59 of 81 
 
STOOL COLLECTION INSTRUCTIONS 
 
For your 2nd and 3rd stool samples in the study, we need you to collect a sample during the 
following date ranges: 
 
 Between mm/dd/yyyy [insert day 38] and mm/dd/yyyy [insert day 40]  AND 
 Between mm/dd/yyyy [insert day 80] and mm/dd/yyyy [insert day 82] 
 
Contact your study coordinator if you notice any of the pieces of the kit below are missing 
or if you have any questions as you complete the stool collection.  
 
Each stool collection kit contains: 
 
One stool collection bucket with a frame, a lid, and a label on the 
outside. 
One gallon-size plastic storage bag 
Four gel ice packs 
One Therapak Shipper: a Styrofoam cooler and lid inside a cardboard 
box, equipped with a Biohazard label, an Exempt Human Specimen 
label, an Excepted Quantities label and a plastic specimen bag.  
One spoon-top labeled vial filled with 5mL ethanol  
 
One Stool Collection form to document date and time of collection and 
date of birth (further instructions for filling out the form are located on 
the form) 

 
Page 59 of 81 
 
 
 
STEP 1. Put the gel ice packs in your freezer at home as soon as you 
get your kit so they are already frozen when you are ready to collect 
your sample(s).   
 
 
 
 
STEP 2. When you are ready to collect the sample, raise the toilet 
seat.  Pass urine into the toilet first, if necessary. Do not let urine 
or water from the toilet get into the collection bucket. Place 
the stool collection frame on the back of the toilet bowl.  All four 
corners of the collection frame should be supported by the toilet 
bowl.  Place collection bucket in the frame.  
 
 
 
 
 
 
STEP 3. Place the toilet seat down.  Do not urinate into the collection 
bucket and do not let urine or water touch the stool sample.  Deposit 
your stool directly into the collection bucket. 
 
STEP 4. After collecting your sample, remove the collection bucket 
from the frame.  Discard the frame.   
 
 
STEP 5. Take the lid off of the spoon-top vial. Scoop a small amount 
of stool from the sample and place this into the vial. Only scoop 
enough to fill the scoop. It does not need to be a heaping scoop. 
Screw the tap on the vial tightly. Shake the vial to make sure the 
sample comes off the spoon.  
 
 
STEP 6.  Write the date on the label on the outside of the vial. Place 
the vial in the plastic bag labeled, “Biohazard” and seal the bag. 

 
Page 60 of 81 
 
 
STEP 7. Put the lid on the stool collection bucket and write the date 
of collection on the label on the outside. Place it in the gallon size 
Ziploc plastic bag and seal the bag. 
 
 
 
 
 
 
 
STEP 8.  Complete the Stool Collection form. Record the date and 
time of collection on the Stool Collection Form. Also record your Date 
of Birth if it is not already recorded there by the Study Coordinator. 
Lastly, choose the type on the Bristol Stool scale that most 
represents your sample and record it in the space provided. 
 
 
 
 
 
STEP 9. Put the frozen gel ice packs in the Styrofoam cooler.  
 
STEP 10. Put the two plastic bags containing your samples into the 
cooler. 
 
 
 
 
 
 
STEP 11. Fold the Stool Collection form and place it on top of the 
samples. Put the lid of the cooler on top. 
 
STEP 12. Close the flaps on the box. The sample is ready to be 
provided to study staff.  
 
***The next steps are for shipping the sample to the study lab 
at the University of Pennsylvania *** 
(if you are a participant at the University of Pennsylvania and this is 
your week 6 or week 12 sample, you may bring you sample to your 
study visit.) 
 
STEP 13: Seal the box with tape to prepare for shipping 
 
STEP 14: Make sure there is a shipping label on the outside of the 
box (should have been already put on the box by study staff) 
 
STEP 15: Make sure the Biohazard sticker, the “Exempt Human 
Specimen,” sticker and the sticker with a red capital letter “E” are on 
the box.  
 
STEP 16: Call 1-800-PICKUPS to arrange a pick-up of the sample. 
Place the sample outside your home for the courier to pick up. You 
will not need to be there when they pick it up. All pick up fees will be 
paid for by the study. 
 
 
 

 
Page 61 of 81 
 
Appendix F 
DSMB Charter 
Randomized, Multicenter, Comparative Effectiveness Trial of Specific Carbohydrate and 
Mediterranean Diets to Induce Remission in Patients with Crohn’s Disease 
James Lewis, M.D., M.S.C.E., Principal Investigator 
Perelman School of Medicine at the University of Pennsylvania 
 
 
1. Introduction 
This Data and Safety Monitoring Board charter is for a clinical trial titled, “Randomized, Multicenter, 
Comparative Effectiveness Trial of Specific Carbohydrate and Mediterranean Diets to Induce Remission in 
Patients with Crohn’s Disease” with a short title Dietary Intervention in Crohn’s Disease (Dine CD).  This 
study is being funded by the Patient-Centered Outcomes Research Institute (PCORI) and the Crohn’s and 
Colitis Foundation (CCF). The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity 
to the investigator sponsor, Dr. Lewis, and the CCF to monitor patient safety and evaluate the efficacy of 
the intervention. 
 
2. MEMBERsHIP  
 
The Data Safety Monitoring Board will consist of at least 5 members. Three members will constitute a 
quorum.  Members of the DSMB shall have no financial, scientific, or other conflict of interest with the 
study. Collaborators or associates of the investigators in this trial are not eligible to serve on the DSMB. 
Written documentation attesting to absence of conflict of interest is required.  
  
Dr. Naihua Duan, Professor Emeritus of Biostatistics (in Psychiatry) at Columbia University has been 
selected to serve as the DSMB Chairperson. He is responsible for overseeing the meetings and developing 
the agenda in consultation with the PI and the Administrative PI, Angela Dobes, MPH of the CCF. Orna 
Ehrlich, CCF’s Senior Director, Professional Education will serve as the DSMB Executive Secretary (ES) 
and is the contact person for the DSMB. Other PCORI and CCF officials may serve as ex-officio members 
of the DSMB.  The University of Pennsylvania shall provide the logistical management and financial support 
for the DSMB.  
 
3. RESPONSIBILITIES 
3.1. Responsibilities of the DSMB 
The initial responsibility of the DSMB will be to approve the initiation of this clinical trial. After this 
approval, and at periodic intervals during the course of the trial, the DSMB responsibilities are to:  
 
review the research protocol and plans for data safety and monitoring, including all proposed 
revisions; 
 
evaluate the progress of the trial, including periodic assessments of data quality and timeliness, 
participant recruitment, accrual and retention, participant risk versus benefit, performance of the 
trial sites, and other factors that may affect study outcome;  
 
consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants 
or the ethics of the trial;  
 
protect the safety of the study participants;  

 
Page 62 of 81 
 
 
report on the safety and progress of the trial;  
 
make recommendations to the CCF, the Principal Investigator (PI), and, if required, to the 
Institution Review Boards (IRBs) concerning continuation, termination or other modifications of 
the trial based on the observed beneficial or adverse effects of the treatment under study;  
 
ensure the confidentiality of the trial data and the results of monitoring;  
 
assist the PI and CCF by commenting on any problems with study conduct, enrollment, sample 
size and/or data collection. 
 
3.2. Responsibilities of the Data Management Center 
The Biostatistics core of the Center for Gastrointestinal Biology and Disease at the University of 
North Carolina Chapel Hill will serve as the Data Management Center (DMC). The DMC will be 
charged with creating, managing, and housing the data management system. 
 
All data will be created, modified, maintained, archived, retrieved and distributed by a computer system. 
The use of electronic records will increase the speed of data collection and exchange.  
The Data Management Center (DMC) at the CGIBD at the University of North Carolina will track the 
data collection, provide data security, control for confidentiality of study data, maintain computer 
backups to protect data until study closure and archive study data according to FDA requirements 
(21 CFR 11). Electronic signatures will be linked to each entry. 
 
All computer systems and programs will be password protected, and all electronic communications of study 
and other confidential information will be encrypted. Personnel at the CGIBD have extensive training and 
experience using electronic data systems. Good computer security practice (restricting physical access to 
machines, prohibition of password sharing, and logging off computers after work hours or when away from 
the machine) will be required of all study personnel.  
 
