Conditions: Eosinophilic Gastrointestinal Disorders (EGIDs) Eosinophilic Esophagitis (EoE)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 129
Healthy volunteers: no

Brief summary:
The purpose of this interventional study is to test and compare the effectiveness of two elimination diets-the 1-food elimination diet (1FED, milk only) and the 6-food elimination diet (6FED, milk, egg, wheat, soy, tree nut/peanuts, and fish/shellfish). The study will also test the effectiveness of swallowed glucocorticoid therapy in some of the study participants for whom diet therapy was not effective.

Detailed description:
This study will consist of two phases, plus a screening period. During the screening period, subject eligibility for the study will be determined. During Phase 1, qualified participants will be randomly assigned to one of two elimination diet therapies--the 1FED or the 6FED. Participants will remain on the assigned dietary therapy for 6 weeks. At the end of 6 weeks of therapy, esophageal biopsies from participant's standard of care (i.e. normal, routine care) endoscopy will be evaluated to determine disease status. Participants whose EoE is in remission (i.e. \<15 eos/hpf) will be done with the study.

Participants whose EoE is still active (i.e. ≥15 eos/hpf) will have the option to continue into Phase 2 of the study. During Phase 2, participants who were on 1FED in Phase 1 will receive 6FED therapy for 6 weeks, and participants who were on 6FED during Phase 1 will receive swallowed glucocorticoid (SGC) therapy for 6 weeks. At the end of 6 weeks of therapy, esophageal biopsies from participant's standard of care (i.e. normal, routine care) endoscopy will be evaluated to determine disease status.

Arms:
arm 1: Participants eliminate milk from the diet in Phase 1 arm 2: Participants eliminate milk, egg, wheat, soy, nuts, fish from the diet in Phase 1 arm 3: Participants that fail to respond to 1FED in Phase 1 eliminate milk, egg, wheat, soy, nuts, fish from the diet in Phase 2 arm 4: Participants that fail to respond to 6FED in Phase 1 administer swallowed glucocorticoids (SGC) (Flovent HFA) 880 mcg twice daily in Phase 2

Interventions: intervention 1: 1 Food Elimination Diet Therapy intervention 2: 6 Food Elimination Diet Therapy intervention 3: 6 Food Elimination Diet (after 1FED failure) intervention 4: Fluticasone Propionate, 880 mcg twice daily (after 6FED failure)
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
ICF_000.pdf: 
Six Food vs One Food Eosinophilic Esophagitis Elimination Diet
(SOFEED) Followed by Swallowed Glucocorticoid Trial
NCT Number: NCT02778867
Document Name/Date: Informed Consent Form, 18 November 2016
Document Last Approval Date: 29 May 2018


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CINCINNATI CHILDRENS HOSPITAL MEDICAL CENTER
&
<INSERT RELYING INSTITUTION>
INFORMED CONSENT FOR PARTICIPATION IN A RESEARCH STUDY
STUDY TITLE: Six Food vs One Food Eosinophilic Esophagitis Elimination Diet (SOFEED)
followed by Swallowed Glucocorticoid Trial
SPONSOR NAME(S): National Institute of Allergy and Infectious Diseases (NIAID)
Division of Allergy, Immunology and Transplantation (DAIT)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Office of Rare Diseases Research (ORDR)
National Center for Advancing Translational Sciences (NCATS)
INVESTIGATOR INFORMATION:
<INSERT SITE PI NAME>
<INSERT SITE CONTACT NUMBER>
Principal Investigator Name
Telephone Number 24 hr Emergency Contact
Participants Name:_______________________________ Date of Birth: ___/____/____
INTRODUCTION:
This is a consent form. It explains this research study.  If you decide that you want to be in this
research study, then you will sign this form to show that you agree to be part of this study.
Your participation is voluntary. We will explain this research study to you.  You may ask questions.
x
Taking part in this study is your decision.
x
You may change your mind at any time.
x
You will be given a chance to speak with your doctor and the study clinicians.
x
You may stop the study at any time.
x
You will be given a copy of this consent form for your records.
WHY HAVE YOU BEEN ASKED TO TAKE PART IN THIS RESEARCH STUDY?
You are being asked to take part in this research study because you have been diagnosed with
Eosinophilic Esophagitis or EoE. EoE is an inflammatory disease in the esophagus (the tube leading


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from the mouth to the stomach) that is typically triggered by exposure to certain substances in food.
In order for you to participate in this study, you must meet certain criteria and sign the consent form.
WHO IS CONDUCTING THE RESEARCH STUDY?
Dr. Marc E. Rothenberg M.D., Ph.D., a researcher at Cincinnati Childrens Hospital Medical Center
(CCHMC), the Division of Allergy and Immunology with collaboration from the Division of
Gastroenterology, Hepatology, and Nutrition at Cincinnati Childrens Hospital Medical Center
is
directing this study.  Dr. Rothenberg is responsible for the medical supervision of this research.
<INSERT LOCAL PI NAME> is responsible for the medical supervision of this study at <INSERT
SITE NAME>.
This research study is funded by the National Institutes of Allergy and Infectious Disease (NIAID),
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Office of Rare Diseases
Research (ORDR), National Center for Advancing Translational Sciences (NCATS) and the Division
of Allergy, Immunology, and Transplantation (DAIT).
WHY IS THIS RESEARCH BEING DONE?
This research study will test the effects (good and bad) of two elimination dietary therapies
the 1
food elimination diet (1FED) (milk) vs the 6 food elimination diet (6FED) (milk, egg, wheat, soy,
peanut/tree nuts, and fish/shellfish) in people diagnosed with EoE.
This research study will also try to find out how well swallowed glucocorticoids help people
diagnosed with EoE. A glucocorticoid is a steroid-like medicine that works to decrease inflammation.
The name of the glucocorticoid used in this study is Flovent. This is not a new treatment. In this
study it is considered an experimental drug, because it has not been approved to treat people with
EoE. However, Flovent is approved by the FDA to treat asthma. Flovent is an inhaler. People with
asthma are told to spray the medicine into their mouths while inhaling. The medicine will go into
their lungs. People with EoE are told to spray the medication into their mouths and then swallow the
medication. If you take the medication this way, it will coat the esophagus (tube leading from your
mouth to your stomach) to reduce inflammation. Only some of the study participants will be given
Flovent.
HOW LONG WILL YOU BE IN THE RESEARCH STUDY?
This study consists of two parts, Part 1 and Part 2.  Screening can last up to 12 weeks, and parts 1 and
2 are each 6 weeks long. Part 2 is optional, so you may choose whether or not you want to participate
in Part 2. You will be in the research study for at least 18 weeks and no more than 27 weeks. Only
participants whose EoE does not improve with elimination diet therapy in Part 1 and who choose to
continue will continue to Part 2 of this study.
HOW MANY PEOPLE WILL TAKE PART IN THE RESEARCH STUDY?


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About 136 people will be in this study. This research study will take place in multiple centers across
the United States.
WHAT IS INVOLVED IN THE RESEARCH STUDY?
The study consists of two phases and a screening. The screening occurs 1 to 12 weeks before the Part
1 visit. The screening is to make sure you are eligible to take part in this study.
During Part 1, you will be randomly assigned (like flipping a coin) to one of the two diets (1FED or
6FED). You cannot pick which diet group you will be in for the study. The choice of which diet you
will be asked to follow is random, meaning that there is an equal chance of being in either group.
You will be on the diet for 6 weeks.
If your EoE is no longer active after being on one of the diets, you will be done with the study.
If you are on the 1 FED or 6 FED in Part 1 and improve you complete the study. If you do not
improve you may choose to continue to Part 2. If you are on the 1 FED and do not improve you will
start the 6 FED. You will stay on this diet for 6 weeks. If you are on the 6 FED in Part 1 and do not
improve you will start to use Flovent (the medicine that you spray into your mouth and swallow) two
times a day for 6 weeks. After 6 weeks you will finish the study.
This study will consist of 6 to 10 visits. For some of the visits you will come to the doctors office
.
Some of the visits will be over the phone.
What might happen at study visits?
The following may happen at your doctor visits
x
You will answer some questions about your family, your diet, about yourself, and about
your health.
x
The doctor will examine your ears, nose, throat, chest and skin
x
Your height, weight, blood pressure, heart rate, breathing rate, and temperature will be
checked
x
We may collect about 7 tablespoons (105 ml) of blood during the study. Blood is usually
collected at every visit. This is to learn more about your EoE and health. We can usually
collect all of the blood in one try. If the blood samples are lost, damaged, or need to be
repeated, we may ask for additional samples from you.
x
We may ask you to collect a stool sample (twice) and bring it to two of your appointments.
x
Collection of up to 4 extra esophageal biopsies (taken during endoscopy)
A biopsy is a
small piece of tissue from your esophagus. This measures your bodys response to diet and/or
swallowed Flovent therapy
x
Study questionnaires


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The questionnaires will ask you about your quality of life, symptoms, and dietary
intake and will take about 15 to 20 minutes for you to complete. You may be able to
complete the questionnaires at home if you do not finish.
x
Pregnancy test - For females, we will ask you to give us a small sample of urine for a
pregnancy test. Results of the pregnancy test will be reported directly to you. If your
pregnancy test is positive, you cannot be in the study.
x
Prick Skin testing for allergies. You will have a skin test for allergy .The skin test takes about
15 to 20 minutes. A drop of allergen is place on the skin. Small pricks are made to let the
solution enter the skin. The area may become red, raised, and itchy.
x
Patch skin testing. A solution with an allergen is placed on a pad that is taped to the skin for
24 to 72 hours.  If a red, raised itchy area develops, the person is probably allergic to the
allergen being tested.
Your Diet and Other Medications
Throughout the study you should not eat foods that are not part of the diet you have been assigned
(1FED or 6FED) or take any medication that is not allowed, if possible. To help you understand your
diet, instruction will be provided by a Registered Dietitian. If there are changes to your diet or
medication at any time, you should contact a research staff member.
Endoscopies (EGDs)
You will have 2 - 3 endoscopies during the time that you are in the study. This is to test how your
EoE is doing. EGDs are considered standard of care for individuals with EoE. The EGDs are not
study procedures.  We will review the pathology reports and biopsy slides from your EGDs as a part
of the study to see how your EoE is doing. We ask your permission for your doctor to take 4 extra
biopsies during the EGDs. We will examine the tissue to see if you are getting better. Before you
come in for an endoscopy you may be asked to collect a stool sample and bring it to your
appointment.
Unscheduled Visits
The study clinician may want to follow up on something from one of your study visits. If this
happens, the study team may ask you to come in for extra visits.
Genetic Tests (DNA)
The testing we do using the biopsy is not a genetic test. However, the optional blood samples will be
stored for future genetic testing. All DNA resulting from blood samples will be processed and stored
at CCHMC.
Genetic and DNA testing in this study is to find risk factor genes for eosinophilic disease. You will
not receive results.
Genetic Information Nondiscrimination Act (GINA)


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A new Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes
it illegal for health insurance companies, group health plans, and most employers to discriminate
against you based on your genetic information. This law generally will protect you in the following
ways:
x
Health insurance companies and group health plans may not request your genetic information
that we get from this research.
x
Health insurance companies and group health plans may not use your genetic information
when making decisions regarding your eligibility or premiums.
x
Employers with 15 or more employees may not use your genetic information that we get from
this research when making a decision to hire, promote, or fire you or when setting the terms of
your employment.
All health insurance companies, group health plans and employers as outlined above must follow this
law. Please note that this new Federal law does not protect you against genetic discrimination by
companies that sell life insurance, disability insurance, or long-term care insurance.
WHAT ARE THE RISKS AND DISCOMFORTS OF THE RESEARCH STUDY?
Esophageal Biopsies
Likely
Fluid may come out of the site that the tissue sample (biopsy) is taken
Less Likely
A hole in the esophagus, stomach, and/or intestines
To minimize the risks of taking extra biopsies during an endoscopy, the endoscopist will only collect
extra biopsies if he/she feels you are able to tolerate the extra biopsies.
Diet Therapy
Less Likely
Lack of proper nutrition
Swallowed Steroids
Likely
Development of oral thrush, (a yeast infection in the mouth/esophagus), which is a known side effect
of topical swallowed steroid use.
Less Likely


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Other potential side effects include a cold or upper respiratory infection, throat irritation, headache,
fever, diarrhea, ear infection, vomiting, bronchitis, inflammation of the nose and throat, and viral
infection.
Rare but Serious
It is also possible that the bodys internal production of steroids could be effected, and this could
increase risk for growth failure and problems with infection and response to other physiological
stress. Additional reported concerns include behavior changes, problems sleeping bone
demineralization, hypertension, eye changes (e.g. glaucoma, cataracts), adrenal suppression, and
immunosuppression. If you experience any side effect that bothers you or that does not go away, talk
to the study staff and/or your doctor.  Your health will be monitored by study staff throughout the
duration of the study.
Blood collection
Likely
The risk of having blood taken may include pain, bleeding, or bruising.
Less Likely
Lightheadedness and fainting rarely occur.
To decrease the pain or stinging sensation you can request the study team use EMLA or Spray and
Stretch Spray before any blood test.
Physical Exam
There are no known risks for the physical exam.
Skin Testing for Allergies (Prick or Patch)
Likely
If you have a positive skin test there will redness, swelling, and itching of the skin at the site of the
test. This may last for 1 to 2 hours.
Less Likely
Redness, swelling, and itching of the skin at the site of the test could occur up to 1 or 2 days after
the skin test. The study clinician may prescribe a cream to treat these symptoms.