Standard Operating Procedures exist for users of the DMC. Only authorized persons are authorized 
for data entry and access. Data security systems require password protected identification codes 
for data entry and provide protection against data manipulation. The database is located on a server 
protected by firewalls. Access to the database server will not be allowed by users on computers 
outside of the firewall-protected zone. Virus protection software is installed on each study machine. 
System access to computer systems will be audited. Redundant backups and off-site backup 
storage will allow for quick restoration of data in the unlikely event that a hardware failure, disaster, 
or security breach should occur. Servers and backups will be located in a secured location with 
access limited to authorized personnel. 
 
Standardized study management reports will be generated monthly during the recruitment phase 
of the study. These reports will be used to track study progress including patient enrollment, 
randomization, compliance, patient status changes, and study events. The data will be reported for 
each Study Center individually and summarized for the study as a whole. Every six months, a 
standardized report will also be generated for the DSMB meeting. This report will include additional 
information on clinical events and adverse events that is coded by treatment group. Other than the 
DSMB, the study statistician and statistical analyst, no study personnel will see this report. 
 
 
3.3. Responsibilities of the Data Coordinating Center 
The University of Pennsylvania will serve as the Data Coordinating Center for this study. The DCC 
will be charged with assuring data is entered and that data are complete and accurate. The DCC will 
also be charged with Data and Safety Monitoring. The DCC will organize all DSMB meetings.  
  
4. BOARD PROCESS  

 
Page 63 of 81 
 
 
The DSMB will at 50% of the accrual goal at at a minimum of annually.  
 
Meetings shall be closed to the public because discussions may address confidential patient data. 
Meetings are attended, when appropriate, by the principal investigator and members of his/her staff.  
 
Meetings may be convened as conference calls as well as in person.  
 
An emergency meeting of the DSMB may be called at any time by the Chairperson or by the CCF or 
PCORI should questions of patient safety arise. The DSMB Chairperson should contact the PCORI 
project officer and the CCF’s Chief Scientific Officer prior to convening an emergency meeting. 
 
5. MEETING FORMAT  
 
An appropriate format for DSMB meetings consists of an open, closed and executive session. This format 
may be modified as needed. 
 
Open Session: 
The voting members of the DSMB, the Executive Committee, the NIDDK staff, the principal investigator 
and members of his staff including the study biostatistician will attend the open session.   
 
Issues discussed will include the conduct and progress of the study, including patient recruitment, data 
quality, general adherence and toxicity issues, compliance with protocol, and any other logistical matters 
that may affect either the conduct or outcome of the study.  Proposed protocol amendments will also be 
presented in this session.  Patient-specific data and treatment group data may not be presented in 
the open session.  
 
Closed Session: 
The closed session will be attended only by voting DSMB members, representatives from the NIDDK, and 
the study biostatistician. The discussion at the closed session is completely confidential. 
 
Analyses of blinded outcome data are reviewed by masked intervention groups, including baseline 
characteristics, primary and secondary outcomes, adverse events, adherence and dropouts, and 
examination of any relevant subgroups. However, the DSMB may request unmasking of the data for 
either safety or efficacy concerns.  Procedures to accomplish unmasking of either individual or treatment 
group data are to be specified in the DSMB plan. 
 
Executive Session: 
The executive session will be attended by voting DSMB members and the NIDDK executive secretary. 
 
The DSMB will discuss information presented to it during the closed and open sessions and decide 
whether to recommend continuation or termination, protocol modification or other changes to the conduct 
of the study.  The DSMB can become unblinded if trends develop either for benefit or harm to the 
participants.  
 
Three members will be required for a quorum; however, any changes to the study will require a full vote of 
the DSMB. 
 
Should the DSMB decide to issue a termination recommendation, full vote of the DSMB will be required. 
In the event of a split vote, majority vote will rule and a minority report should be appended.  Reasons for 
early termination include: 
 
Serious adverse effects in entire intervention group or in a dominating subgroup; 
 
Greater than expected beneficial effects; 
 
A statistically significant difference by the end of the study is improbable; 
 
Logistical or data quality problems so severe that correction is not feasible. 

 
Page 64 of 81 
 
 
Final Open Session (optional): 
The final session may be attended by voting DSMB members, the principal investigator, the study 
biostatistician or other study members, and the NIDDK staff. 
 
The Chair of the DSMB or the Executive Secretary shall report on the  recommendations of the DSMB 
regarding study continuation and concerns regarding the conduct of the study.  Requests regarding data 
presentation for subsequent meetings will be made.  Scheduling of the next DSMB meeting may be 
discussed. 
 
REPORTS  
 
Interim Reports: Interim reports are generally prepared by the study statistician(s) and distributed to the 
DSMB and the NIDDK Project Officer at least 14 days prior to a scheduled meeting. These interim reports 
are numbered and provided in sealed envelopes within an express mailing package or by secure email as 
the DSMB prefers. The contents of the report are determined by the DSMB. Additions and other 
modifications to these reports may be directed by the DSMB on a one-time or continuing basis. Interim data 
reports generally consist of two parts: 
 
Part 1 (Open Session Report) provides information on study aspects such as accrual, baseline 
characteristics, and other general information on study status.  This report is generally shared 
with all investigators involved with the clinical trial. 
 
Part 2 (Closed Session Report) may contain data on study outcomes, including safety data, and 
depending on the study, perhaps efficacy data. The Closed Session Report is considered 
confidential and should be destroyed at the conclusion of the meeting. Data files to be used for 
interim analyses should have undergone established editing procedures to the extent possible. 
Interim analyses of efficacy data are performed only if they are specified and approved in 
advance and criteria for possible stopping is clearly defined.  This report should not be viewed by 
any members of the clinical trial except the designated study statistician. 
 
Reports from the DSMB: A formal report containing the recommendations for continuation or 
modifications of the study, prepared by the ES with concurrence from the DSMB, will be sent to the PI. 
This report will also contain any recommendations of  the NIDDK in reference to the DSMB 
recommendations.  It is the responsibility of the PI to distribute this report to all co-investigators and to 
assure that copies are submitted to all the IRBs associated with the study. 
 
Each report should conclude with a recommendation to continue or to terminate the study. This 
recommendation should be made by formal majority vote. A termination recommendation may be made 
by the DSMB at any time by majority vote. The NIDDK is responsible for notifying the PI of a decision to 
terminate the study. In the event of a split vote in favor of continuation, a minority report should be 
contained within the regular DSMB report. The report should not include unblinded data, discussion of the 
unblinded data, or any other confidential data.  
 
Mailings to the DSMB: On a scheduled basis (as agreed upon by the DSMB) blinded safety data should 
be communicated to all DSMB members, the NIDDK project officer and the designated safety officer.   
Any concerns noted by the DSMB or the safety officers should be brought to the attention of the NIDDK 
Project Officer.  
 
Access to Interim Data: Access to the accumulating endpoint data should be limited to as small a group 
as possible. Limiting the access to interim data to the DSMB members relieves the investigator of the 
burden of deciding whether it is ethical to continue to randomize patients and helps protect the study from 
bias in patient entry and/or evaluation.  
 
CONFIDENTIALITY  

 
Page 65 of 81 
 
 
All materials, discussions and proceedings of the DSMB are completely confidential. Members and other 
participants in DSMB meetings are expected to maintain confidentiality.       
 
 

 
Page 66 of 81 
 
Appendix G 
DINE-CD Analytic and Statistical Analysis Plan 
This document will outline the analytic and statistical plan for the DINE-CD clinical trial.  
1. Definitions and roles 
Principal investigator – Dr. James Lewis at the University Pennsylvania will be the principal investigator for 
this clinical trial and will be responsible for oversight of all aspects of the trial. 
Lead data analyst – Ms Colleen Brensinger at the University of Pennsylvania’s Center for Clinical 
Epidemiology and Biostatistics (CCEB) will conduct all statistical analyses for this clinical trial. 
Study biostatistician – Dr. Hongzhe Li at the University of Pennsylvania will serve as the lead biostatistician 
and will supervise the work of Ms. Brensinger. 
Data coordinating center – Dr. Lewis and colleagues at the University of Pennsylvania will serve as the 
data coordinating center for this clinical trial. 
Data management center – the University of North Carolina in collaboration with the CCFA Partners Patient 
Powered Research Network (PPRN) will build the data warehouse and database structure and will house 
all of the data from this trial. 
2. Overview 
This is a randomized, multicenter, comparative effectiveness trial of the specific carbohydrate diet (SCD) 
and a Mediterranean style diet (MSD) to induce remission in patients with Crohn’s disease. The study is 
funded by PCORI, will be conducted in up to 50 centers throughout the United States over a period of three 
years. 
The primary and secondary objectives of this clinical trial are the following: 
Primary:  
1. To compare the effectiveness of the specific carbohydrate diet and a Mediterranean style diet to 
induce symptomatic and clinical remission in patients with Crohn’s disease. 
2.  
3. Secondary:  
1. To compare the effectiveness of the specific carbohydrate diet and a Mediterranean style diet to 
reduce mucosal inflammation in patients with active Crohn’s disease. Mucosal inflammation will be 
assessed by measuring the concentration of calprotectin in the feces (FCP). 
2. To compare the effectiveness of the Specific Carbohydrate Diet and a Mediterranean style diet to 
reduce systemic inflammation in patients with active Crohn’s disease. Systemic inflammation will be 
assessed by measuring the concentration of C reactive protein (CRP). 
3. To compare the effectiveness of the specific carbohydrate diet and a Mediterranean style diet to 
improve the following symptoms in patients with Crohn’s disease: a) fatigue, b) pain, c) joint 
symptoms. 
4. To determine the proportion of patients who continue the study diets when prepared food is no longer 
provided without cost and the reasons for discontinuation of the diets.   
 
The clinical trial will enroll 194 participants who will be randomly assigned in a 1 to 1 ratio to the two study 
diets. The main inclusion criteria are Crohn’s disease with mild to moderately active symptoms as measured 
by the short CDAI (sCDAI) score greater than 175 and less than 400, and at least 18 years of age. The 
main exclusion criteria are the following: 
◦ 
Pregnancy 
◦ 
Hospitalized pts. or surgery planned within 6 wks 
◦ 
Ostomy or known symptomatic intestinal stricture 
◦ 
Start of thiopurines,natalizumab, vedolizumab or methotrexate(w/in 12 wks) or anti-TNF (w/in 8 wks) 
◦ 
Start or change corticosteroids within 1 week of screening or dose >20mg prednisone or equivalent 
◦ 
Use of antibiotics w/in 2 weeks of screening  
◦ 
Start or change of dose of 5-ASA type medication w/in 2 weeks of screening 
◦ 
Baseline stool frequency >4 bowel movements/day when well 
◦ 
BMI<16 or ≥40 
◦ 
Celiac disease, recent c diff colitis, or diabetes 

 
Page 67 of 81 
 
◦ 
Albumin<2.0mg/dl (if part of routine clinical care) 
 
The primary outcome measures will be assessed six weeks following randomization. Additional secondary 
outcome measures will be assessed 12 weeks following randomization. The study diets will be provided to 
the participants at no cost for the first six weeks following randomization. Subsequently, participants will be 
required to obtain their own food. However, participants will be provided with instructions on how to continue 
to follow the study diets during weeks 7 to 12 of the clinical trial. 
3. Data Collection and Management 
3.1. Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and complete, 
subject files, and records kept at the food dispensing company, and at the laboratories.   
3.2. Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained. 
Data on CRFs will be collected via direct electronic data capture using a secure web-based database 
designed by and housed in the University of North Carolina. The eCRFs will be the source document in 
some cases. These eCRFs will not include PHI or participants’ identifiable information. Instead, eCRFs will 
be labeled with a unique study identification number.  
Study personnel are instructed that if a space on the CRF is left blank because the procedure was not done 
or the question was not asked, type “N/D”.  If the item is not applicable to the individual case, type “N/A”.  
3.3. Data access 
TO BE COMPLETED WITH HELP FROM UNC 
During the conduct of the trial, the data management team at the University of North Carolina and the lead 
data analyst at the University of Pennsylvania will have access to the raw study data. Standardized reports 
will be generated to allow data coordinating center to monitor recruitment and retention, completion of 
eCRFs, and for quality control purposes prior to the end of the trial. The analyst will prepare summary 
documents for the investigative team without separating the data by study group. The analyst will prepare 
separate files stratifying the data by study group for the data and safety monitoring board (DSMB). 
At the conclusion of the trial, the data analyst and study biostatistician will prepare the analytic data files to 
be used in the final analyses. They will work with the data coordinating center and the data management 
team to resolve any outstanding queries prior to conducting the final analyses. Review of descriptive data 
of the combined cohort may be conducted with the data management team and the data coordinating center 
to facilitate data cleaning.  
The analytic plan will be reviewed and agreed upon by the data coordinating center and study steering 
committee prior to conducting the final analyses. A copy of the locked final analytic data set will be 
preserved as a backup. All analyses will be conducted using fast computer programs such that no changes 
will be made to the locked final data set. 
4. Data collection 
Baseline and follow-up data will be collected through a combination of electronic CRFs completed by the 
participants and by the research team. The former will be used to collect symptoms used to define the 
PROs. The latter will be used to collect data on patient characteristics and adverse events. 
Baseline data are described in the following table. 
Variable 
Variable 
name 
Categorization 
Age 
 
Continuous 

 
Page 68 of 81 
 
Sex 
 
Male=0; Female=1 
Race 
 
Caucasian=0; 
Black=1; 
Asian=3; 
American Indian / Alaska Native=4; 
Pacific Islander / Hawaiian = 5; Multi 
racial = 6  
Ethnicity 
 
Non-Hispanic=0; Hispanic=1 
Weight in Kg 
 
Continuous 
BMI 
 
Continuous 
Tobacco use 
 
0=never; 1=former; 2=current 
Current medications 
 
 
     Current corticosteroid use 
 
0=no; 1=yes 
     Current mesalamine use 
 
0=no; 1=yes 
     Current azathioprine or 6MP use 
 
0=no; 1=yes 
     Current methotrexate use 
 
0=no; 1=yes 
     Current anti-TNF use 
 
0=no; 1=yes 
     Current vedolizumab/natalizumab  
 
0=no; 1=yes 
Former medications 
 
 
     Former corticosteroid use 
 
0=no; 1=yes 
     Former mesalamine use 
 
0=no; 1=yes 
     Former azathioprine or 6MP use 
 
0=no; 1=yes 
     Former methotrexate use 
 
0=no; 1=yes 
     Former anti-TNF use 
 
0=no; 1=yes 
     Former vedolizumab or natalizumab   
0=no; 1=yes 
Disease distribution 
 
 
     Ileum 
 
0=no; 1=yes 
     Colon 
 
0=no; 1=yes 
     Ileocolon 
 
0=no; 1=yes 
Duration of current flare 
 
Continuous in days 
Current symptoms 
 
 
     Bowel frequency 
 
Continuous 
     Abdominal pain rating  
 
Ordinal 
     General Wellbeing 
 
Ordinal 
     Fatigue (PROMIS) 
 
Continuous 
     Sleep (PROMIS) 
 
Continuous 
     Pain interference (PROMIS) 
 
Continuous 
     Social Isolation (PROMIS) 
 
Continuous 
Baseline diet from DHQ 
 
 
     Percent calories from Fat 
 
Continuous 
     Percent calories from Carbohydrates  
Continuous 
     Percent calories from Protein 
 
Continuous 
     Gluten free diet  
 
0=no; 1=yes 
     Other 
dietary 
descriptions 
– 
Charlene 
 
 
Back pain screening* 
 
 
    Age at onset <40 years 
 
0=no; 1=yes 
    Insidious onset 
 
1=no; 0=yes 
    Improvement with exercise 
 
0=no; 1=yes 
    Improvement with rest 
 
1=no; 0=yes 
Wake up in the second half of the   
0=no; 1=yes 

 
Page 69 of 81 
 
night with pain 
Bath Index if screen positive for back 
pain 
 
Continuous  
*If at least four out of these five parameters were fulfilled, the criteria had a sensitivity of 77.0% and specificity of 
91.7% for axial spondyloarthritis in the patients participating in the workshop, and 79.6% and 72.4%, respectively, 
in the validation cohort. 
 