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There is a very small chance that you could have hives, congestion, asthma symptoms or fainting
during the test. A study Clinician will always be available to treat these rare symptoms, if they
occur.
Rare but Serious
While it is very rare, anaphylactic shock (a whole-body allergic reaction) can occur with allergy skin
testing.  Anaphylaxis can be life threatening, but a study clinician will always be available when you
receive the injection and during the waiting period, and will be prepared to treat this serious reaction.
Stool Sample
There are no known risks.
Study Questionnaires
There are no foreseeable physical discomforts or significant risks related to answering the study
questionnaires.  However, some questions may be difficult and may be uncomfortable to answer.
You may also feel inconvenienced to complete the questionnaires. You may refuse to answer any
questions asked on the survey.  The study questionnaires typically take approximately 20 to 30
minutes to complete.  You will be given ample time to complete the surveys.
Other Risks
There is the unlikely chance that your information is viewed by someone outside the research team
who is not authorized to see your health information.
Treatment and procedures in this research study may involve risks that are not possible to predict.
You will be informed of any new risks that may be identified during the study. Please ask your
study doctor or the research staff to explain any procedures or risks that you do not understand.
WHAT ARE THE REPRODUCTION RISKS?
There is no way to guarantee that the study drug will not have a harmful effect on a developing baby
(embryo, fetus, or infant).  Therefore, you will not be able to take part in this study if you are
pregnant or nursing.  If you are sexually active, you may participate in this study if you use an
effective form of contraception.  You should discuss birth control options with your study doctor.
WHAT ARE THE RISKS OF STOPPING STUDY TREATMENTS?
During the study, treatment for your EoE will be managed by the research staff.  You should not stop
or alter study medication dosage and/or dietary therapy on your own.
ARE THERE DIRECT BENEFITS TO TAKING PART IN THE RESEARCH STUDY?


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If you agree to take part in this research study, there may not be any direct medical benefits to you.
Other studies of swallowed fluticasone have shown some benefit for people with EoE. The 1FED and
6FED elimination diet therapies have not been formally proven in EoE. The information learned from
this research study may benefit other patients with EoE in the future.
WHAT OTHER CHOICES ARE THERE?
Instead of being in this research study, you may choose not to participate. You do not have to be a
part of this study to receive treatment for your EoE. There may be other therapies that could be
prescribed for your EoE. You should discuss the alternatives with your doctor.
HOW WILL INFORMATION ABOUT YOU BE KEPT PRIVATE?
Making sure that information about you remains private is important to us. To protect your privacy in
this research study we will do the following:
x
Electronic records will be protected with passwords
x
Paper records will be secured in locked cabinets
x
Access to records will be limited to only research staff members
x
You will be assigned and identified by a unique study identification number
x
The link to your study identification number and PHI will be kept in a secure location.
x
A copy of this consent form will be included in your research medical record
A description of this clinical trial will be available on http://www.clinicaltrials.gov/ as required by
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site
will include a summary of the results.  You can search this Web site at any time.  The information
from the research study may also be published; however, you will not be identified in such a
publication. The publication will not contain information about you that would enable someone to
determine your identity as a research participant without your authorization.
The Food and Drug Administration (FDA) may choose to inspect your records since you are a
participant in this investigation of an unapproved drug.
You will not be identified in any publication or in the sharing of your data about this study.  After the
study is completed, the data may be placed in a central storage location.  These data will not include
your name or other information that can identify you.  The purpose is to make study data available to
other researchers.  Information from this study may be put into databases along with information
from other studies.  There are different kinds of databases; some are publicly accessible and some are
restricted.  Anyone on the internet can access publicly accessible databases.  Only researchers who
apply and are approved can access restricted databases.  Traditionally used identifying information
about you (such as name, phone number, address) will NOT be included or shared with others.


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While we will not use information that is traditionally used to identify you, people may develop ways
in the future that would allow someone to link your genetic or medical information in our databases
back to you.   For example, someone could compare information in our databases with information
from you (or a blood relative) in another database and be able to identify you (or your blood relative).
It is also possible there could be violations to the security of the computer systems used to store the
codes linking your genetic and medical information to you.   There may also be other privacy risks
that we have not foreseen.
The clinical information collected for this study will be stored at the Data Management and
Coordinating Center at the University of South Florida in Tampa, FL and also sent to a Federal data
repository. The data management center uses several layers of protection for the clinical data stored
there. It meets all of the local and federal security requirements for research datacenters. Your
information is stored only using a study ID.
WILL THE RESULTS OF MY RESEARCH-RELATED TESTS BE AVAILABILE?
Some research-related test results and information obtained from this study will be made directly
available to you.  After the results from the EGD you have at the end of Part 1 are known, you will be
told if you should continue on to study Part 2. The information collected from the quality of life
questionnaires are for research purposes only and will not have a direct affect in your care.  For
information regarding the study, including the research and the research participants rights, you may
contact the research study team physician, <INSERT LOCAL PI NAME, PHONE NUMBER, and
ADDRESS>.
WHAT IF NEW INFORMATION BECOMES AVAILABLE DURING THE RESEARCH?
A member of the research study team will tell you about new information from this or other studies
that may affect your health, welfare, or willingness to remain in this study.  The information from this
research study may be published; however, you will not be identified in such publication. The
publication will not contain information about you that would enable someone to determine your
identity as a research participant without your authorization.
WHAT ARE YOUR COSTS TO BE IN THIS STUDY?
All study visits and study treatments are provided to you without charge.  Study treatments include:
x
allergy skin testing
x
research blood draws
x
physical examinations and vital signs
x
pregnancy tests
x
research biopsies


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During the study, treatment for your EoE will be managed by the research staff. Care of your other
medical conditions will continue to be provided by your regular doctor.   The costs associated with
EGDs and treatment of your other medical conditions will not be paid for by the study.
WILL YOU BE PAID TO PARTICIPATE IN THIS RESEARCH STUDY?
You will not incur additional medical costs associated with your participation in this research. You
will receive the following reimbursement for the time associated with your participation in the study
for the study visits outlined below:
Visit
Reimbursement amount
for time
Screening and Enrollment
$125
EOT Phase 1
$125
Phase 2 Visit 1
$125
EOT Phase 2 (participation required)
$125
Total for completion of all study visits
$500
WHAT COMPENSATION IS AVAILABLE IN CASE OF INJURY?
If you believe that you have been injured as a result of participation in biomedical or behavioral
research, you are to contact <INSERT PI NAME>, to discuss your concerns.
<INSERT SITE SPECIFIC COMPENSATION INFORMATION>
IF SITE SPECIFIC COMPENSATION POLICY NOT ENTERED USE:
Doctors at the clinic or hospital can arrange for emergency medical care, <INSERT SITE NAME>
The Hospital and the Study Sponsors do not offer compensation or payment for injuries due to
participation in this research study. You and your insurance company will be billed for the costs of
any care or injuries.
In case of injury resulting from this study, you will not lose any legal rights by signing this form.
WHAT ARE YOUR RIGHTS AS A PARTICIPANT?
Taking part in this study is completely voluntary. You may choose either to take part or not to take
part in this research study. Your decision as to whether or not to take part will not result in any
penalty or loss of benefits to you and the standard medical care for your EoE will remain available to
you.


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If you decide to take part in the research study, you are free to withdraw your consent and
discontinue your participation at any time.  Leaving the study will not result in any penalty or loss of
benefits to you. If you choose to withdraw from the study, you should contact your doctor to seek
alternative treatment for your EoE.
The research study team doctor may stop your participation in the study at any time without your
consent if, in their opinion, you require alternative or additional treatment for your EoE, you
experience side effects that require your permanent withdrawal, or for other reasons. You may also
be removed from the study if the study is stopped by the Institution, the Sponsor(s), or other health
authorities.
If you have questions about the study, you will have a chance to talk to one of the research study team
members or your regular doctor.  Do not sign this form unless you have had the chance to ask
questions and have received satisfactory answers.  Nothing in this consent form waives any legal
rights you may have nor does it release the investigator, the sponsor, the institution, or its agents from
liability for negligence.
ABILITY TO CONDITION TREATMENT ON PARTICIPATION IN THIS STUDY
You have a right to refuse to sign this consent form and Authorization to use/disclose your Protected
Health Information for research purposes.  If you refuse to sign this consent, you may not be able to
receive research-related treatment.  If you refuse to sign this consent, your rights concerning
treatment, payment for services, and enrollment in a health plan or eligibility for benefits will not be
affected.
WHO DO YOU CALL IF YOU HAVE QUESTIONS OR PROBLEMS?
For questions, concerns, or complaints about this research study or to report a research-related injury,
you can contact the research study team physician, <INSERT LOCAL PI NAME> at <INSERT
PHONE AND ADDRESS>. Research study team members are available to answer any questions you
may have about the research at any time.
If you have general questions about your rights as a research participant in this research study, or
questions, concerns, or complaints about the research, you can call the <INSTITUTION NAME>
Institutional Review Board at <IRB PHONE NUMBER>. You can also call the Cincinnati
Childrens Hospital Medical Center Institutional Review Board at
513-636-8039. You can also call
these numbers if the research team members could not be reached, or if you wish to talk to someone
other than the research team members.
AUTHORIZATION FOR USE/DISCLOSURE OF HEALTH INFORMATION FOR
RESEARCH


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To be in this research study you must also give your permission (or authorization) to use and disclose
(or share) your protected health information (called PHI for short).
What protected health information will be used and shared during this study?
x
Your medical records
x
Your research record for this study
The types of information that will be used and shared from these records include:
x
Your laboratory test results
x
Clinical and research observations made during your participation in the study
x
Imaging (like CT scans, MRI scans, x-rays, etc.) studies and reports
x
Your medical record if it contains information concerning HIV testing or the treatment of
AIDS or AIDS-related conditions, drug or alcohol abuse, drug-related conditions, alcoholism,
and/or psychiatric/psychological conditions (but not psychotherapy notes)
<INSERT SITE SPECIFIC HIPAA LANGUAGE OR PROVIDE SEPARATE HIPAA
AUTHRORIZATION FORM FOR REVIEW
IF YOUR SITE DOES NOT HAVE SITE SPECIFIC HIPAA LANGUAGE USE THE
FOLLOWING>.
Authorization to Use and Disclose Protected Health Information (HIPAA Language)
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 <INSTITUTION NAME> !  !
WHO WILL SHARE, RECEIVE AND/OR USE YOUR PROTECTED HEALTH
INFORMATION IN THIS STUDY?
This form authorizes the following to disclose, use and receive your PHI:

Every research site of the study (including Cincinnati Childrens and each sites research
and medical staff)

Every health care provider who provides services to you in connection with the study

Any laboratories and other individuals and organizations that analyze your PHI in
connection with the study

Data Safety Monitoring Board for this study


IRB #: 2015-3622
Approved:
5/29/2018
Do Not Use After:
5/28/2019
 &$ 
 ,% 
$-.(,+ 
,1

The National Institute of Allergy and Infectious Diseases (NIAID), sponsor of the
research, and the people and companies they use to oversee, administer and/or conduct the
study

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Office of Rare Diseases Research (ORDR), National Center for Advancing Translational
Sciences (NCATS)

Federal regulatory agencies, such as the Food and Drug Administration (FDA), other
foreign regulatory agencies, and others as required by law

The members of the Cincinnati Childrens Institutional Review Board and staff of th
e
Office of Research Compliance and Regulatory Affairs

The Principal Investigator and research staff members

The clinical information collected for this study will be stored in a computer database at
the Data Management and Coordinating Center at the University of South Florida in
Tampa, FL
HOW WILL YOU KNOW THAT YOUR PHI IS NOT MISUSED?
People that receive your PHI as part of the research are generally limited in how they can use your
PHI. In addition, most people who receive your PHI are also required by Federal Privacy Laws to
protect your PHI. However, some people that may receive your PHI may not be required to protect it
and may share the information with others without your permission, if permitted by laws that apply to
them.
CAN YOU CHANGE YOUR MIND?
You may choose to withdraw your permission at any time. A withdrawal of your permission to use
and share your PHI would also include a withdrawal from participation in the research study. If you
wish to withdraw your permission to use and share your PHI, you need to notify the study doctor,
listed on the first page of the document, in writing. Your request will be effective immediately and no
new PHI about you will be used or shared. The only exceptions are (1) any use or sharing of PHI that
has already occurred or was in process prior to you withdrawing your permission and (2) any use or
sharing that is needed to maintain the integrity of the research.
When you withdraw permission, you are no longer part of the study.  No new information about you
will be gathered for the study except when it is on an adverse (unfavorable) event that is related or
potentially related to the study.  If one happens, your entire medical record may need to be reviewed.
CAN I SEE MY PHI RELATED TO THE STUDY?
You may have the right to see and copy your protected health information related to the study for as
long as this information is held by the study doctor or the healthcare institution. However, to ensure
the scientific integrity of the study, you agree that you may not be able to review some of your
records related to the study until after the study has been completed.


IRB #: 2015-3622
Approved:
5/29/2018
Do Not Use After:
5/28/2019
 &$  ,% 
$-.(,+ 
,1
WILL THIS PERMISSION EXPIRE?
Your permission will expire at the end of the study.
FUTURE USE OF YOUR DATA/BIOLOGICAL MATERIALS
We are asking your permission to store blood or saliva, stool, and tissue samples of biological
specimens collected during the course of this study to be used in the future for tests that arent yet
planned. These tests may or may not be related to the study of EoE.
Your stored samples will be used to obtain knowledge about genetic information in relation to your
disease. Genetic tests study an individuals inherited characteristics, found in DNA, which is present
in each of the cells of your body. DNA contains information needed to construct and operate the human
body.
The results of tests performed on stored samples or reports resulting from the analysis of your samples
will not be given to you or your doctor and they will not be put in your medical record.  They will not
identify you and will not affect your routine medical care.
There is no benefit to you from the storage of samples and information.  However, the use of your
samples and information may help researchers learn more about your disease or the genetics related
to a specific condition. The purpose of storage and sharing data is to make information available for
use in health research and to share what is stored with other researchers.  Collecting, storing, sharing
information and making it available for other studies may help people in the future.   Coded
information put into databases together with other stored information from many studies conducted in
different places allow researchers to study the combined information and learn even more about
health and many different diseases.
Samples will be stored at Cincinnati Children€s Hospital Medical Center (CCHMC) and/or at the
Data Management and Coordinating Center at the University of South Florida
. If you decide to
allow storage, your samples and information may be stored for an unknown length of time.
Although your stored research samples will not be sold, the information obtained from the research
performed on your samples may in the future lead to the development of commercial products. You
will not receive any money from research using your stored samples and information.
There may be unknown risks associated with the storage of samples and information.    For example,
if the future research involves genetic testing it is possible that it could be traced back to you because
your genes are specific to you. We will make every attempt to protect your confidentiality and to
make sure that your personal identity does not become known.
You can change your mind at any time and ask to have your samples destroyed.  This request should
be made in writing to the study doctor.  If you make this request, all remaining stored samples will be
destroyed.  However, the results of any previous tests using your stored samples will be used.    Your


IRB #: 2015-3622
Approved:
5/29/2018
Do Not Use After:
5/28/2019
Page 15 of 18
Version 5.0
18Nov16
decision regarding the storage of samples or the information resulting from the analysis of your
samples will not affect your ability to participate in this study.  The future use of your samples and
information may contribute to learning more about disease or help to study the genetics related to a
specific condition.


IRB #: 2015-3622
Approved:
5/29/2018
Do Not Use After:
5/28/2019
Page 16 of 18
Version 5.0
18Nov16
Please indicate your response below:
I agree to the collection of additional biopsies (up to 4) for research.
Yes
No
_______________________
Initials of Research Subject
I agree to the collection of 7 tablespoons (105 ml) of blood for research.
Yes
No
_______________________
Initials of Research Subject
I agree to the collection of saliva (spit into a tube) for research.
Yes
No
_______________________
Initials of Research Subject
I agree to collect a stool sample (if I am asked to do so)
Yes
No
_______________________
Initials of Research Subject
I agree to the storage and sharing of samples (blood, saliva, and tissue) for genetic tests not currently
planned.
Yes
No
_______________________
Initials of Research Subject
I agree to the storage and sharing of samples (blood, saliva, stool, and tissue) and information
resulting from the analysis of my samples for other tests not currently planned.
Yes
No
_______________________
Initials of Research Subject
I choose to participate in Part 2 of the study
Yes
No
_______________________
Initials of Research Subject
May we contact you in the future regarding this study or to inform you of additional studies that may
be related to this disease that we are studying?
Yes
No
_______________________
Initials of Research Subject


IRB #: 2015-3622
Approved:
5/29/2018
Do Not Use After:
5/28/2019
 &$  ,% 
$-.(,+ 
,1
SIGNATURES:
I have read the information given above. The investigator or his/her designee have personally
discussed the research study with me and have answered my questions. I am aware that, like in any
research, the investigators cannot always predict what may happen or possibly go wrong. I have been
given sufficient time to consider if I should participate in this study. I hereby give my consent to take
part in this study as a research study participant.  I will receive a copy of this signed form for my
records.
Signature of Participant indicating consent
Date
Signature of Participants Personal Representative*
Date
*Complete below if signed by a Personal Representative (parent, legal guardian, etc.)
Description of Personal Representatives Authority to Sign for Participant
Printed Name of Personal Representative
Person Obtaining Consent and Authorization
Date


IRB #: 2015-3622
Approved:
5/29/2018
Do Not Use After:
5/28/2019
Page 18 of 18
Version 5.0
18Nov16
Schedule of Study Assessments
Phase
Pre-treatment
Visit Number
1
2
3
4
5
6
7
8
9
10
Visit Description
Screening
Enrollment/
Baseline
Phone
Visit #1
Phone
Visit #2
Phone
Visit #3
EOT or Early
Withdrawal
Phase 2
Visit 1
Phone
Visit #4
Phone
Visit #5
EOT or Early
Withdrawal
Week
-12 to -1
0
1
3
5
6
10
11
15
16
Perform Informed Consent
X
Assess Eligibility
(inclusion/exclusion criteria)
X
X
Obtain medical & dietary history
X
Assess con-meds and/or con-
therapies
X
X
X
X
X
X
X
X
X
X
Vitals (height, weight, BP, heart
rate, respiratory rate, temperature)
X
X
X
X
X
Physical Exam
X
X
X
Research Biopsies (taken during
SOC EGD)
Xa
X
Xb
Study Questionnaires
X
X
X
DSQ
X
Xe
X
Xe
Dietary Questionnaires
X
X
X
X
X
X
Skin testing for allergies (prick and
patch)
X
Research Lab Samples
EDP, otherc
Serum food
IgE, CRD, &
IgG4; T cells
EDP, serum
food IgE,
CRD, &
IgG4, T
cells, otherc
otherc
Morning cortisol (serum)
X
X
CBC with differential
X
X
X
Stool sample
Xd
Xd
X
Pregnancy test (urine)
X
X
X
Assess AEs
X
X
X
X
X
X
X
X
Provide food diary
X
X
X
X
X
Provide instructions for diet or
medication
X
X
Determine compliance with
treatment
X
X
X (diet)
X (diet)
X (SGC)
Dispense SGC
X
Collect SGC
X
Collect compliance logs
X
a First SOC EGD used to determine eligibility may be conducted within 4 weeks prior to enrollment visit.
bThis EOT SOC EGD pertains only to Phase 1 Non-Responders.
Each visit window (for visits 2-10) is ±3 days.
Treatment Phase 1
Optional Treatment Phase 2
cOther refers to collection of blood or saliva for future genetic testing.  These samples will only be collected once, but may be collected at any of the visits indicated.
dStool samples may be collected at some participating centers from subjects who consent to stool collection.  Stool may be obtained either at Screening/Baseline OR
Enrollment, as well as at EOT Phase 1.
eThe DSQ should be completed daily in the 2 weeks prior to each endoscopy.

Prot_002.pdf: 
Six Food vs One Food Eosinophilic Esophagitis Elimination Diet 
(SOFEED) Followed by Swallowed Glucocorticoid Trial 
Protocol Date: 11/22/2017 
NCT02778867 


Page 1 of 63
Rare Diseases Clinical Research Network
Six Food vs One Food Eosinophilic Esophagitis Elimination
Diet (SOFEED) followed by Swallowed Glucocorticoid Trial
Consortium for Eosinophilic Gastrointestinal Disease
Researchers
Marc E. Rothenberg, MD, PhD
Cin
3333 Burnet Avenue, MLC 7028
Cincinnati, OH 45229
Phone: 
Version Number: V6.0 22 Nov 17
othenbe
henbe
Burnet A
urnet
Cincin
Cinc
Phon
Ph
ointesti
ointest
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rs


Page 2 of 63
KEY ROLES
Protocol Chair: Marc Rothenberg, MD, PhD
Institution:
Cincinn
Address:
3333 Burnet Avenue, MLC 2010
Cincinnati, OH 45229-3039
Phone:
Fax:
Email:
NIAID Medical Monitor: 
Institution:
Division of Allergy, Immunology, and Transplantation
NIAID/NIH
Address:
5601 Fishers Lane, 
Bethesda, MD 20892 
Phone:
Fax:
Email:
NIAID Project Manager: 
Institution:
Division of Allergy, Immunology, and Transplantation
NIAID/NIH
Address:
P.O. Box 7
Lecanto, FL 34460
Phone:
Email:
Data Management and Coordinating Center Director: Jeffrey Krischer, PhD
Institution:
Health Informatics Institute at the University of South Florida
Address:
3650 Spectrum Blvd., Suite 100.
Tampa, Florida 33612
Phone:
Fax:
Email:
er Director:
Directo
at the Unive
the Univ
uite 100.
e 100.
ation
ation
NIA
NIA


Page 3 of 63
INVESTIGATOR SIGNATURE PAGE
Protocol: CEGIR 7802
Version/Date: V6.0 11/22/17
Site Principal Investigator:
Title:
Six Food vs One Food Eosinophilic Esophagitis Elimination
Diet (SOFEED)
followed by Swallowed Glucocorticoid Trial
Study Sponsors:
National Center for Advancing Translational Sciences    (NCATS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) The
National Institute of Allergy and Infectious Diseases   (NIAID)
INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated
location below. A copy should be kept for your records and the original signature page sent.
After signature, please upload the signed document to the DMCC E-regulatory binder, IoRA
cubby:
Christina Carpenter, Research Project Manager
Data Management and Coordinating Center (DMCC)
Health Informatics Institute; University of South Florida, 3605 Spectrum Blvd Suite 100
Tampa, FL 33612
I confirm that I have read the above protocol in the latest version. I understand it, and I will
work according to the principles of Good Clinical Practice (GCP) as described in the United
States Code of Federal Regulations (CFR)
45 CFR part 46 and 21 CFR parts 50, 56, and 312,
and in the International Conference on Harmonization (ICH) document Guidance for Industry:
E6 Good Clinical Practice: Consolidated Guidance dated April 1996. Further, I will conduct
the study in keeping with local legal and regulatory requirements.
As the site Principal Investigator, I agree to carry out the study by the criteria written in the
protocol and understand that no changes can be made to this protocol without the written
permission of the IRB and NIAID.
Confidentiality Statement
This document contains confidential information of the Sponsor. This information is to be
disclosed only to the recipient study staff and the Institutional Review Board or Board of
Ethics Committee reviewing this protocol. This information can be used for no other purpose
than evaluation or conduct of this study without prior written consent from the Sponsor
Site Principal Investigator (Print)
Site Principal Investigator (Signature)
Date
tatement
atement
contains c
contains c
o the r
o the r
5 CF
5 C
monizatio
onizati
ed Guidance
Guida
and regulato
nd regu
tor, I agree to
, I agre
at no change
no chang
d NIAID.
NIAID.
atest versio
test versio
Practice (
Practice (
R par
pa
signat
igna
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gulatory
Manager
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2


Page 4 of 63
PROTOCOL SYNOPSIS
Protocol Title:
Six Food vs One Food Eosinophilic Esophagitis Elimination Diet
(SOFEED) followed by Swallowed Glucocorticoid Trial
Short Title
SOFEED
Clinical Phase
Phase II/III
Consortium:
Consortium for Eosinophilic Gastrointestinal Disease Researchers
(CEGIR)
IND Sponsor/Number
Marc Rothenberg, MD, PhD / IND # 76820
Study Objectives
Primary Objective:
Determine the rate of remission following 1FED vs. 6FED and
evaluate the relative efficacy of these dietary therapies
Secondary Objectives:
To extend Phase 1 of this study with a prospective non-blinded
trial that determines the rate of remission following SGC in the
6FED diet non-responders (Phase 2).
To extend Phase 1 of this study with a prospective non-blinded
trial that determines the rate of remission following 6FED in the
1FED non-responders (Phase 2).
To evaluate the effect of each therapy on histological remission
defined by a variety of changes in eosinophils, including (a) pre-
and post-therapypeak eosinophil counts; (b) partial remission (2-
14
peak
eosinophils/hpf);
and
(c)
complete
histological
eosinophils/hpf).
To evaluate the effect of each therapy by utilizing the histology
scoring system (HSS) created to express the severity and extent
of other abnormalities in the gastrointestinal (GI) tract that often
accompany eosinophilic inflammation.
To evaluate endoscopic outcomes as assessed by the endoscopy
scoring system (EREFS).
To determine the impact of each therapeutic intervention on
biomarkers using the EoE Diagnostic Panel (EDP).
To evaluate the clinical and psychosocial effect of each therapy
utilizing surveys to assess EoE symptoms andproblems/feelings
related to eating.
Phase 
hase
at determine
determin
D non
non-respo
res
To evaluate t
evaluat
defined
define b
and
and po
14
1
following 1
ollowing 1
f these die
f these d
f this stud
this stud
nes the rate
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Page 5 of 63
To determine if any clinical parameters predict response to
therapeutic intervention.
To determine if any biomarkers including serum food specific
IgE, CRD, and IgG4 predict response to therapeutic intervention.
To determine if skin testing, in the form of prick and patch
testing, predicts response to therapeutic intervention.
To determine if milk-driven T cells in the blood positively
correlate with milk atopy patch test results and effectiveness of
dietary therapies.
To bank DNA so that we can later elucidate genetic components
of EoE
Study Design
Prospective, non-blinded clinical trial of individuals ages 18-60 years
with EoE
Primary Endpoint(s)
The primary endpoint for this study will be the percent of participants
who achieve histologic remission (<15 peak eosinophils/HPF) post
therapy assessed via endoscopy with biopsy after the end of the 6 week
Phase 1.
Secondary
Endpoint(s)
Histology and endoscopy measures
Division of patients into complete (peak
remission
Histology Scoring system
Endoscopic scoring system (EREFS)
Biomarkers pre- and post-treatment
Assessment of EDP Score
Patient Reported Outcome (PRO) metrics pre- and post-
treatment
EoE Adult Symptom Score Activity Index, and Adult
EoE Quality of Life Score
PROMIS General Health Questionnaire
Clinical parameters and biomarkers to predict responsiveness to
diet and SGC therapy
Correlation of clinical characteristics to response to
therapy
Assessment of predictive value of skin prick and patch
allergy testing
Correlation between presence of positive milk
component allergy testing to response to 1FED
Correlation of level of circulating milk-specific T cells
with patch testing and response to 1FED
Predictive biomarker-analysis of EoE transcriptome
from EDP analysis on baseline biopsies in correlation to
response to treatment.
doscop
scop
rkers pre
rs pre- an
Assessm
Assess
Patient Repo
tient R
treatment
treatm
py
py measure
measur
patients into
tients int
gy Scorin
y Scorin
s
he percen
he perc
eak eosinop
ak eosinop
biopsy after
iopsy aft