Baseline and follow-up clinical data will be collected as described in the following table 
Variable 
Variable 
name 
Categorization 
Data source 
When 
collected 
Number of liquid or 
soft stools each 
day 
 
Continuous 
Participant 
Daily 
Abdominal pain 
 
0=none; 
1=mild; 
2-
moderate; 3=severe 
Participant 
Daily 
General wellbeing 
 
0=generally 
well; 
1=slightly under par, 
2=poor; 3= very poor; 
4= terrible 
 
Participant 
Daily 
Arthralgia 
 
0=no; 1=yes 
Investigator 
0,6,12 
Uveitis 
 
0=no; 1=yes 
Investigator 
0,6,12 
Erythema 
nodosum 
 
0=no; 1=yes 
Investigator 
0,6,12 
Abscess  
 
0=no; 1=yes 
Investigator 
0,6,12 
Pyoderma 
gangrenosum 
 
0=no; 1=yes 
Investigator 
0,6,12 
Fissure 
 
0=no; 1=yes 
Investigator 
0,6,12 
New fistula 
 
0=no; 1=yes 
Investigator 
0,6,12 
Abscess 
 
0=no; 1=yes 
Investigator 
0,6,12 
Aphthous ulcers 
 
0=no; 1=yes 
Investigator 
0,6,12 
PROMIS 
measures 
 
 
 
 
   Pain 
Interference 
6a 
short form 
 
Continuous 
Participant 
0,6,12 
    v1.0 Fatigue 7a 
short form 
 
Continuous 
Participant 
0,6,12 
    v1.0 
Sleep 
Disturbance 
8a 
short form 
 
Continuous 
Participant 
0,6,12 
    V2.0 
Social 
Isolation 4a 
 
 
 
 
 
 
 
 
 
RAPID-3 
 
Continuous 
Participant 
0,6,12 
BASFI* 
 
Continuous 
Participant 
0,6,12 
* Only if screen positive on back pain screen 

 
Page 70 of 81 
 
4.1. Best Practices in Administration of PROMIS measures 
 
PROMIS self-report measures are intended to be completed by the respondent without help from 
anyone else. 
 
If respondents are unable to answer on their own, have someone else (“proxy”) report on their behalf. 
Respondents requiring a proxy may include: young children, people in the early stages of dementia 
who may not recognize the extent of their impairment, people with cognitive or communication deficits, 
and people with severe disease burden. PROMIS Parent Proxy measures are available. 
 
Keep respondents’ privacy in mind, but have staff readily available to help with any technology issues 
that may arise. 
 
It is acceptable for staff to define a term (e.g., “nausea”), but not to define a concept where the 
respondent’s subjective interpretation is the goal of the question (e.g., “quality of life”). 
 
Utilize the same method (e.g., computer, telephone, or paper) and mode (e.g., self vs. interviewer) of 
administration. However, this is not always possible, and PROMIS measures have produced similar 
scores when the method of administration varied. See the Forum for more information on method 
/ mode effects. 
 
In clinical settings, give respondents the optimal time needed to capture the most relevant perspective 
and complete data (e.g., before/after clinician visit or in between visits). This may depend on the study 
aims and/or clinic work flow. 
 
The text and responses of PROMIS items cannot be altered in any way and still be considered a 
PROMIS item. Users are welcome to modify the items, but cannot refer to these modified items as 
PROMIS and we have no data about whether or not this modified version would have the same 
psychometric properties as the original PROMIS item.  If you do modify items, please clearly specify in 
what ways the items were modified in any publications or other publicly disseminated work products. 
There are multiple different versions of the PROMIS measures. The recommended shortform versions can 
be 
found 
at 
http://www.healthmeasures.net/applications-of-healthmeasures/in-research/selecting-a-
healthmeasure. For pain interference, v1.0 Pain Interference 6a short form is recommended. For fatigue, 
v1.0 Fatigue 7a short form is recommended. For sleep, v1.0 Sleep Disturbance 8a short form is 
recommended. For social isolation, we selected a brief version (Social Isolation Short Form 4a). Scoring 
guidelines are included in the appendices. We will use the PROMIS Assessment Center Scoring Service 
to obtain the most accurate scores. 
 
5. Analytic plan 
5.1. Overview 
This clinical trial will examine the effects of a low risk intervention. A total of 194 participants are anticipated 
to be included in the study. Enrollment is anticipated to be completed over a two-year time period. Because 
this clinical trial will compare two different diets, both of which have potential health benefits, no interim 
safety or effectiveness analyses are planned. However, analyses will be conducted to monitor recruitment, 
retention, and data quality. 

 
Page 71 of 81 
 
5.2. Sample size  
The study is designed to enroll 97 patients into each of the treatment arms. Specific aims 1 and 2 will be 
considered separately and no reduction in type 1 error will be applied for multiple testing. The anticipated 
remission rate in the group receiving the MSD is unlikely to exceed 40% given the historical remission rates 
in placebo arms of Crohn’s disease trials1 and assuming only a modest therapeutic benefit of this less 
restrictive of the two diets. Sample size calculations assume no loss to follow-up since all participants who 
are lost to follow-up will be categorized as non-responders in the analyses of both dichotomous primary 
outcomes (symptomatic remission and reduction in mucosal inflammation). Our PPRN Patient Governance 
Council met and determined that the minimum clinically important difference in remission rates is 20% as 
smaller differences are unlikely to justify the challenges of following a strict restriction diet such as the SCD. 
Thus, we used an anticipated remission rate of 40% with the MSD and 60% with the SCD to determine the 
sample size. With 97 participants per group, the study will have 80% power with a type 1 error of 5% to 
detect a difference of 40% vs 60% in effectiveness of the two diets using a chi2 test.  
In reality, we anticipate that the remission rate in the MSD will be less than 40%. The power curve shown 
below depicts the power to detect a 20% difference based on the remission rate in the MSD arm of the trial 
where p1 represents the remission rate in the SCD arm (i.e., p1=0.3 represents power to detect a difference 
of 10% vs 30% across a sample size ranging from 60 to 120). With 97 participants per group, there is more 
than 90% power to detect a difference of 10% vs 30% and 80% power to detect a difference of 40% vs 
60%.   
Finally, all of the power estimates are likely slight under estimates. We expect even more power when the 
Cochran-Mantel-Haenszel (CMH) chi2 test is used since we expect that the odds ratios in different strata 
are in the same direction.  
 
Viewed alternatively, with 97 participants per arm, there is 80% and 90% power to detect the following 
differences based on the effectiveness of the control diet (i.e. the MSD).  
Proportion of MSD group 
achieving the outcome 
80% power to detect an 
absolute difference (SCD -
MSD) greater than or equal 
to 
90% power to detect an 
absolute difference (SCD -
MSD) greater than or equal 
to 
10% 
15% 
18% 
20% 
18% 
21% 
30% 
20% 
22% 
40% 
20% 
23% 
Assumes 97 participants per group, type 1 error rate of 5%, and chi2 test 
All power calculations were computed using PS Power and Sample Size Calculations Version 3.0, January 
2009 (Copyright © 1997-2009 by William D. Dupont and Walton D. Plummer).  
  