Page 6 of 63
Sample Size:
136
Study Duration
Minimum 18 weeks to maximum 27 weeks
Inclusion Criteria
Subject must be able to understand and provide informed consent
Have diagnosis of EoE (based on consensus criteria)1.
Are aged 18 to 60 years
Have histologically confirmed active disease >15 eosinophils/hpf in
the esophagus within 12 weeks of screening visit
Symptomatic (have experienced symptoms within the last month
prior to enrollment)
PPI confirmation. (As a part of the diagnosis of active EoE, it must
be demonstrated that acid reflux disease is not the primary cause of
ation that the participant
has been on a high dose of PPI (at least one dose, once daily) for at
least 8 weeks prior to a diagnostic endoscopy of EoE without
of doses and various PPIs available, the dose will be confirmed
adequate at the discretion of the PI).)
Have a negative urine pregnancy test at screening if of childbearing
potential. Females of childbearing potential must have a negative
-hCG) prior to enrollment into the study (i.e.,
at screening). These participants must agree to use adequate birth
control measures (e.g., condom, oral/injectable/subcutaneous
contraceptives, intrauterine device, or sexual abstinence) during the
study and for at least one month after the last dose of study drug
which will be documented in the source documents.
Exclusion Criteria
Inability or unwillingness of a participant to give written informed
consent or comply with study protocol
Have been treated with topical swallowed steroids within the last 2
months or systemic steroids within the last 3 months
Have pathological eosinophilia in segments of the GI tract other
than the esophagus determined by local review
Have been diagnosed with a GI malabsorption disorder (i.e.,
disease
Are currently on dietary therapy strictly avoiding milk or on a
6FED
Have concurrent H. pylori gastritis or parasitic infection
Have history of anaphylaxis to milk (with current avoidance of
milk)
Unable to complete study procedures, including EGD.
Have previously failed strict dietary therapy clearly documented
with one of these regimens or topical steroid treatment (i.e. have
not achieved histological remission of <15 eos/hpf after having
Inability or u
ability o
consent o
consent
Have b
Have
mo
(e(e
s, intraute
ntraut
for at least o
r at least
will be docu
ll be d
H
py of 
py o
the dose w
he dose w
PI).)
I).)
ncy test at s
cy test at 
bearing po
bearing po
hCG) prio
hCG) prio
participan
participan
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Page 7 of 63
been on 2 mg of budesonide per day or 1760 mcg of fluticasone per
day for 8 weeks prior to the EGD)
.
Use of investigational drugs within 4 weeks (one month) prior to
enrollment
Are concurrently receiving any of the prohibited medications listed
in section 8.3
Not fluent in English
On immunotherapy for pollen (if not on maintenance therapy) or
IgE-mediated food allergy.
Past or current medical problems or findings from physical
examination or laboratory testing that are not listed above, which,
in the opinion of the investigator, may pose additional risks from
participation in the study, may interfere with the parti
ability to comply with study requirements or that may impact the
quality or interpretation of the data obtained from the study.
Statistical
Considerations
(sample size and
analysis plan):
Conduct a prospective non-blinded randomized trial that compares a 1-
food elimination diet (1FED) versus a 6-food elimination diet (6FED)
for 6 weeks (Phase 1).
Subjects who fail 6FED (i.e. dietary non-responders) in Phase 1 may
choose to continue into Phase 2, where they will receive topical
swallowed steroid therapy (swallowed fluticasone at a dose of 880 mcg
twice a day) for 6 weeks, while on an unrestricted diet. Subjects who
fail 1FED will also continue into Phase 2, but they will maintain 6FED
for 6 weeks instead of receiving SGC. Participants receiving SGC will
return to an unrestricted diet prior to initiating SGC therapy.
Empiric dietary therapy interventions are as follows: 1-food
elimination diet (1FED)
avoidance of milk vs. 6-food elimination diet
(6FED)
avoidance of milk, egg, wheat, soy, fish/shellfish, and
peanut/tree nuts, for 6 weeks.
p
er
 weeks, 
eeks,
l also continu
lso conti
s instead of r
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Empiric dieta
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e. dietary n
Phase 2, w
Phase 2, w
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Page 8 of 63
Table of Contents
Glossary of Abbreviations ....................................................................................................................................15
1.
INTRODUCTION ............................................................................................................................................17
2.
BACKGROUND AND RATIONALE.............................................................................................................18
Background and Scientific Rationale Eosinophilic Esophagitis ............................................................18
Rationale for Selection of Investigational Product or Intervention ........................................................19
Preclinical Experience ............................................................................................................................19
3.3.1
Previous Research on the Use of Dietary Therapy in Eosinophilic Esophagitis ................................19
Clinical Studies.......................................................................................................................................19
3.
STUDY HYPOTHESES/OBJECTIVES..........................................................................................................20
Hypotheses..............................................................................................................................................20
Primary Objectives .................................................................................................................................20
Secondary Objective(s)...........................................................................................................................21
4.
STUDY DESIGN..............................................................................................................................................21
Description of Study Design...................................................................................................................21
Primary Endpoints ..................................................................................................................................23
Secondary Endpoints ..............................................................................................................................23
Exploratory Endpoint(s)/Outcome(s) .....................................................................................................23
End of therapy (EOT) and Follow-up.....................................................................................................26
Stratification, Randomization, and Blinding/Masking ...........................................................................26
5.
SELECTION OF PARTICIPANTS AND CLINICAL SITES/LABORATORIES.........................................27
Rationale for Study Population...............................................................................................................27
Inclusion Criteria ....................................................................................................................................27
Exclusion Criteria...................................................................................................................................27
s
ndpoint(s)/
ndpoint(s)/
y (EO
y (E
......
................
........
.................
.........
................
..........
...........
..
ph
p
.............
..........
..............
.............
.............
.............
.............
........
...


Page 9 of 63
6.
KNOWN AND POTENTIAL RISKS AND BENEFITS TO PARTICIPANTS .............................................28
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert
Treatment with topical swallowed steroids ............................................................................................28
Risks of Investigational Product or Intervention cited in Medical Literature ........................................28
Risks of Other Protocol Specified Medications......................................................................................28
Risk of Study Procedures .......................................................................................................................28
6.4.1 Treatment with Dietary Therapy..............................................................................................................28
6.4.2 Histology Scoring System (HSS) ............................................................................................................30
6.4.3 Study Survey............................................................................................................................................30
6.4.4 Esophageal Biopsies ................................................................................................................................30
6.4.5 Blood Draws ............................................................................................................................................30
6.4.6 Skin Testing For Allergies
Prick Testing..............................................................................................31
6.4.7 Skin Testing For Allergies
Patch Testing.............................................................................................31
6.4.8 Swallowed Glucocorticoids .....................................................................................................................31
Standard of Care Procedures Associated with This Study Esophagogastroduodenoscopy (EGD)........31
Potential Benefits....................................................................................................................................31
7.
INVESTIGATIONAL AGENT /DEVICE/INTERVENTION ........................................................................32
Investigational Agents/Devices/Interventions Investigational Agent #1................................................32
7.1.1 Formulation, Packaging, and Labeling ....................................................................................................32
7.1.2 Dosage, Preparation, and Administration ................................................................................................32
7.1.3 Drug Accountability.................................................................................................................................32
7.1.4 Assessment of Participant Compliance with Investigational Agent ........................................................33
7.1.5 Toxicity Prevention and Management.....................................................................................................33
7.1.6 Premature Discontinuation of Investigational Agent...............................................................................33
8.
OTHER MEDICATIONS.................................................................................................................................33
gents/D
gents/D
Packaging
Packaging
titi
.........
..........
iated with Th
ed with 
............
... ....
T /DEVICE/
T /DEVICE
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Page 10 of 63
8.1 Concomitant Medications ...............................................................................................................................33
8.1.1 Protocol-mandated ...................................................................................................................................33
8.1.2 Other permitted concomitant medications...............................................................................................33
8.2
Prophylactic Medications .......................................................................................................................33
8.3
Prohibited Medications...........................................................................................................................33
8.4 Rescue Medications ........................................................................................................................................34
9.
STUDY PROCEDURES ..................................................................................................................................34
Screening/Baseline Visit (Weeks -12 to -1) ...........................................................................................34
Enrollment (Week 0) ..............................................................................................................................35
Phone Visits, Phase 1..............................................................................................................................36
End of 1st Treatment phase or Early Withdrawal (Week 6) ..................................................................36
Phase 2 Visit 1 (Week 10) ......................................................................................................................37
Phone Visits, Phase 2..............................................................................................................................37
End of 2nd treatment phase or Early Withdrawal (Week 16).................................................................37
Unscheduled Visits.................................................................................................................................37
Visit Windows ........................................................................................................................................38
10. MECHANISTIC ASSAYS...............................................................................................................................38
EDP.........................................................................................................................................................38
T Cell Studies .........................................................................................................................................38
Biospecimen Storage ..............................................................................................................................38
11. CRITERIA FOR PARTICIPANT AND STUDY COMPLETION AND PREMATURE STUDY
TERMINATION...............................................................................................................................................39
Participant Completion ...........................................................................................................................39
Participant Stopping Rules and Withdrawal Criteria..............................................................................39
Participant Replacement .........................................................................................................................39
.
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Page 11 of 63
Follow-up after Early Study Withdrawal ...............................................................................................39
Study Stopping Rules .............................................................................................................................39
12. SAFETY MONITORING AND REPORTING................................................................................................40
Overview ................................................................................................................................................40
Definitions ..............................................................................................................................................40
12.2.1 Adverse Event (AE)...............................................................................................................................40
12.2.2. Study mandated procedures:.................................................................................................................41
12.2.3 Suspected Adverse Reaction (SAR) ......................................................................................................41
12.2.4 Unexpected Adverse Event....................................................................................................................41
12.2.5 Serious Adverse Event (SAE)................................................................................................................41
Grading and Attribution of Adverse Events...........................................................................................42
12.3.1 Grading Criteria .....................................................................................................................................42
12.3.2 Attribution Definitions...........................................................................................................................43
Collection and Recording of Adverse Events.........................................................................................43
12.4.1 Collecting Adverse Events.....................................................................................................................43
12.4.2 Recording Adverse Events.....................................................................................................................43
Reporting of Serious Adverse Events and Adverse Events....................................................................44
12.5.1 Reporting of Serious Adverse Events to Sponsor DAIT/NIAID...........................................................44
12.5.2 Reporting to the FDA.............................................................................................................................44
12.5.3 Annual Reporting...................................................................................................................................44
12.5.4 Expedited Safety Reporting ...................................................................................................................45
12.5.5 Reporting of Adverse Events to IRBs/IECs...........................................................................................45
12.5.6 Pregnancy Reporting..............................................................................................................................45
12.5.7 Reporting of Other Safety Information..................................................................................................46
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Page 12 of 63
12.5.8 Review of Safety Information................................................................................................................46
12.5.9 Medical Monitor Review .......................................................................................................................46
12.5.10 DSMB Review.....................................................................................................................................46
13. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN..............................................................47
Overview ................................................................................................................................................47
Endpoints/Outcomes...............................................................................................................................47
Measures to Minimize Bias ....................................................................................................................47
Analysis Plan ..........................................................................................................................................48
13.4.1 Analysis Populations..............................................................................................................................48
13.4.2 Primary Analysis of Primary Endpoint(s)/Outcome(s)..........................................................................48
13.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s) ..............................................................48
13.4.4 Analyses of Secondary and Other Endpoint(s)/Outcome(s)..................................................................49
13.4.5 Analyses of Exploratory Endpoint(s)/Outcome(s).................................................................................50
13.4.6 Descriptive Analyses .............................................................................................................................50
Interim Analyses.....................................................................................................................................51
13.5.1 Interim Analysis of Efficacy Data .........................................................................................................51
13.5.2 Interim Analysis of Safety Data.............................................................................................................51
13.5.3 Futility Analysis.....................................................................................................................................51
13.5.4 Statistical Hypotheses ............................................................................................................................51
Sample Size Considerations ...................................................................................................................51
14. IDENTIFICATION AND ACCESS TO SOURCE DATA..............................................................................52
Source Data.............................................................................................................................................52
Access to Source Data ............................................................................................................................52
15. PROTOCOL DEVIATIONS ............................................................................................................................52
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Page 13 of 63
Protocol Deviation Definitions...............................................................................................................52
15.1.1 Protocol Deviation .................................................................................................................................52
15.1.2 Major Protocol Deviation (Protocol Violation) .....................................................................................52
15.1.3 Non-Major Protocol Deviation ..............................................................................................................52
15.1.4 Reporting and Managing Protocol Deviations.......................................................................................52
16. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE .................53
Statement of Compliance........................................................................................................................53
Informed Consent Process ......................................................................................................................53
17. INVESTIGATOR REQUIREMENTS .............................................................................................................54
Protocol Adherence ................................................................................................................................54
Case Report Forms .................................................................................................................................54
Source Document Maintenance..............................................................................................................54
Data Quality and Monitoring Measures .................................................................................................54
Registration.............................................................................................................................................54
Laboratory Data Flow.............................................................................................................................55
Study Completion...................................................................................................................................55
Audits and Inspections............................................................................................................................55
Institutional Review Board Approval.....................................................................................................55
18. ETHICS.............................................................................................................................................................56
Ethics Review.........................................................................................................................................56
Ethical Conduct of the Study..................................................................................................................56
Privacy and Confidentiality....................................................................................................................56
19. DATA HANDLING AND RECORDKEEPING .............................................................................................56
Inspection of Records .............................................................................................................................57
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Page 14 of 63
Retention of Records ..............................................................................................................................57
20. PUBLICATION POLICY ................................................................................................................................57
21. REFERENCES .................................................................................................................................................58


Page 15 of 63
Glossary of Abbreviations
CCHMC
CI
Confidence level
CFR
Code of Federal Regulations
CHCO
CRF
Case Report Form
CRPC
Central Review Pathology Committee
Ct
Threshold Cycle
CTCAE
Common Terminology Criteria for Adverse Events
DAIT
Division of Allergy, Immunology, and Transplantation
DMCC
Data Management and Coordinating Center
DSMB
Data Safety Monitoring Board
DSQ
Dysphagia Symptom Questionnaire
EDP
EoE Diagnostic Panel
EGD
Esophagogastroduodenoscopy
EoE
Eosinophilic Esophagitis
EOT
End of treatment
FDA
Food and Drug Administration
1FED
1-food elimination diet
6FED
6-food elimination diet
FP
fluticasone propionate
GCP
Good Clinical Practice
GI
Gastrointestinal
HPF
high power field
HSS
Histology Scoring System
ICH
International Conference on Harmonization
IND
Investigational New Drug
IRB
Institutional Review Board
MOP
Manual of Procedures
NIAID
National Institute of Allergy and Infectious Diseases
uticaso
uticaso
Good C
Good 
Gas
Gas
mination diet
ation di
py
py
s
Administrat
minis
elimination
elimination
ne pro
e
tion
on


Page 16 of 63
NIH
National Institutes of Health
NW
Northwestern University
PHI
Protected health information
PI
[Site] Principal Investigator
PPI
Proton pump inhibitor
PRO
Patient Reported Outcomes
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAR
Suspected Adverse Reaction
SGC
Swallowed Glucocorticoid
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction


Page 17 of 63
1. INTRODUCTION
The primary objective of this proposal is to conduct a prospective, non-blinded randomized trial comparing rates
of remission of novel empiric elimination dietary therapies in eosinophilic esophagitis (EoE) in order to assess the
therapeutic viability of empiric elimination diets. Moreover, we aim to assess response to topical swallowed
steroids in non-responders to empiric six food dietary therapy regimens and the response to 6FED in 1FED non-
responders. Participants aged 18 to 60 years with active EoE will be enrolled and the primary efficacy outcome
will be the rate of histologic remission assessed using esophageal biopsies obtained following a six week
randomized trial of one of two empiric diets. During the screening process, active EoE will be confirmed by
histologic evaluation of esophageal biopsies obtained during an esophagogastroduodenoscopy (EGD) in subjects
with a history consistent with EoE.
This trial is comprised of a screening (up to 12 weeks in duration) and 2 phases, with each phase lasting 6 weeks.
Phase 2 is optional, and eligible participants may choose whether or not to continue into Phase 2. In the first phase,
all participants will be randomized 1:1 to either 1 food elimination (milk elimination alone, 1FED) or 6 food
elimination (milk, egg, wheat, soy, fish/shellfish, peanut/tree nuts elimination, 6FED) therapeutic diet. At the end
of this phase, an EGD will be performed to assess remission. Attainment of remission (esophageal eosinophil
counts <15 eosinophils/high powered field) after phase 1 will result in study discontinuation and maintenance of
-responders who were on 6FED during Phase 1 and choose
to continue into Phase 2 will receive topical swallowed steroids for 6 weeks (Phase 2) while on an unrestricted
diet, followed by EGD with esophageal biopsies. Dietary therapy non-responders who were on 1FED during Phase
1 and choose to continue into Phase 2 will proceed to 6FED for six weeks (Phase 2) followed by EGD with
esophageal biopsies.
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Page 18 of 63
The primary efficacy endpoint will assess and compare the percentage of patients achieving remission by following
the two diets. Pre- and post-therapy peak eosinophil counts per hpf and percentages of patients that attain histologic
remission (<15 eosinophils/hpf) will be reported. The peak eosinophil level refers to the peak eosinophil count from
the esophagus as a whole, although peak eosinophil levels are recorded by the esophageal segment. During Phase
1 screening, the peak eosinophil count obtained from local pathology review will be used to assess subject
eligibility for study participation. Eligibility for entry into Phase 2 of the study will be determined by the peak
count obtained from the central
including more detailed histologic and endoscopic scores, novel biomarkers, and several Patient Reported Outcome
(PRO) measures will also be assessed. In addition, we will assess the possible value of a variety of clinical
characteristics and biomarkers in terms of predicting response to therapy.
This study will provide significant novel information. The use of 6FED after 1FED failure will provide practical
information for clinical recommendations. This will be a prospective dietary therapy trial using these empiric
elimination diets. As part of our secondary aims, we will also be utilizing a number of novel potential biomarkers
to assess their ability in predicting and assessing response to therapy as well as a number of PRO metrics.
2. BACKGROUND AND RATIONALE
Background and Scientific Rationale
Eosinophilic Esophagitis
EoE represents a complex clinical entity often requiring coordinated care within the fields of both allergy and
gastroenterology. EoE is diagnostically defined by revised consensus criteria, that in brief require esophageal-
the esophagus, and that is not mitigated by the use of proton pump inhibitor (PPI) therapy1. Symptomatically,
patients with EoE often complain of dysphagia, vomiting, reflux, food aversion, and food impaction1-3. These
patients commonly have diagnoses associated with atopy and other allergic disorders such as IgE-mediated food
allergy, asthma, allergic rhinoconjunctivitis, and eczema. Current treatment modalities focus on the use of the six
food elimination diet (6FED), which consists of the empiric avoidance of the top 6 most common food allergens
in the U.S. (milk, egg, wheat, soy, peanut/tree nuts, and fish/shellfish); implementation of a variety of directed
elimination diets that rely on the use of allergy test results; the elimination of all antigenic proteins via the use of
elemental formulas; or the use of swallowed steroid therapies (topical swallowed preparations of fluticasone or
budesonide or oral systemic steroids) 4-13. While all of these treatments are efficacious, they require continuous use
or the disease will recrudesce in the majority of patients. Due to concerns about the risk of chronic topical
swallowed steroid, patients and/or their families frequently opt to initially implement dietary therapy. This study
is designed in keeping with this preference; therefore one of two empiric dietary therapies will be implemented
initially prior to the use of topical swallowed steroids in participants who do not respond to the dietary treatment.
The use of dietary restrictions as a treatment modality requires family and/or personal commitment to eliminating
food, which may lead to significant nutritional deficiencies and is often life-altering.
, soy,
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Page 19 of 63
Rationale for Selection of Investigational Product or Intervention
Current treatment modalities focus on the use of the six food elimination diet (6FED), which consists of the empiric
avoidance of the top 6 most common food allergens in the U.S. (milk, egg, wheat, soy, peanut/tree nuts, and
fish/shellfish); implementation of a variety of directed elimination diets that rely on the use of allergy test results;
the elimination of all antigenic proteins via the use of elemental formulas; or the use of swallowed steroid therapies
(topical swallowed preparations of fluticasone or budesonide or oral systemic steroids) 4-13. While all of these
treatments are efficacious, they require continuous use or the disease will recrudesce in the majority of patients.
Strictly adhering to any of these elimination diets is challenging for most patients, and so comparing response rates
to a minimally restrictive therapy (1FED) against a more rigorous therapy (6FED) would be informative and
potentially valuable.
It is considered standard of care for adults to undergo 6 weeks of dietary therapy, and studies have demonstrated
that a 6-week trial of dietary therapy or even shorter for swallowed glucocorticoids is adequate for detecting change
in disease status.58, 59, 31, 21Compliance is expected to be greater with a shorter therapy period as opposed to a longer
one. It is also noted that the standard of care for children is to undergo 12 weeks of dietary therapy, at least in part
because esophageal biopsies every 6 weeks may be a higher risk to children than biopsies every 12 weeks.
Preclinical Experience
3.3.1
Previous Research on the Use of Dietary Therapy in Eosinophilic Esophagitis
EoE is a chronic esophageal inflammatory disease typically triggered by exposure to food antigens. Given this,
dietary elimination of these antigens has been tested as a therapeutic option. Previous work has shown that the
exclusive use of elemental formula resulted in a response rate from 88-100% when histology and symptoms are
considered, but difficulties with compliance, cost, and formula palatability have led to attempts to find alternative
dietary approaches9, 13, 14. Use of allergy testing to direct dietary elimination has been advocated, and in studies
response rates from 53-77% have been reported. However, in practice the utility of allergy testing is very dependent
on local expertise, and the response rate has been lower than hoped8, 13, 15. Given this, there has been an attempt to
use an empiric 6FED, which removes milk, soy, wheat, egg, peanuts/tree nuts, and fish/shellfish from the diet.
This intervention has shown response rates ranging from 53-81% and is attractive due to the fact that no allergy
testing is required. In all of these currently prescribed dietary therapies, the goal is to reintroduce foods
systematically with subsequent endoscopy to try to identify specific causative antigens. A single small study of 17
children showed a partial or complete response rate of 65% using milk elimination alone16. In published reports
where causative antigens have been identified, milk, wheat, and eggs have consistently been reported to be the top
3 offending food antigens8, 13, 17. Strictly adhering to any of these elimination diets is challenging for most patients,
and so comparing response rates to a minimally restrictive therapy (1FED) against a more rigorous therapy (6FED)
would be informative and potentially valuable.
Clinical Studies
In a randomized controlled trial conducted by our group we assessed the efficacy of high dose fluticasone. Forty-
two participants were enrolled in this study (28 FP, 14 placebo). After 3 months, 65% of FP-treated and 0% of
placebo-treated participants had complete remission (P = 0.0001); 12% of FP-treated and 8% of   placebo-treated
em
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Page 20 of 63
participants had partial remission. Of the FP-treated participants in complete remission, 73% continued in complete
remission, and 20% were in partial remission after halving the daily FP dosage.53 Vital signs and lab results were
stable throughout the study. No participant was reported to exhibit clinical signs of adrenal insufficiency or
glucocorticoid toxicity.53
3. STUDY HYPOTHESES/OBJECTIVES
Hypotheses
We hypothesize that 6FED will be superior to 1FED, although we expect that a substantial (meaningful) percentage
of patients will respond to 1FED.
We hypothesize that some patients who fail to respond to 1FED will respond to 6FED.
We hypothesize that some patients who fail to respond to 6FED will respond to SGC.
We hypothesize that HSS will more accurately quantify histological changes associated with EoE and be reversible
following each therapeutic intervention. Furthermore, we hypothesize that some patients may show partial
responses, where a subset of the HSS may be improved earlier or in dissociation with eosinophil levels, for
example.
We hypothesize that molecular biomarkers will change (improve) with each treatment phase, at least in part.
Furthermore, we hypothesize that biomarkers may reveal (a) novel insight into therapeutic resistance and/or
relapse; (b) reveal patient sub-groups not identified by histology; and (c) ultimately prove to be readily usable
biomarkers in clinical settings and possess personalized medicine value. If our hypotheses are proven to be correct,
they have potential to transform monitoring of patients during therapeutic intervention, by identifying molecular
markers that have therapeutic significance, and also by reducing the need for biopsies, particularly after therapy is
initiated.
We hypothesize that the therapeutic interventions utilized in this studywill improve clinical symptoms as measured
by PRO metrics.
We hypothesize that certain patient phenotypes will correlate with response to each intervention in the trial.
We hypothesize that skin test results (prick testing to the 6 test foods and atopy patch testing to milk) will provide
significant predictive value for outcomes in the diet trial phases.
Primary Objectives
To perform a prospective, randomized, non-blinded trial that determines the rate of remission following 1FED
(milk elimination alone) vs. 6FED (milk, egg, wheat, soy, fish/shellfish, and peanut/tree nuts avoidance)
and evaluates the relative efficacy of these dietary therapies (Phase 1).
The primary endpoint for this study will be the percent of participants who achieve histologic remission
(<15 peak eosinophils/HPF) post therapy assessed after the end of the six week Phase 1.
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Page 21 of 63
Secondary Objective(s)
To extend Phase 1 of this study with a prospective non-blinded trial that determines the rate of remission
following SGC in the 6FED non-responders and the rate of remission following 6FED in the 1FED non-
responders (Phase 2).
To extend Phase 1 of this study with a prospective non-blinded trial that determines the rate of remission
following 6FED in the 1FED non-responders (Phase 2).
To evaluate the effect of each therapy on histological remission defined by a variety of changes in
eosinophils, including (a) pre- and post-therapy peak eosinophil counts; (b) partial remission (2-14 peak
eosinophils/hpf).
To evaluate the effect of each therapy by utilizing the histology scoring system (HSS) created to express
the severity and extent of other abnormalities in the gastrointestinal (GI) tract that often accompany
eosinophilic inflammation.
To evaluate endoscopic outcomes as assessed by the endoscopy scoring system (EREFS).
To determine the impact of each therapeutic intervention on biomarkers using the EoE Diagnostic Panel
(EDP).
To evaluate the clinical and psychosocial effect of each therapy utilizing surveys to assess EoE symptoms
and problems/feelings related to eating.
To determine if any clinical parameters predict response to therapeutic intervention.
To determine if any biomarkers including serum food specific IgE, CRD, and IgG4 predict response to
therapeutic intervention.
To determine if skin testing, in the form of prick and patch testing, predicts response to therapeutic
intervention.
To determine if milk-driven T cells in the blood positively correlate with milk atopy patch test results and
effectiveness of dietary therapies.
To bank DNA so that we can later elucidate genetic components of EoE
4.
STUDY DESIGN
Description of Study Design
We will be recruiting a total of 136 participants, between the ages of 18-60. Participants will be enrolled in this
studybased on the presence of active eosinophilic esophagitis and adherence to the inclusion and exclusion criteria.
We intend to conduct a prospective non-blinded randomized trial that compares a 1-food elimination diet (1FED)
versus a 6-food elimination diet (6FED) for six weeks (Phase 1). Subsequently, non-responders to 1FED dietary
elimination therapy will be treated with 6FED and non-responders to 6FED will be treated with SGC (swallowed
fluticasone at a dose of 880 mcg twice a day) for six weeks (Phase 2) while on an unrestricted diet, if the participant
chooses to continue in to Phase 2. The empiric dietary therapy interventions are as follows: 1-food elimination diet
(1FED)
avoidance of milk vs. 6-food elimination diet (6FED)
avoidance of milk, egg, wheat, soy,
fish/shellfish, and peanut/tree nuts, for six weeks. Milk elimination for both 1FED and 6FED includes all mammal
Figure
1 Study Design Flowchart.
Desi
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l of 136 
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Page 22 of 63
In Phase 1, all participants will be randomized 1:1 to either 1 food elimination (milk elimination alone, 1FED) or
6 food elimination (milk, egg, wheat, soy, fish/shellfish, peanut/tree nuts elimination, 6FED) therapeutic diet. At
the end of this phase, an EGD will be performed to assess remission. Attainment of remission (esophageal
eosinophil counts <15 eosinophils/high powered field) after Phase 1 will result in study discontinuation and
maintenance of the
dietary therapy. Treatment non-responders may choose whether or not to continue
into Phase 2. Dietary therapy non-responders who were on 6FED in Phase 1 and continue in to Phase 2 will receive
topical swallowed steroids for six weeks (Phase 2) followed by EGD with esophageal biopsies. These participants
will return to an unrestricted diet (i.e. stop 6FED) prior to beginning topical swallowed steroid therapy. Dietary
non-responders in Phase 1 who were on 1FED and continue in to Phase 2 will continue to a 6FED therapeutic diet
(Phase 2) for six weeks followed by EGD with esophageal biopsies to assess remission.
The instructions for the 1FED and 6FED therapeutic diets will be standardized across sites by providing consensus
documents produced by a central Registered Dietitian who is an expert in dietary elimination in EoE. There are
currently no validated dietary questionnaires for measuring food allergen intake in adults in the US. Dietary intake
and consumption of the allergens will be measured at the start of the trial and adherence to the dietary elimination
(i.e. avoidance
intake/diet 
history 
questionnaires 
and 
food 
diaries 
from 
published 
pediatric 
EGID 
studies
(http://cancercontrol.cancer.gov) and assisted by metabolomics. Stool samples may be collected from subjects who
consent to stool collection to evaluate the effect of diet on the microbiome.
Similarly, standardized instructions for using SGC will be provided, based on our prior studies. We have chosen
to use fluticasone propionate (FP) rather than budesonide in this study, given our prior work in this area, and our
recent finding that high-dose fluticasone is well tolerated and highly effective, and our preliminary findings
concerning esophageal transcripts that predict responsiveness to FP therapy. The study design is shown
schematically in Figure 1 Study Design Flowchart.
Figure 1 Study Design Flowchart
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Page 23 of 63
Primary Endpoints
AIM 1: To determine the efficacy of a 1FED vs. 6FED in EoE.
a. Primary end-point The primary efficacy endpoint will be determined at the end of Phase 1 at which time
all participants will undergo EGD with biopsy and the percentage of patients who have <15 peak
eosinophils/hpf will be determined. The slides will be reviewed by local pathologists for clinical purposes,
who will be blinded to the treatment group. The Central Review Pathology Committee (CRPC), who will
also be blind to the treatment group, will also review the slides, and the peak eosinophil count from this
CRPC review will be used to determine whether or not participants are eligible to continue into Phase 2 of
peak eosinophils/hpf who were on 1FED during Phase 1 and choose to continue into Phase 2 will maintain
the 6FED therapeutic diet for 6 weeks. The CRPC will subsequently review the esophageal biopsy slides
to determine other parameters (such as the Histology Scoring System (HSS)). CRPC review will be
co
histologic remission at the end of Phase 1 (as determined by CRPC review) or who complete Phase 1 and
opt out of Phase 2 will have completed the study and will resume follow-up care with their primary
gastroenterologist or allergist.
Secondary Endpoints
Secondary end-point analysis: histology and endoscopy. Change in peak eosinophil count will be measured and
we will also aim to determine the percentage of patients who achieve remission by more stringent requirements
than the primary end-
(<10 and <6 peak eosinophils/HPF) as reported6. This will allow us to compare with other studies that have used
hils/HPF) 
hils/HPF) 
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and e
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Page 23 of 63
6FED14,17,23,24,. Furthermore, we aim to more broadly examine the impact of each therapeutic intervention on other
histological parameters associated with EoE using a quantitative histology scoring system (HSS) that has been
developed by our expert pathologist, Dr. Margaret Collins26. The HSS evaluates esophageal biopsies for various
features (ex: basal layer hyperplasia, dilated intercellular spaces, surface epithelial alteration, apoptotic epithelial
cells), eosinophilic inflammation (peak count, eosinophil abscess, eosinophil surface layering), and lamina propria
(fibrosis). For central review, slides of relevant esophageal biopsies obtained during the course of the study will