 
Page 72 of 81 
 
5.3. Analyses for recruitment, retention and data quality 
Monthly recruitment statistics will be generated for the study as a whole and by clinical site. Run charts will 
plot cumulative recruitment and anticipated recruitment rates required to fully enroll the clinical trial 
according to the study timeline. Tabular data will be provided for the number of screen failures and the 
number of participants withdrawing from the study before week six and without reaching a study endpoint 
(i.e. lost to follow-up). 
Tabular in distribution data will be generated to monitor data completeness and quality. Tables will describe 
the number of participants for whom eCRF data are incomplete, overall and stratified by study site. Baseline 
characteristics data and components of the sCDAI will be generated to identify outliers that may represent 
data entry errors. These data points will be confirmed or corrected by queries to the clinical site 
coordinators. Variables for which distributions will be generated will include: age, height, weight, body mass 
index, duration of Crohn’s disease, and time since onset of the most recent flare of Crohn’s disease. 
Additional data will be evaluated for illogical values or protocol violations including: baseline sCDAI score, 
current dose of prednisone, serum albumin, and body mass index. 
5.4. Analysis of Baseline Data 
The initial analyses will utilize descriptive statistics to define the characteristics of the study cohort. 
Continuous variables will be described as medians and interquartile ranges. Categorical variables will be 
defined as proportions. Formal statistical comparisons of these descriptive variables will be performed 
comparing the two arms of the study using the Wilcoxon rank sum test for continuous variables and the chi 
squared or Fisher’s exact test for categorical variables 2. Because any unbalance in the two groups is by 
definition a chance occurrence, these analyses will be used to highlight areas of substantial unbalance 
between the study arms.  
5.5. Efficacy Analysis  
Analysis of the primary outcome: The primary outcomes will be measured at 6 weeks after the start of the 
study diets. The primary analyses for the RCT will use 2-sided tests of statistical significance and will be 
performed using the intention-to-treat principle.3 Thus, patients will be classified according to the study arm 
that they were assigned, regardless of the amount of food from the assigned diet consumed.  
5.5.1. Outcome definitions 
Clinical remission will be defined use the sCDAI which provides a composite measure of relevant patient 
reported outcomes (PROs). Symptomatic remission will be defined as a sCDAI <1504 in the absence of the 
need for increasing corticosteroid dose or initiation of new therapies for CD during the study period. 
Participants who withdraw from the study prior to week 6 will be categorized as failing to achieve 
symptomatic remission and other related outcomes.  
5.5.1.1. 
sCDAI 
The sCDAI was derived from the Crohn’s Disease Activity Index5 , the standard disease activity index for 
CD clinical trials in adults for the last several decades6. The original index includes the number of liquid 
stools per day, abdominal pain, general wellbeing, extraintestinal complications of CD, use of Lomotil or 
opiates for diarrhea, anemia, weight loss, and the presence of an abdominal mass on physical exam. The 
CDAI has increasingly fallen out of favor as it combines PROs with physical exam, medication use, and 
laboratory data7. As such, investigators validated the sCDAI which patients can complete using a simple 
web-based survey tool without an office visit or blood draw4,8. The sCDAI uses the same scale as the full 
CDAI, such that scores <150 define remission, 150-219 mild activity, 220-450 moderate activity, >450 
severe activity. The correlation between the full CDAI and sCDAI for baseline scores and score change 
was 0.90 and 0.96, respectively4. Our research team has subsequently demonstrated that the sCDAI can 
be accurately measured with less than 7 days of data, thereby reducing participant burden and allowing for 
use of data with missing values for selected days8.  
Computation is straightforward: 

 
Page 73 of 81 
 
𝑠𝐶𝐷𝐴𝐼= 44 + (2 ∗∑𝐿
7
𝑛=1
) + (5 ∗∑𝐴
7
𝑛=1
) + (7 ∗∑𝑊
7
𝑛=1
) 
where L is the number of liquid stools, A is the rating of abdominal pain (0-3, none to severe), W is the 
rating of general wellbeing (0-4, generally well to terrible), and n is the day of follow-up. 
Similarly, when computing the sCDAI scores for fewer than 7 days, the individual component scores from 
the available days can be weighted to take on the value as if there were 7 days of data and the available 
data are considered to be reflective of the missing data. The computation is to multiply the sum of the 
individual components by 7 and divided by the number of total days of data used (d) to adjust for the missing 
days: 
𝑠𝐶𝐷𝐴𝐼= 44 + 7
𝑑∗((2 ∗∑𝐿
𝑑
𝑛=1
) + (5 ∗∑𝐴
𝑑
𝑛=1
) + (7 ∗∑𝑊
𝑑
𝑛=1
)) 
 
  
5.5.1.2. 
Secondary Endpoints  
5.5.1.3. 
Reduction in fecal calprotectin 
We will compare the proportion of patients who achieve reduction in FCP to less than 250mcg/g and by 
greater than 50% from baseline. Fecal concentration of calprotectin, a calcium binding protein found in 
neutrophilic granulocytes, will be measured by LabCorp Diagnostics. FCP concentration is correlated with 
endoscopic findings of mucosal inflammation and decreases following initiation of medications in active 
CD11,12. There is no single standard to define mucosal healing with FCP13-15; a recent meta-analysis 
identified 250 µg/g as the optimal cut point for endoscopically defined inflammation among patient with 
IBD16,17.  Participants with a baseline FCP less than than 250mcg/g will be excluded from this 
analysis. 
5.5.1.3.1. 
Reduction in systemic inflammation 
Reduction in systemic inflammation based on measurement of hsCRP will be defined as having a final 
hsCRP <5mg/L and >50% reduction from the baseline hsCRP concentration.  
5.5.1.3.2. 
Crohn’s Disease Activity Index (CDAI)  
As a secondary clinical outcome, we will measure the CDAI at baseline, 6 weeks and 12 weeks.  
Computation of the CDAI is the sum of the following components over the course of 7 days and multiplied 
by the weighting factor: 
 
Variable  
Weighting factor 
Number of liquid or soft stools each day for seven days 
x 2 
Abdominal pain (graded from 0-3 on severity) each day for seven 
days 
x 5 
General well being, subjectively assessed from 0 (well) to 4 (terrible) 
each day for seven days 
x 7 
Presence of complications* 
x 20 
Taking Lomotil or opiates for diarrhea 
x 30 
Presence of an abdominal mass (0 as none, 2 as questionable, 5 as 
definite) 
x 10 
Hematocrit below normal of 0.47 in men and 0.42 in women 
x 6 
Percentage deviation from standard weight^ 
x 1 

 
Page 74 of 81 
 
*One point each is added for each set of complications: 
 
the presence of joint pains (arthralgia) or frank arthritis 
 
inflammation of the iris or uveitis 
 
presence of erythema nodosum, pyoderma gangrenosum, or aphthous ulcers 
 
anal fissures, fistulae or abscesses 
 
other fistulae 
 
fever during the previous week. 
^ Standard weight is derived from the patients sex and height 
 
CDAI remission will be defined as a CDAI<150 in the absence of the need for increasing corticosteroid 
dose or initiation of new therapies for CD during the study period 
5.5.1.3.3. 
PRO2 and PRO3 
The same data elements included in the sCDAI have been combined into two item (stool frequency and 
abdominal pain) and three item patient reported outcome measures using the original weights derived from 
the full CDAI. PRO2 includes only stool frequency and abdominal pain while PRO3 includes stool 
frequency, abdominal pain and general well-being. These outcome measures are calculated as the sum of 
the mean of the daily value for each domain. 
PRO2 = mean daily soft or loose stool frequency + mean abdominal pain score 
PRO3 = mean daily soft or loose stool frequency + mean abdominal pain score + mean general wellbeing 
score 
In one validation study of the PRO2 and PRO3, optimum cut-points for CDAI remission were mean daily 
stool frequency ≤1.5, abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC curve 
0.79, 0.91 and 0.89, respectively).PRO2 and PRO3 values corresponding to CDAI scores of 150, 220, and 
450 points were 8, 14, and 34 and 13, 22, and 53 respectively, and the corresponding values for CDAI 
changes of 50, 70, and 100 points, were 2, 5, and 8 and 5, 9, and 14, respectively18. We will examine the 
individual components of these PROs to determine the proportion of each group that met the optimum 
cutpoint for remission that met the PRO2 definition of remission. Finally, we will determine the proportion 
of each group with a reduction in the PR02 and PRO3 that corresponds to 100 point reduction in the CDAI. 
5.5.1.4. 
Combined PRO and FCP outcome 
As a secondary outcome, we will assess the proportion of patients achieving combined clinical remission 
based on the sCDAI and reduction in FCP using the same criteria described above.  
5.5.1.5. 
PROMIS measures 
The Patient Reported Outcome Measurement System (PROMIS) questionnaire contains several measures 
previously show to correlate with disease activity and to have construct validity in CD.  These include 
measures of fatigue, pain interference, and sleep19. PROMIS items are calibrated using a T score such that 
50 is the mean for the general US population with a standard deviation of 10. Higher scores reflect greater 
level of the domain. 
5.5.1.6. 
Physical function and joint pain 
Physical function and joint pain will be assessed with a subset of core variables found in the Multi-
dimensional Health Assessment Questionnaire (MD-HAQ)20,21. We will screen for inflammatory back pain 
using the criteria developed by Sieper et al.22 and assess symptom severity with the Bath AS Functional 
Index in those who screen positive23. 
5.5.2. Statistical analysis for primary and secondary outcome measures 
  
The primary analysis will compare the proportion of patients who achieve a symptomatic remission 
(aim 1) and reduction of inflammation (aim 2) at week 6 using the Cochran-Mantel-Haenszel (CMH) chisq 
test, which is equivalent to the score test derived from the conditional logistic regression with treatment 

 
Page 75 of 81 
 
strata as the conditioning factor.2 All patients who are withdrawn or lost to follow-up prior to week 6 will be 
considered treatment failures.  The MSD will be considered the reference group for all analyses. Although 
randomization should minimize unbalance between the groups, it is still possible that unbalance may occur. 
As such, we will use stratified analyses and conditional logistic regression analysis to adjust for potential 
unbalance between the two groups as observed in the descriptive analyses.24 Age, sex, smoking status, 
duration of CD, presence of disease involving the colon and/or rectum, use of corticosteroids during the 
trial, current use of biologic therapy, and current use of immunomodulator therapy will be examined 
individually for potential confounding of the main outcome using logistic regression analysis. All variables 
that affect the crude estimate of the relative risk of effectiveness by 10% or greater will be included in the 
final model25.  
Stratified analyses will be used to assess for treatment effect heterogeneity based on the following 
variables: duration of CD (as EEN appears to work better in newly diagnosed patients), presence of colonic 
and/or rectal disease (EEN has been hypothesized to work better in patients with only small bowel disease), 
and use of corticosteroids during the trial (these patients may have more severe disease). We will use the 
logistic regression models to look for evidence of treatment-covariate interactions. Although pre-specified, 
we have not powered the study for these subgroup analyses and as such they will be considered hypothesis 
generating. Therefore, we will report the overall results as well as results for each subgroup. We note that 
the strongest a priori hypothesis for treatment effect heterogeneity is with the presence or absence of 
inflammation. We hypothesize that the SCD may appear relatively more effective among those patients 
without active inflammation than among those with confirmed active inflammation at baseline. 
 
Analysis of secondary outcomes (Secondary Aim 1): hsCRP data will be analyzed in the same manner as 
FCP data.  
Analysis of secondary outcomes (Secondary Aim 2): The secondary outcomes of clinical remission as 
assessed by the CDAI, PRO2, PRO3 and combined clinical remission and resolution of inflammation will 
be analyzed using the same methods described for the primary outcomes. We will compare PROMIS 
scores at baseline and at the end of the trial using a t-test. If there are meaningful differences in baseline 
scores between the treatment arms, comparison of the PROMIS measures at the end of follow-up will be 
adjusted for the baseline value using linear regression.  
Analysis of data from the Extension Phase (Secondary Aim 2): After week 6, participants will need to provide 
for the meals on their own if they choose to remain on the diet. This provides an opportunity to further 
assess the combined feasibility of the diets in the real world and patients’ satisfaction with following the 
diet. Utilizing results from 24-hour dietary recalls, we will determine the proportion of patients assigned to 
each arm who elect to remain on the diet through week 12. We will also determine the proportion of patients 
who were able to discontinue steroid use by week 12 among the subgroup who were taking steroids in 
weeks 1-6. Finally, we will assess reasons for discontinuation of the diet among those who did not continue. 
Comparisons will be made using Fisher’s exact test following the principle of intention to treat. The analysis 
will be repeated among the subgroup of participants who achieved remission by week 6. These results will 
be qualitatively compared to the free text data on satisfaction and personal experience with the diets. 
Change from baseline stratified by treatment arm: For continuous outcome measures, such as sCDAI, 
PRO2, PRO3, and FCP, we will compare the week 6 and week 12 values to the baseline value using the 
Wilcoxon sign rank test, a nonparametric paired test. These analyses will be conducted separately for each 
treatment group. Imputation of missing data for this analysis will assume that the worst case scenario that 
the outcome measure was worse during follow-up than at baseline. (Note that approach to missing data for 
other analyses are described below).  
Approach to missing data: It is possible that missing follow-up data will be more common among 
participants who did not have reduced symptoms, particularly those whose symptoms worsened. There are 
several approaches to missing data in clinical trials. Complete case analysis violates the principle of 
intention to treat and as such will not be employed. For continuous measures, last observation carried 
forward (LOCF) is the most commonly used, but it is not necessarily the most conservative26.  Baseline 
observation carried forward (BOCF) may be more appropriate, particularly in circumstances where the 
outcome would be expected to return to the baseline level if the treatment is discontinued26. The European 
Medicines Agency recommends picking the most conservative approach depending on the individual trial, 
favoring a responder analysis (i.e. converting continuous variables to dichotomous variables) and 
categorizing all dropouts as treatment failures26. We will use this approach in analyses for aims 1 and 2. 
For the continuous variables in the secondary outcomes, we will use BOCF as the most conservative 

 
Page 76 of 81 
 
approach. Sensitivity analyses will compare results of our BOCF analysis with that obtained using LOCF or 
multiple imputation methods.  All results will be interpreted and reported after taking into account the results 
of the sensitivity analyses, applying the principle put forth by the EMA to not favor the “experimental” arm, 
which in this RCT would be the SCD. 
5.5.3. Analysis of PROMIS and arthritis measures 
PROMIS measures will be compared at baseline, week 6 and week 8 using a t-test or with adjusted linear 
regression if there is evidence of confounding despite randomization. Additional analyses will compare 
change in PROMIS measures from baseline to week 6 and week 12 between groups. The RADAI arthritis 
screen, RAPID3, and BAS-FI will be treated as a continuous measures and compared between groups 
similar to the approach for PROMIS.  
 
5.5.4. Safety analysis 
All adverse events will be graded according to the NCI's Common Toxicity Criteria. A serious adverse event 
(SAE) will be defined as any of the following outcomes: death, life threatening adverse event, inpatient 
hospitalization or prolongation of stay, persistent or significant disability, congenital anomaly or birth defect, 
or other medically significant event as deemed such by the investigator.  
The proportion of patients in each treatment arm who experience the following safety outcomes will be 
compared using the Fisher’s exact test.2 
 
Any adverse event 
 
Any serious adverse event 
 
Any adverse event occurring in at least 5% of either arm of the trial 
 
5.6. Ancillary biomarker discovery studies:  
Stool samples will be banked as part of this study for future research aimed at identifying biomarkers that 
can predict which patients will respond to dietary interventions and to help understand the mechanisms by 
which diet influences the course of Crohn’s disease. The University of Pennsylvania Intestinal Microbiome 
Project Group is well positioned to analyze fecal samples from this study in search of new biomarkers. This 
group consists of a dozen PIs with expertise in microbiology, high throughput DNA sequencing, 
bioinformatics, computational biology, metabolomics, animal modeling, and human subject research. 
Together, we have published 20 primary manuscripts over the past four years in journals such as Science, 
Nature Medicine, PNAS, Cell Host & Microbe, and Immunity. These publications focus not only on the 
bacterial microbiota but also on fungi, Archaea, and viruses as well as the metabolome. Importantly, we 
also have expertise in the development of computational tools needed for the analysis of complex 
multidimensional datasets such as those needed for biomarker discovery research 27-32.  Note that 
requested funds are solely to bank the stool samples. Separate funding is being sought for the analysis of 
these samples. 
Our approach to the analysis of the samples will depend both on the results of the clinical trial and, given 
the rapid developments in this field, the state of the art in translational science at the time the samples are 
analyzed. The following is a provisional plan to address these questions. First, we will characterize the gut 
microbiome by DNA sequencing of fecal samples. Samples will be analyzed by metagenomic sequencing. 
For DNA isolation, the MoBio Power Soil Kit will be used, implemented in 96-well format. Isolated DNA will 
be quantified using the Picogreen system. Primers will be barcoded to label each sample as described 
previously33.  PCR reactions will be carried out in triplicate using Accuprime polymerase (Invitrogen, 
Carlsbad, CA, USA).  Each reaction will contain 50 nanograms of DNA and 10 pM of each primer.  To 
characterize bacterial populations, we will use 16S rRNA gene tags, as described in our previous work27-
31,34-47.  Primers annealing to the V1V2 region of the 16S bacterial gene will be used, as described 
previously48.  Amplified 16S rDNA will be purified using a 1:1 volume of Agencourt AmPure XP beads 
(Beckman-Colter, Brea, CA, USA).  The purified products from the stool samples will be pooled in equal 
amounts and analyzed by DNA sequencing using the Bushman Lab Illumina MiSeq.  Negative controls 
(mock purification of DNA-free water) and positive controls (standard fecal and synthetic community 
samples) will be included in each run.  Most liquid handling steps will be carried out using EpMotion 
(Eppendorf) automation. Sequence data will be processed using QIIME49, augmented by the in-house R 