be scanned using an Aperio Imaging scanner and viewed by the CRPC using Aperio Imaging Software. Each
member of the CRPC has access to an Aperio scanner in his or her pathology department and to the Aperio Imaging
Software. Slides may be scanned into Aperio at the local site, or they may be sent to Cincinnati
Hospital
Medical Center (CCHMC) to be scanned into Aperio (if the local site does not have an Aperio scanner). These
slides will be returned to the local site once they have been scanned in. A password-protected website housing the
scanned images will be created at CCHMC, and the CRPC will have access to that site. A secure image repository
may also be housed at the Data Management Coordinating Center of the Rare Diseases Clinical Research Network
at the University of South Florida. The CRPC will establish interobserver and intraobserver variability in their
evaluation of eosinophils and other pathologic features: The central pathologists will re-count eosinophils in the
scanned images of biopsies and compare the peak eosinophil counts that they obtained by viewing the scanned
images to evaluate the variability in the counts. The CRPC pathologists will compare their results amongst
themselves and resolve differences via teleconferences in which the scanned images are displayed (meetings hosted
by GoToMeeting or equivalent sites). Ten percent intraobserver and interobserver variability will be considered
optimum. Each review pathologist will review study slides from subjects enrolled at their own institution (Dr.
Collins, CCHMC; Dr. Capocelli, CHCO; Dr. Yang, NW). Relevant biopsy slides from the other participating sites
will also be reviewed by the CRPC. The workload will be distributed as equally as possible among the CRPC
pathologists with the assistance of the DMCC. Gastric and/or duodenal biopsies will only be reviewed by local
is unclear (for example, when it is unclear whether a potential participant does or does not have eosinophilic
gastritis or colitis). In such cases, the CRPC will review gastric and/or duodenal slides to confirm the appropriate
diagnosis. Subjects may be included, without stomach or duodenal biopsies, if there is no clinical history of
involvement of stomach or duodenum. We hypothesize that HSS will more accurately quantify changes associated
with EoE and be reversible following each therapeutic intervention. Furthermore, we hypothesize that some
patients may show partial responses, where a subset of the HSS may be improved earlier or in dissociation with
eosinophil levels, for example. Finally, we will aim to determine the impact of the various therapeutic interventions
on gross endoscopic changes, as determined by a recently developed endoscopy scoring system (EREFS)
developed by Dr. Hirano and colleagues27.
Exploratory Endpoint(s)/Outcome(s)
Secondary end-point analysis: biomarkers. In this sub-aim, we hypothesize that molecular biomarkers will
change (improve) with each treatment phase, at least in part. Furthermore, we hypothesize that biomarkers may
reveal (a) novel insight into therapeutic resistance and/or relapse; (b) reveal patient sub-groups not identified by
histology; and (c) ultimately prove to be readily usable biomarkers in clinical settings and possess personalized
medicine value. We will focus on molecular profiling of esophageal genes with the EoE Diagnostic Panel (EDP),
a set of 94 mRNA transcripts that have been established to differentiate EoE from controls (e.g. GERD and normal
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Page 24 of 63
individuals), and to identify exposure and transcriptional signaling to SGCs28. The EDP is typically performed on
an extra biopsy taken from the distal esophagus28. If our hypotheses are proven to be correct, they have potential
to transform monitoring of patients during therapeutic intervention, by identifying molecular markers that have
therapeutic significance, and also by reducing the need for biopsies, particularly after therapy is initiated.
Essentially, the associated EDP algorithm renders the raw Ct. values of each embedded gene after real-time PCR
in a way such that the upregulated genes and downregulated genes are summed up individually. A quantitative
statistical analysis. Utilizing different gene sets, EDP is also able to predict steroid exposure and remission status
based on the same algorithm 28. In this case, the EoE score will be calculated at baseline endoscopy and in the
posttreatment biopsies to assess change with treatment.
Secondary end-point analysis: Patient Reported Outcome (PRO) metrics. In this sub-aim, we hypothesize that
therapeutic interventions will improve clinical symptoms as measured by PRO metrics. This is an important issue
to resolve as only a few prior studies have shown the clinical efficacy of therapeutic interventions. In fact, several
studies have shown dissociation between histology (eosinophil levels) and clinical improvement31,32, but these
studies have not used validated metrics for measuring symptoms. The measurement of pre/post diet symptoms
using tools that have undergone at least some validation is a novel aspect of our study. While we have made
substantial progress with the development and validation of a number of PRO measurements, there is still not
agreement around the best measurements, related in part by 1the uncertainty of whether these instruments truly
measure meaningful and accurate parameters. Agreement about these measurements has significant bearing on the
eventual FDA approval of therapeutic agents33. As such, we will take several approaches in this sub-aim. First, we
will employ EoE specific measurement tools, including the adult EoE dysphagia questionnaire, EoE Adult
Symptom Score Activity Index (EESAI), and the adult EoE quality of life score (EoE-QOL-A36,37,38,39. In addition,
we will also employ generic Health Related QOL metrics, such as PROMIS General Health Questionnaire, and
eventually compare the changes in disease specific versus general health questionnaires. These PROs will be
assessed at the screening visit and again at the end of each treatment phase to assess the effects of treatment.
AIM 2: To determine clinical parameters and biomarkers that predict responsiveness to therapies.
2a. Clinical phenotypes. In this sub-aim, we hypothesize that certain patient phenotypes will correlate with
response to each intervention in the trial. We will assess the relationship between response to 1FED, 6FED,
and SGC on age, height, weight, BMI Z-score, race, ethnicity, allergic status, participant compliance
(defined by diet and SGC usage diaries), and screening eosinophil levels as readouts.
2b. Skin testing. In this sub-aim, we hypothesize that skin test results (prick testing to the 6 foods in the 6FED
and atopy patch testing to milk) will provide significant predictive value for outcomes in the diet trial
phases. While a substantial body of work has already been done concerning skin testing, there still remains
clinic
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Page 25 of 63
debate about its practice in managing EoE. As such, in this sub-aim, we will take several different
approaches compared with prior work. In particular, we will be conducting a multi-site trial and have the
advantage that we can standardize the skin testing procedure, by using agreed upon techniques, including
food extracts, skin test reagents, and measurement parameters. We will thus be in a good position to dissect
discrepant results between centers. Furthermore, our trial is unique in that half of the patients will undergo
a milk elimination diet as part of the first phase. Thus, we will be in a position to focus on the value of skin
testing for milk, which is particularly attractive as milk is the number one food trigger of EoE 19. It is
important to point out that although skin testing (including patch testing) is now readily performed in EoE,
there have been no studies that have assessed the local response. For example, it has not yet even been
determined if positive responses involve immunological reactions, so basic cytokine and histological
analyses are likely to be fundamentally informative.
2c. Serum food specific IgE, CRD, and IgG4. The level of food specific IgE, CRD, and IgG4 will be
determined by a solid phase immunoabsorbent assay (ELISA) focusing on the 6FED foods. Serum will be
banked and processed in batches. Component testing for at least each of the 6 foods will be performed as
feasible. The Investigators reserve the right to perform these analyses using commercially available
platforms including UniCAP and the Immuno Solid-phase Allergen Chip (ISAC, Thermo Scientific).
2d. Assessment of milk-driven T cells. In this sub-aim, we will perform exploratory studies designed to test
the presence and significance of circulating milk-specific T cells in EoE patients. We will test the
hypothesis that milk-specific T cells will be primarily CD4+, IL-5+, IL-13+, consistent with prior work.47-
49 Furthermore, we will test the sub-hypothesis that the level of milk-specific T cells will positively
correlate with positive atopy patch tests to milk and the response rate to milk elimination (1FED and
secondarily 6FED, which also contains milk). The frequency of Th2 cells will be determined by FACS
analysis, and milk-specificity will be estimated by milk protein stimulation in vitro, particularly looking at
CD154 induction, a marker of T cell activation. These exploratory studies, will be performed with shipped
blood samples, by Dr. Jonathan Spergel, as published.47,48,50,51 The study will be limited to a pilot analysis
of patients who only enter the 1FED and we will compare patients with positive and negative skin tests
(prick and patch).
2e. Predictive Biomarker-analysis of EoE transcriptome. In this sub-aim, we aim to identify biomarkers
that may predict responsiveness to any or all of the treatment interventions associated with this trial.
Determining such a biomarker would have a profound effect on disease management as patients could be
quickly triaged into different therapies, e.g. diet versus SGC; thus saving time, reducing the number of
endoscopies and potentially improving quality of life issues. As such, in this sub-aim, we will perform the
EDP analysis on baseline biopsies, focused on identifying transcript levels that differentiate patients that
respond to each of the interventions. In preliminary studies, we have conducted this type of analysis on
patients that recently participated in the randomized controlled trial of high dose fluticasone (1760 mcg per
day) for the treatment of EoE. Forty-two participants were enrolled in this study (28 FP, 14 placebo). After
3 months, 65% of FP-treated and 0% of placebo-treated participants had complete remission (P = 0.0001);
12% of FP-treated and 8% of placebo-treated participants had partial remission. Of the FP-treated
participants in complete remission, 73% continued in complete remission, and 20% were in partial
remission after halving the daily FP dosage.53
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Page 26 of 63
Baseline esophageal gene expression was compared between FP responders and non-responder patients by
statistically screening two cohorts of samples before the FP exposure, namely the FP responders and FP-
non-responders. A total of 15 genes (Figure 4 in the reference, p < 0.05, fold change > 2.0) on the EDP
the distal esophagus). It is interesting to note that some of these transcripts include cardinal EoE
transcriptome genes such as CCL26 (eotaxin-3) and periostin and CLC (Charcot-Leyden crystals, a marker
of eosinophils) suggesting that elevated production was a positive prognostic factor for FP responsiveness;
these findings are consistent with a recent report suggesting that more severe tissue inflammation including
eosinophil levels was associated with FP responsiveness.52 This preliminary result highlights thepotential
ability of baseline molecular transcripts to differentiate patients but also importance of repeating this
analysis with an independent cohort of FP treated patient samples, as preliminarily identified genes have
not yet passed the false discovery rate (FDR) correction due to a relatively small n. It is expected that a
replication cohort will bring in a higher power to pass the FDR filter. Meanwhile, multiple false-correction
methods will be applied to the collective data set, such as the West-Young and Bonferroni methods.
2f. Elucidation of genetic components of EoE. In this sub-aim, we seek to elucidate the genetic components
of EoE through the collection of blood and/or saliva for genetic analysis. Blood and/or saliva specimens
drawn by a certified phlebotomist or an RN, LPN, DO, or MD. A standard protocol for collection of blood
derived DNA will be utilized, and approximately 2 teaspoons (10 milliliters) of blood will be collected. If
blood cannot be obtained or the subject elects to limit DNA collection to non-blood sources, an oral DNA
specimen (saliva) will be obtained instead. Whether the sample collected is blood or saliva, samples will
be deidentified, processed, and shipped to CCHMC for storage. DNA will remain available for future
genetic testing.
End of therapy (EOT) and Follow-up
The primary efficacy endpoint (e.g. achievement of histologic remission of less than 15 eosinophils/HPF) will be
determined at the end of phase 1 (week 6) at which time all participants will undergo EGD with biopsy. Participants
who achieve histologic remission at the end of phase 1 will have completed the study and will resume follow-up
care with their primary GI or Allergy physician. Participants whose disease remains active after being on 1FED
and choose to continue into Phase 2 will continue on to 6FED in Phase 2. Participants whose disease remains
active after being on 6FED in Phase 1 and choose to continue into Phase 2 will receive 6 weeks of SGC in Phase
2.
Stratification, Randomization, and Blinding/Masking
All eligible participants will be randomized 1:1 to either the 1FED or 6FED. Following this six week phase 1, all
patients will undergo EGD with biopsy, and those whose disease remains active may choose to move on to Phase
2 (to either 6FED or treatment with swallowed SGC). The sponsor, investigator, study staff, and participant will
all have knowledge of the treatment being received.
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Page 27 of 63
5. SELECTION OF PARTICIPANTS AND CLINICAL
SITES/LABORATORIES
Rationale for Study Population
Participants of any gender or race who are between the ages of 18-60 years old are eligible for entry into this study.
We have chosen to limit our study to adult (ages 18-60) subjects due to evidence from previous studies that there
may be different rates of response to given antigens between adult and pediatric populations (for instance, pediatric
trials of dietary intervention have consistently shown that milk is the most common causative antigen in this age
group, while studies in adult populations have suggested that other antigens including wheat are more likely to
drive eosinophilia in adults.)23, 24. Given this apparent difference in response, we will limit the study population to
ensure that we can accurately identify responses to the different dietary regimens.
Inclusion Criteria
Individuals who meet all of the following criteria are eligible for enrollment as study participants:
Subject must be able to understand and provide informed consent
Have diagnosis of EoE (based on consensus criteria)1
Are aged 18 to 60 years
Have histologically confirmed active disease >15 eosinophils/hpf in the esophagus within 12 weeks of
screening visit
Symptomatic (have experienced symptoms within the last month prior to enrollment)
PPI confirmation. (As a part of the diagnosis of active EoE, it must be demonstrated that acid reflux disease
on a
high dose of PPI (at least one dose, once daily) for at least 8 weeks prior to a diagnostic endoscopy of EoE
without his
available, the dose will be confirmed adequate at the discretion of the PI).)
Have a negative urine pregnancy test at screening if of childbearing potential. Females of childbearing
-hCG) prior to enrollment into the study (i.e., at
screening). These participants must agree to use adequate birth control measures (e.g., condom,
oral/injectable/subcutaneous contraceptives, intrauterine device, or sexual abstinence) during the study and
for at least one month after the last dose of study drug which will be documented in the source documents.
Exclusion Criteria
Individuals who meet any of these criteria are not eligible for enrollment as study participants:
Inability or unwillingness of a participant to give written informed consent or comply with study
protocol
Have been treated with topical swallowed steroids within the last 2 months or systemic steroidswithin
the last 3 months
Have pathological eosinophilia in segments of the GI tract other than the esophagus determined by
local review
disease) or Celiac disease
Are currently on dietary therapy avoiding milk or on a 6FED.
Have concurrent H. pylori gastritis or parasitic infection
fter
fte
ia
ny of the
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Page 28 of 63
Have history of anaphylaxis to milk (with current avoidance of milk)
Unable to complete study procedures, including EGD.
Have previously failed strict dietary therapy clearly documented with one of these regimens or topical
steroid treatment (i.e. have not achieved histological remission of <15 eos/hpf after having been on 2
mg of budesonide per day or 1760 mcg of fluticasone per day for 8 weeks prior to the EGD).
Use of investigational drugs within one month prior to enrollment
Are concurrently receiving any of the prohibited medications listed in section 8.3
Not fluent in English
On immunotherapy for pollen (if not on maintenance therapy) or IgE-mediated food allergy.
Past or current medical problems or findings from physical examination or laboratory testing that are
not listed above, which, in the opinion of the investigator, may pose additional risks from participation
in the study, may interfere with the
ability to comply with study requirements or that may
impact the quality or interpretation of the data obtained from the study.
6. KNOWN AND POTENTIAL RISKS AND BENEFITS TO PARTICIPANTS
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert
Treatment with topical swallowed steroids
In the short term (such as the Phase 2 six week period steroid study interval), the primary risk is the development
of oral thrush, which is a known side effect of topical swallowed steroid use6. Other reported concerns include
behavior changes and difficulty sleeping. Such side effects are reversible with medication reduction or
discontinuation. Risks from longer term use of topical swallowed corticosteroid are less well understood, but might
include bone demineralization, trouble with elevated blood sugar or hypertension, and/or eye changes such as
glaucoma or cataracts. However, these have not been commonly seen with use of inhaled steroids for other diseases
such as asthma and have not yet been seen in any of the controlled studies with topical steroids for EoE. There is
also a concern about the potential for adrenal suppression with chronic steroid use, and we will monitor for this
with morning cortisol levels at the beginning and end of Phase 2. There is also a theoretical risk for
immunosuppression due to the chronic use of high-dose swallowed inhaled steroids, although this has never been
shown to occur in previous studies or in the collective experience of the centers involved in the trial.
Risks of Investigational Product or Intervention cited in Medical Literature
N/A
Risks of Other Protocol Specified Medications
N/A
Risk of Study Procedures
6.4.1 Treatment with Dietary Therapy
Minimal risk exists related to implementation of short-term dietary therapies in EoE. Dietary instruction regarding
tudies o
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Page 29 of 63
tenets of each dietary therapy and nutrition-related recommendations will be provided by a Registered Dietitian,


Page 30 of 63
who will show participants how to implement and make appropriate substitutions for foods eliminated to ensure
nutritional adequacy. A central dietitian will develop standardized instructional materials for use at all of the
participating sites.
6.4.2 Histology Scoring System (HSS)
The histology scoring system is a method to evaluate esophageal biopsies containing eosinophils for various
features (ex: basal layer hyperplasia, dilated intercellular spaces, surface epithelial alteration, apoptotic epithelial
cells), eosinophilic inflammation (peak count, eosinophil abscess, eosinophil surface layering), and lamina propria
(fibrosis).  There is no risk associated with the utilization of the HSS.
6.4.3 Study Survey
Each participant between the ages of 18 to 60 years old will be asked to complete several surveys, includingPRO
measures regarding both Health Related Quality of Life as well as disease-specific symptom scores and QOL
measures in order to address their EoE symptoms and problems/ feelings related to eating. The data gathered from
these questionnaires will be correlated with several biomarkers of interest that have been associated with EoE.
These surveys will be conducted at baseline and the end of each study phase. There are no foreseeable physical
discomforts or significant risks related to answering the PROs or study questionnaires. However, some questions
may be difficult or uncomfortable for participants to answer. Participants may refuse to answer any questions that
they are uncomfortable with. The participants may also feel inconvenienced by completing the questionnaires. The
participant questionnaires typically take approximately 15 to 20 minutes to complete. All participants will be given
ample time to complete the questionnaires. Please reference the table below for guidelines regarding study
questionnaire completion.
6.4.4 Esophageal Biopsies
The risks associated with collecting additional esophageal biopsies (up to a total of four obtained from the proximal
and/or distal esophagus) for research at the time of the endoscopy include: bleeding at the site of tissue (biopsy)
collection, and a small chance of perforation (hole) of the stomach, duodenum, or esophagus. Perforation is the
most severe gastrointestinal complication, but generally it is self-resolving and poses no life-threatening risk.
Transient bacteremia as a result of diagnostic UGI endoscopy has been reported at rates as high as 8%, but the
frequency of infectious endocarditis and other clinical sequelae is extremely low, such that current American Heart
Association and American Society for Gastrointestinal Endoscopy guidelines do not recommend antibiotic
prophylaxis with diagnostic UGI endoscopy solely to prevent infectious endocarditis.54-57 The risk of aspiration
during endoscopy is miniscule. To minimize the risks of collecting additional biopsies during endoscopy, the
procedure will be performed or supervised by a skilled endoscopist, and additional biopsies will only be collected
if the endoscopist feels it is appropriate to do so. Some samples that are collected during an endoscopy for research
purposes may be frozen and shipped to other hospitals, institutions, and testing companies for analysis. Data may
also be shared. The data and/or samples will be de-identified per HIPPA and have no PHI associated with them.
The data and/or samples will be used in a collaborative relationship between institutions, or testing companies
receiving the data and/or samples. All of these samples will be shared under a MTA, or other applicable agreement.
6.4.5 Blood Draws
Risks associated with the collection of blood are bleeding, bruising, and swelling, dizziness, fainting and infection
at the site where the blood is drawn. In general, these procedures will be performed by individuals with expert
skills in phlebotomy. To minimize the additional risks associated with phlebotomy, blood will be obtained during
arditis
diti
n Society
Society
ostic UGI 
ostic UGI 
niscule
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Page 31 of 63
the standard placement of intravenous lines when possible. The amount of blood drawn will adhere to institutional
policy.
6.4.6 Skin Testing For Allergies
Prick Testing
Skin testing for allergies may cause mild discomfort when the skin is pricked. Participants may experience
symptoms such as itching, stuffy nose, red watery eyes, or a skin rash if they are allergic to the substance being
tested. A rare but serious whole-body allergic reaction, known as anaphylaxis, may occur. Anaphylaxis can be life
threatening, but this usually only occurs with intradermal testing, and the health care provider performing the skin
testing will be prepared to treat this serious reaction.
6.4.7 Skin Testing For Allergies
Patch Testing
Skin patch testing for allergies may cause mild discomfort at the local site including rash, itching and skin redness.
6.4.8 Swallowed Glucocorticoids
Swallowed glucocorticoids may cause oral or esophageal candidiasis; if this is noted, it will be treated with topical
or systemic anti-fungal therapy, as clinically indicated. Swallowed glucocorticoids may cause adrenal suppression
which will be monitored by serum AM cortisol determination before and after the study protocol. If a depressed
value of AM cortisol is found at study completion, this information will be provided to the primary doctor and
patient.
Standard of Care Procedures Associated with This Study Esophagogastroduodenoscopy (EGD)
Endoscopy with biopsy is a well-established procedure. Few patients have unexpected or serious complications.
Since it is considered standard of care for adult patients with EoE to have an EGD with biopsies within a six week
time frame to monitor the disease when trialing new therapies (foods or medications), the EGDs with biopsies that
are associated with this study are not study procedures. Endoscopies will be performed regardless of study
participation as
standard of care, and additional endoscopic procedures will not be performed because of
participation in this study. It is considered standard of care for biopsies to be collected from the esophagus,
stomach, and duodenum during endoscopy, and biopsies from all of these sites will be collected during endoscopic
procedures at all participating sites whenever possible. Biopsies collected from the stomach and duodenum are
evaluated to determine study eligibility. Subjects may be included, without stomach or duodenal biopsies, if there
is no clinical history of involvement of stomach or duodenum.
Potential Benefits
Standard therapies for EoE consist of allergy test-directed and empiric elimination dietary therapies, complete
elimination of all dietary antigens requiring the exclusive use of elemental formula, or the chronic use of topical
swallowed steroids. These therapies are all associated with risks and benefits. Comparing a minimally restrictive
dietary elimination regimen to a more restrictive dietary regimen to control esophageal inflammation may permit
earlier identification of a diet that controls symptoms and achieves remission. In addition, by limiting the number
of potential reintroductions, this less restrictive diet has the potential to limit the need for endoscopies and attendant
sedation and thus reduce risk to patients and costs to the health care system.
There are no guaranteed benefits for any study participant. Potential benefits to the individual participant would
include the use of a less restrictive diet compared to the standard 6FED, as well as a reduction in the time to
identification of a minimally restrictive effective diet
vement
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(f