 
Page 77 of 81 
 
package QIIMER. Taxonomy will be assigned to the sequences using Ribosomal Database Project (RDP) 
for 16S50, augmented by BLAST. The 16S tag sequences will be collected into operational taxonomic units 
(OTUs) with 97% sequence identity and samples summarized as vectors of proportions. 
Fungal communities will be characterized by ITS gene tag sequencing as described in our published 
work35,37,39,40,43.  Extensive characterization of positive control specimens will document the organisms 
queried with this approach40.  Taxonomy will be assigned using the in house software program BROCC 40, 
which mitigates extreme problems with fungal databases and underlying taxonomy by implementing a 
voting-based analytical strategy taking advantage of multiple top-scoring alignments. 
We will conduct targeted fecal metabolomics of bile acids and their conjugates/metabolites, short chain 
fatty acids (SCFAs), and amino acids.  
Fecal Bile acids: Weighed stool and small intestinal fluid samples will be suspended in 15 l/mg methanol. 
Following vortex for 1 minute (for 96-well plates we will use adapter SI-0510 two-tier microplate foam insert), 
samples will be centrifuged at 13,000g for 5 minutes.  Supernatant will be transferred to new tube/plate. 
Plates will be covered and stored at -20oC until high performance liquid chromatography (HPLC) is 
performed. Each plate will be on HPLC with the following settings: Acquity UPLC I-Class/Fixed Loop with 
QDa mass detection, ESI Negative mode, Scan and Single Ion Monitoring modes. UPLC will be performed 
using a Cortecs UPLC C-18+ 1.6 m 2.1 x 50 mm column.  
Fecal short chain fatty acids (SCFAs): Weighed fecal samples will be suspended in phosphate buffered 
saline (PBS), vortexed, and centrifuged to remove particulate matter. The supernatant will be vacuum 
filtered in a 96-well plate and transferred to an autosampler for injection into a HPLC for a run under the 
following conditions: Mobile phase: 0.01 N H2SO4, Flow rate: 0.6 mL/minute, Initial column temperature: 
50oC, Run time: 30-50 minutes (depending on complexity of the samples), System pressure: 900-1000 psi, 
Injection volume: 10 uL, Standards range: 0.1-20 mM. 
Fecal Amino Acids: Fecal amino acids will be quantified using the Amino Acid AccQTag Analysis Kit (Waters 
Corporation, Milford, MA). Briefly, fecal samples will be homogenized in PBS (10 uL/mg) and centrifuged 
at 13,000g for 5 minutes. Supernatant will be derivatized with AccQTag reagents, and stored at -80C until 
analysis. Samples will be analyzed on a Waters uPLC with an AccqTag Amino Acid Column using eluents 
and standards provided in the Amino Acid Analysis Kit. Concentration of samples will be calculated against 
dilutions of the Amino Acid Hydrolysate Standard (Waters Corporation). 
Our analytic approach will be tailored to the specific research question. The following is a general overview 
of our approach to identifying biomarkers that predict patients who will respond to the dietary intervention. 
We anticipate implementing analyses using a traditional case-control design nested within the cohort of 
patients receiving the specific carbohydrate diet (SCD) where case subjects are those who responded to 
therapy and controls are the remaining subjects. As we have done in our prior work27,32,51, the microbiome 
composition will then be compared among cases and controls using principle coordinate and random forest 
analyses and by relative abundance of unique taxa after accounting for multiple comparisons using false 
discovery rate methodology. Prediction models will be developed using logistic regression. Internal 
validation methods such as bootstrapping techniques will be used to assess for overfitting52. Similar 
approaches will be used to analyze fecal metabolites. Subsequently predictors identified from different 
analytic methods can be combined and the incremental predictive accuracy from adding biomarkers can 
be assessed using methods such as net reclassification improvement52.  
 
References 
 
1. 
Su C, Lichtenstein GR, Krok K, Brensinger CM, Lewis JD. A meta-analysis of the placebo rates of 
remission and response in clinical trials of active Crohn's disease. Gastroenterology. 
2004;126(5):1257-1269. 
2. 
Armitage P, Berry G. Statistical Methods in Medical Research. 2nd ed. Oxford: Blackwell Scientific 
Publications; 1987. 
3. 
Piantadosi S. Clinical trials: A methodological perspective. New York: John Wiley & Sons, Inc.; 
1997. 
4. 
Thia K, Faubion WA, Jr., Loftus EV, Jr., Persson T, Persson A, Sandborn WJ. Short CDAI: 
development and validation of a shortened and simplified Crohn's disease activity index. Inflamm. 
Bowel Dis. Jan 2011;17(1):105-111. 
5. 
Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Crohn's disease activity index. 
National Cooperative Crohn's Disease Study. Gastroenterology. 1976;70(3):439-444. 

 
Page 78 of 81 
 
6. 
Sandborn WJ, Feagan BG, Hanauer SB, et al. A review of activity indices and efficacy endpoints 
for clinical trials of medical therapy in adults with Crohn's disease. Gastroenterology. Feb 
2002;122(2):512-530. 
7. 
Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory 
Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target. Am. J. 
Gastroenterol. Aug 25 2015. 
8. 
Henao MP, Bewtra M, Osterman MT, et al. Measurement of Inflammatory Bowel Disease 
Symptoms: Reliability of an Abbreviated Approach to Data Collection. Inflamm Bowel Dis. Jul 17 
2015. 
9. 
Lee D, Baldassano RN, Otley AR, et al. Comparative Effectiveness of Nutritional and Biological 
Therapy in North American Children with Active Crohn's Disease. Inflamm Bowel Dis. Aug 
2015;21(8):1786-1793. 
10. 
Osterman MT, Aberra FN, Cross R, et al. Mesalamine dose escalation reduces fecal calprotectin 
in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol. Nov 2014;12(11):1887-
1893 e1883. 
11. 
Lewis JD. The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. 
Gastroenterology. May 2011;140(6):1817-1826 e1812. 
12. 
Summerton CB, Longlands MG, Wiener K, Shreeve DR. Faecal calprotectin: a marker of 
inflammation throughout the intestinal tract. Eur J Gastroenterol Hepatol. Aug 2002;14(8):841-845. 
13. 
D'Haens G, Ferrante M, Vermeire S, et al. Fecal calprotectin is a surrogate marker for endoscopic 
lesions in inflammatory bowel disease. Inflammatory bowel diseases. Dec 2012;18(12):2218-2224. 
14. 
Sipponen T, Karkkainen P, Savilahti E, et al. Correlation of faecal calprotectin and lactoferrin with 
an endoscopic score for Crohn's disease and histological findings. Aliment. Pharmacol. Ther. Nov 
15 2008;28(10):1221-1229. 
15. 
Schoepfer AM, Beglinger C, Straumann A, et al. Fecal calprotectin correlates more closely with the 
Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the 
CDAI. The American journal of gastroenterology. Jan 2010;105(1):162-169. 
16. 
Waugh N, Cummins E, Royle P, et al. Faecal calprotectin testing for differentiating amongst 
inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation. 
Health technology assessment. Nov 2013;17(55):xv-xix, 1-211. 
17. 
Lin JF, Chen JM, Zuo JH, et al. Meta-analysis: fecal calprotectin for assessment of inflammatory 
bowel disease activity. Inflammatory bowel diseases. Aug 2014;20(8):1407-1415. 
18. 
Khanna R, Zou G, D'Haens G, et al. A retrospective analysis: the development of patient reported 
outcome measures for the assessment of Crohn's disease activity. Aliment Pharmacol Ther. Jan 
2015;41(1):77-86. 
19. 
Kappelman MD, Long MD, Martin C, et al. Evaluation of the patient-reported outcomes 
measurement information system in a large cohort of patients with inflammatory bowel diseases. 
Clinical gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association. Aug 2014;12(8):1315-1323 e1312. 
20. 
Pincus T, Swearingen CJ, Bergman MJ, et al. RAPID3 (Routine Assessment of Patient Index Data) 
on an MDHAQ (Multidimensional Health Assessment Questionnaire): agreement with DAS28 
(Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity categories, scored in 
five versus more than ninety seconds. Arthritis Care Res (Hoboken). Feb 2010;62(2):181-189. 
21. 
Pincus T, Yazici Y, Bergman M. A practical guide to scoring a Multi-Dimensional Health 
Assessment Questionnaire (MDHAQ) and Routine Assessment of Patient Index Data (RAPID) 
scores in 10-20 seconds for use in standard clinical care, without rulers, calculators, websites or 
computers. Best Pract Res Clin Rheumatol. Aug 2007;21(4):755-787. 
22. 
Sieper J, van der Heijde D, Landewe R, et al. New criteria for inflammatory back pain in patients 
with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis 
international Society (ASAS). Ann. Rheum. Dis. Jun 2009;68(6):784-788. 
23. 
Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing 
spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J. Rheumatol. 
Dec 1994;21(12):2281-2285. 
24. 
Meinert C, Tonascia S. Clinical Trials: Design, Conduct, and Analysis. Oxford: Oxford university 
Press; 1986. 

 
Page 79 of 81 
 
25. 
Mickey RM, Greenland S. The impact of confounder selection criteria on effect estimation 
[published erratum appears in Am J Epidemiol 1989 Nov;130(5):1066]. Am. J. Epidemiol. 
1989;129(1):125-137. 
26. 
Agency EM. Guideline on Missing Data in Confirmatory Clinical Trials 10 July 2010. 2010. 
27. 
Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial 
enterotypes. Science. Oct 7 2011;334(6052):105-108. 
28. 
Wu GD, Compher C, Chen EZ, et al. Comparative metabolomics in vegans and omnivores reveal 
constraints on diet-dependent gut microbiota metabolite production. Gut. Nov 26 2014. 
29. 
Minot S, Grunberg S, Wu GD, Lewis JD, Bushman FD. Hypervariable loci in the human gut virome. 
Proceedings of the National Academy of Sciences of the United States of America. Mar 6 
2012;109(10):3962-3966. 
30. 
Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in 
red meat, promotes atherosclerosis. Nature medicine. May 2013;19(5):576-585. 
31. 
Chen J, Bittinger K, Charlson ES, et al. Associating microbiome composition with environmental 
covariates using generalized UniFrac distances. Bioinformatics. Aug 15 2012;28(16):2106-2113. 
32. 
Lewis JD, Chen EZ, Baldassano RN, et al. Inflammation, Antibiotics, and Diet as Environmental 
Stressors of the Gut Microbiome in Pediatric Crohn's Disease. Cell host & microbe. Oct 14 
2015;18(4):489-500. 
33. 
Hoffmann C, Minkah N, Leipzig J, et al. DNA bar coding and pyrosequencing to identify rare HIV 
drug resistance mutations. Nucleic acids research. 2007;35(13):e91. 
34. 
Albenberg L, Esipova TV, Judge CP, et al. Correlation between intraluminal oxygen gradient and 
radial partitioning of intestinal microbiota. Gastroenterology. Nov 2014;147(5):1055-1063 e1058. 
35. 
Bittinger K, Charlson ES, Loy E, et al. Improved characterization of medically relevant fungi in the 
human respiratory tract using next-generation sequencing. Genome biology. 2014;15(10):487. 
36. 
Bushman FD, Lewis JD, Wu GD. Diet, gut enterotypes and health: is there a link? Nestle Nutrition 
Institute workshop series. 2013;77:65-73. 
37. 
Chehoud C, Albenberg LG, Judge C, et al. Fungal Signature in the Gut Microbiota of Pediatric 
Patients With Inflammatory Bowel Disease. Inflammatory bowel diseases. Aug 2015;21(8):1948-
1956. 
38. 
Chen J, Bushman FD, Lewis JD, Wu GD, Li H. Structure-constrained sparse canonical correlation 
analysis with an application to microbiome data analysis. Biostatistics. Apr 2013;14(2):244-258. 
39. 
Dollive S, Chen YY, Grunberg S, et al. Fungi of the murine gut: episodic variation and proliferation 
during antibiotic treatment. PloS one. 2013;8(8):e71806. 
40. 
Dollive S, Peterfreund GL, Sherrill-Mix S, et al. A tool kit for quantifying eukaryotic rRNA gene 
sequences from human microbiome samples. Genome biology. Jul 3 2012;13(7):R60. 
41. 
Han D, Walsh MC, Cejas PJ, et al. Dendritic cell expression of the signaling molecule TRAF6 is 
critical for gut microbiota-dependent immune tolerance. Immunity. Jun 27 2013;38(6):1211-1222. 
42. 
Hildebrandt MA, Hoffmann C, Sherrill-Mix SA, et al. High-fat diet determines the composition of the 
murine gut microbiome independently of obesity. Gastroenterology. Nov 2009;137(5):1716-1724 
e1711-1712. 
43. 
Hoffmann C, Dollive S, Grunberg S, et al. Archaea and fungi of the human gut microbiome: 
correlations with diet and bacterial residents. PloS one. 2013;8(6):e66019. 
44. 
Minot S, Bryson A, Chehoud C, Wu GD, Lewis JD, Bushman FD. Rapid evolution of the human gut 
virome. Proceedings of the National Academy of Sciences of the United States of America. Jul 23 
2013;110(30):12450-12455. 
45. 
Minot S, Sinha R, Chen J, et al. The human gut virome: inter-individual variation and dynamic 
response to diet. Genome research. Oct 2011;21(10):1616-1625. 
46. 
Minot S, Wu GD, Lewis JD, Bushman FD. Conservation of gene cassettes among diverse viruses 
of the human gut. PloS one. 2012;7(8):e42342. 
47. 
Wu GD, Lewis JD, Hoffmann C, et al. Sampling and pyrosequencing methods for characterizing 
bacterial communities in the human gut using 16S sequence tags. BMC Microbiol. 2010;10:206. 
48. 
McKenna P, Hoffmann C, Minkah N, et al. The macaque gut microbiome in health, lentiviral 
infection, and chronic enterocolitis. PLoS Pathog. Feb 8 2008;4(2):e20. 
49. 
Caporaso JG, Kuczynski J, Stombaugh J, et al. QIIME allows analysis of high-throughput 
community sequencing data. Nat Methods. May 2010;7(5):335-336. 

 
Page 80 of 81 
 
50. 
Cole JR, Wang Q, Cardenas E, et al. The Ribosomal Database Project: improved alignments and 
new tools for rRNA analysis. Nucleic acids research. Jan 2009;37(Database issue):D141-145. 
51. 
Wu GD, Compher C, Chen EZ, et al. Comparative metabolomics in vegans and omnivores reveal 
constraints on diet-dependent gut microbiota metabolite production. Gut. Jan 2016;65(1):63-72. 
52. 
Moons KG, Kengne AP, Woodward M, et al. Risk prediction models: I. Development, internal 
validation, and assessing the incremental value of a new (bio)marker. Heart. May 2012;98(9):683-
690.