Page 32 of 63
7. INVESTIGATIONAL AGENT /DEVICE/INTERVENTION
Investigational Agents/Devices/Interventions
Investigational Agent #1
Flovent HFA Inhalation aerosol: swallowed fluticasone propionate 1760mcg daily (in Phase 2), manufactured by
GlaxoSmithKline.
7.1.1 Formulation, Packaging, and Labeling
FP HFA (GSK Lab Code GR106642X) inhalation aerosol is a pressurized MDI for oral inhalation. Each inhaler
consists of a white to off-white suspension of FP (micronized) in a liquefied HFA propellant (GR106642X) which
is contained in an aluminium can sealed with a metering valve. The canister is presented in a plastic actuator fitted
with a dust cap.
Ingredients include FP (micronized), and GR106642X (1,1,1,2-Tetrafluoroethane). No other excipients are
included in the formulation. Stability is at most 18 months when stored under labeled storage conditions of 25°C.
As further real-time stability data become available, the shelf life will be extended.
A placebo inhaler containing GR106642X propellant 75mg per actuation alone is also available.
7.1.2 Dosage, Preparation, and Administration
For all products, storage should be at a controlled room temperature between 25-30°C in a dry place and not above
30°C.
7.1.3 Drug Accountability
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will maintain adequate
records of the disposition of the investigational agent, including the date and quantity of the drug received, to
whom the drug was dispensed (participant-by-participant accounting), and a detailed accounting of any drug
accidentally or deliberately destroyed.
Records for receipt, storage, use, and disposition will be maintained by the study site. A drug-dispensing log will
be kept current for each participant. This log will contain the identification of each participant and the date and
quantity of drug dispensed.
the in
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Page 33 of 63
All records regarding the disposition of the investigational product will be available for inspection.
7.1.4 Assessment of Participant Compliance with Investigational Agent
Compliance with the dietary therapies will be assessed via completion of a food diary that will be reviewed by a
registered dietitian at regular intervals throughout the study.
Compliance with Flovent will be determined by the counter that is on the Flovent inhaler. Greater than 80%
ompliance will be
encouraged by study staff to adhere to study dosages. All non-compliance issues will be documented, and
compliance that is <70% or >120% will be reported to the study sponsor.
7.1.5 Toxicity Prevention and Management
In order to measure potential systemic toxicity of FP we have chosen to measure AM serum cortisol levels as a
measure of adrenal suppression. Cortisol will be collected at the Treatment Phase 2 and the EOT Phase 2 visits. If
the AM cortisol is low at the EOT Phase 2 visit, th
primary care physician for appropriate follow-up care.
7.1.6 Premature Discontinuation of Investigational Agent
Study therapy may be prematurely discontinued for any participant for any of the following reasons:
The PI feels that the study treatment is no longer in the best interest of the participant.
The participant experiences an AE that the PI feels warrants discontinuation of the study therapy.
8. OTHER MEDICATIONS
8.1 Concomitant Medications
8.1.1 Protocol-mandated
N/A
8.1.2 Other permitted concomitant medications
Throughout the study duration, all participants are expected to maintain medications such as a PPI, oral or nasal
allergy medications such as antihistamines and any asthma-related medications that were prescribed prior to study
entry.
8.2 Prophylactic Medications
N/A
8.3 Prohibited Medications
N/A
, all
al
antihistam
ntihista
M
d concomita
concomita
participa
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Page 34 of 63
Medication
Washout 
Time 
Prior 
to
Screening Visit (i.e., Study
Entry)
Anti-immunoglobulin E [IgE] mAb
Methotrexate, cyclosporine, interferon-
Anti-tumor necrosis factor [TNF] mAb)
Other systemic immunosuppressive or
immunomodulation agents
Oral or intravenous systemic steroids
Topical swallowed steroids
Other investigative biologic
Anti-IL 5 agents
Anti-IL 13 agents
Other investigative drugs or device
6 months
3 months
6 months
3 months
3 months
2 months
1 month
3 months
6 months
1 month
8.4 Rescue Medications
If a subject has a worsening of EoE symptoms, any treatment that the subject would take for EoE, besides the
study drug, would then exclude the subject from the study. As such, there are no treatments that will be provided
9. STUDY PROCEDURES
Screening/Baseline Visit (Weeks -12 to -1)
The screening visit should occur at a maximum of twelve weeks and a minimum of 1 week prior to the enrollment
visit. A research staff member will perform the informed consent process. After obtaining informed consent, the
following study procedures will be performed and documented:
Assess eligibility (inclusion and exclusion criteria)
Collect Medical, surgical and diet history
Vitals (height, weight, blood pressure, heart rate, respiratory rate, temperature)
Demographics (age, gender, race)
Physical exam performed by a study clinician or qualified staff member
Collect stool sample (if possible) from subjects who have consented to stool collection
(Week
(Wee
occur
ccur at a
member wi
member wi
es wi
es w
any treatme
ny treatm
om the study
m the stu
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Page 35 of 63
Obtain up to 4 biopsies from the distal and proximal esophagus for research purposes (taken during
standard of care EGD)
One of these esophageal biopsies will be used for EDP
Research lab samples
Blood (6-10 mL) or saliva (1-2 mL for future genetic testing may be collected at this visit
Blood for metabolomics  (3-5 mL)
CBC with differential (2-3 mL)- if a CBC with differential was obtained clinically as part of
standard of care within the screening period, obtain the results from the standard of care CBC
Assessment of concomitant medications and therapies
Pregnancy Test (urine)
Participants may qualify for rescreening if they are ineligible due to any of the reversible illnesses listed in the
exclusion criteria if their condition improves while recruitment is ongoing and they still fall within the screening
window.
participant has had an EGD and biopsies performed prior to the screening visit, the results of the EGD may be
used to determine eligibility if it falls within the four-week window prior to enrollment. EGDs performed at an
outside institution may be used as baseline if the corresponding pathology report and slides are available and the
concerns regarding the eosinophil count, slides may be sent to the CRPC for rapid review in order to verify
eligibility.
Th
Stool samples may be collected from participants who have consented to stool collection at the Screening/Baseline
visit. If it is difficult to obtain the stool sample at this visit, it may alternatively be collected at the Enrollment visit.
Stool will only be collected at some, but not all, participating centers.
Enrollment (Week 0)
All eligible participants will be enrolled into the study at Week 0 if they meet all entry criteria and have completed
the screening procedures. Study procedures will not be repeated if the enrollment visit takes place within 5-10
business days of the screening visit.  At this visit, staff members will:
Assess eligibility (inclusion and exclusion criteria)
Measure vitals (blood pressure, heart rate, respiratory rate, temperature), height and weight
Obtain stool sample (if possible and not collected at Screening/Baseline) from subjects who have consented
to stool collection
Administer patient reported outcome questionnaires, which will include dietary questionnaires to measure
intake of the food allergens and a food diary to assess baseline diet
Completion of DSQ
Assess concomitant medications and/or therapies
0)
0)
will
ill be
be enr
en
s. Stud
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Page 36 of 63
Skin testing for allergies including prick and patch testing
Randomize eligible participants to the 1FED or 6FED diet
Provide standardized dietary instructions for 1FED or 6FED
Research lab samples
Blood serum (~1-2 tsp, or 5-10 mL) for food IgE, CRD, and IgG4
Blood serum (~3-6 tsp, or 15-30 mL) for T cell studies
The participants will be encouraged to call the PI and/or study coordinator if they have any questions, concerns,
adverse events, or changes in medication.
Stool samples may be collected from participants who have consented to stool collection at the Enrollment visit if
they were unable to be obtained at the Screening/Baseline visit. Stool will only be collected at some, but not all,
participating centers.
Phone Visits, Phase 1
A study staff member will conduct three phone visits (at weeks 1, 3, and 5) during Phase 1 in order to monitor
ing these phone visits:
Assess con-med and/or con-therapy compliance
Assess AEs
Determine compliance with treatment
A dietaryquestionnaire to measure intake of the food allergens will be completed bythe participants
during weeks 1 and 5
A food diary will be completed by participants during weeks 1 and 5 to measure adherence
Daily completion of the DSQ within the two weeks prior to the Phase 1 EOT EGD (Weeks 4 and 5)
End of 1st Treatment phase or Early Withdrawal (Week 6)
For participants who have completed the 6 week Phase 1 or have withdrawn early from the study, the following
procedures will occur:
Measure vitals (blood pressure, heart rate, respiratory rate, temperature), height and weight
Physical exam performed by a study clinician or qualified staff member
Collect stool sample (if possible) from subjects who have consented to stool collection
Administer patient reported outcome questionnaires
Assess AEs
Obtain up to 4 biopsies from the esophagus for research purposes (taken during SOC EGD)
One of these esophageal biopsies will be used for EDP
Research lab samples
Blood serum (~1-2 tsp, or 5-10 mL) for food IgE, CRD, and IgG4
Blood serum (~3-6 tsp, or 15-30 mL) for T cell studies
Blood (6-10 mL) or saliva (1-2 mL) for future genetic testing may be collected at this visit (if not
collected previously)
Blood for metabolomics (1 tsp, or 3-5 mL)
CBC with differential - if a CBC with differential was obtained clinically as part of standard of
ress
res
ormed by 
rmed by 
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rticipant
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wo week
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Page 37 of 63
care, obtain the results from the standard of care CBC
Assess participant compliance with diet therapy and concomitant medications
Pregnancy Test (urine)
Stool samples may be collected from participants who have consented to stool collection. Stool will only be
collected at some, but not all, participating centers.
If a participant withdraws from the study before completing 6 weeks of dietary therapy, the end of treatment/early
should stay on their dietary therapy until results of biopsies are communicated to them.
Those participants who have resolution of their inflammation on endoscopy at the end of Phase 1 will complete
the study at this time. Subjects with continued active inflammation will move on to phase 2, 6FED non responders
will start treatment with swallowed SGC (880mcg BID fluticasone propionate) and unrestricted diet and 1FED
non- responders will start treatment of 6FED.
Phase 2 Visit 1 (Week 10)
Those participants who have completed the phase 1 diet protocol but have continued active inflammation may
choose to continue into Phase 2 and will return to clinic once their biopsies have been read. This visit should
happen within 4 weeks of their EGD.  At this visit, the following procedures will occur:
Measure vitals (blood pressure, heart rate, respiratory rate, temperature), height and weight
Assess AEs
Assess participant compliance with concomitant medications
Provide standardized instructions for administration of the fluticasone (for participants who will be on
fluticasone)
Provide standardized instructions for 6FED for participants who will be on 6FED
Provide diet or medication diary/log to participants
Administer dietary questionnaire to measure intake of the 6FED food allergens (for those who will be on
6FED)
Complete DSQ
Dispense fluticasone to participant (for those moving on to SGC)
Measure morning cortisol (serum, ~1 tsp or 5 mL) (for those moving on to SGC in Phase 2)
Phone Visits, Phase 2
A study staff member will conduct two phone visits (at weeks 11 and 15) during Phase 2 in order to monitor
Assess con-med and/or con-therapy compliance
Assess AEs
Determine compliance with dietary treatment
estion
tion
one to
one 
irator
ato
comitant
mitant me
m
r administrat
administr
ions for 6FE
ns for 6F
diary/log to
diary/log
naire to
air
and un
and u
col but hav
ol but hav
nce their b
e their b
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Page 37 of 63
A dietary questionnaire to measure intake of the food allergens will be completed by participants
who are on 6FED during weeks 11 and 15
A food diary will be completed by participants who are on 6FED during weeks 11 and 15 to measure
adherence
Daily completion of the DSQ within the two weeks prior to the Phase 2 EOT EGD (Weeks 14 and 15)
End of 2nd treatment phase or Early Withdrawal (Week 16)
For those participants who have completed the phase 2 therapy or have withdrawn early from the study, the
following procedures will occur:
Measure vitals (blood pressure, heart rate, respiratory rate, temperature), height and weight
Physical exam performed by a study clinician or qualified staff member
Administer patient-reported outcome questionnaires
Assess AEs
Obtain up to 4 biopsies from the esophagus for research purposes (taken during SOC EGD)
One of these esophageal biopsies will be used for EDP
Assess participant compliance with therapy (SGC) and concomitant medications
Pregnancy Test (urine)
Measure morning cortisol (serum, ~1 tsp, or 5 mL)
Collect fluticasone from participant (for those on SGC)
Collect participant compliance logs; dietary log or SGC log
Research lab samples
Blood (6-10 mL) or saliva (1-2 mL) for future genetic testing may be collected at this visit (if not
collected previously)
Obtain CBC with differential (2-3 mL)- IF a CBC with differential was obtained clinically as part
of standard of care within the screening period, obtain the results from the standard of care CBC
If a participant withdraws from the study before completing 6 weeks of SGC or 6FED therapy in Phase 2, the end
Participants should stay on SGC or 6FED until results of biopsies are communicated to them.
Following the receipt of their biopsy results, the participant will return to standard clinical care.
Should pregnancy occur during either phase of the study, dietary therapy and/or dosing of study medication will
be discontinued and the participant will be withdrawn from the study. The pregnancy will be followed clinically
to term.
Unscheduled Visits
Unscheduled visits will take place for any complication or AE/SAE that requires an extra visit. The proceduresto
be performed at the unscheduled visits will be at the discretion of the PI. Procedures that may be performed at an
unscheduled visit include:
Vital signs (blood pressure, heart rate, respiratory rate, temperature), height and weight
Physical exam
Assess AEs
C o
C o
ir biopsy 
ir biopsy
r during 
r during 
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Page 38 of 63
Lab tests
Assess/address problems with dietary adherence
These visits will be documented in the unscheduled visit case report.
Visit Windows
Study visits should take place within the time limits specified below: the designated visit windows (i.e. +/- n days)
for each scheduled visit are also indicated on the Table 1 Schedule of Assessments.
Each visit window (for visits 2-10) is ± 3 days.
10.MECHANISTIC ASSAYS
EDP
We will focus on molecular profiling of esophageal genes with the EoE Diagnostic Panel (EDP), a set of 94 mRNA
transcripts that have been established to differentiate EoE from controls (e.g. GERD and normal individuals), and
to identify exposure and transcriptional signaling to SGCs28. The EDP is typically performed on an extra biopsy
taken from the distal esophagus28. If our hypotheses are proven to be correct, they have potential to transform
monitoring of patients during therapeutic intervention, by identifying molecular markers that have therapeutic
significance, and also by reducing the need for biopsies, particularly after therapy is initiated. Essentially, the
associated EDP algorithm renders the raw Ct. values of each embedded gene after real-time PCR in a way such
that the upregulated genes and downr
Utilizing different gene sets, EDP is also able to predict steroid exposure and remission status based on the same
algorithm 28. In this case, the EoE score will be calculated at baseline endoscopy and in the posttreatment biopsies
to assess change with treatment.
T Cell Studies
We will test the hypothesis that milk-specific T cells will be primarily CD4+, IL-5+, IL-13+, consistent with prior
work.47-49 Furthermore, we will test the sub-hypothesis that the level of milk-specific T cells will positively
correlate with positive atopy patch tests to milk and the response rate to milk elimination (1FED and secondarily
6FED, which also contains milk). The frequency of Th2 cells will be determined by FACS analysis, and milk-
specificity will be estimated by milk protein stimulation in vitro, particularly looking at CD154 induction, a marker
of T cell activation. These exploratory studies, will be performed with shipped blood samples, by Dr. Jonathan
Spergel, as published.47,48,50,51The study will be limited to a pilot analysis of patients who only enter the 1FED and
we will compare patients with positive and negative skin tests (prick and patch).
Biospecimen Storage
Blood, saliva, and/or esophageal biopsies may be collected and stored for future analysis. Specimens will be
e used for DNA isolation. Blood will be drawn by a
certified phlebotomist or an RN, LPN, DO, or MD. A standard protocol for collection of blood derived DNA will
be utilized, and approximately 2 teaspoons (10 mL) of blood will be collected. If blood cannot be obtained or the
subject elects to limit DNA collection to non-blood sources, an oral DNA specimen (saliva) will be obtained
ll te
l t
y patch te
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ains milk).
ains milk)
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by
predict steroi
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Page 39 of 63
instead. Whether the sample collected is blood, tissue, or saliva, samples will be deidentified, processed, and
shipped to CCHMC for storage.  DNA will remain available for future genetic testing.
11.CRITERIA FOR PARTICIPANT AND STUDY COMPLETION AND
PREMATURE STUDY TERMINATION
Participant Completion
Participant completion is defined by completion of the EGD at the end of Phase 1 and Phase 2 (for those who
choose to continue into Phase 2); there are two levels of completion, those that complete Phase 1 and those that
complete Phase 2.
Participant Stopping Rules and Withdrawal Criteria
Participants may be prematurely terminated from the study for the following reasons:
The participant elects to withdraw consent from all future study activities, including follow-up.
Participant is unable to comply with the dietary restrictions.
Participant develops severe complications from their EoE (for instance, esophageal strictures)
Participant becomes pregnant.
-
-up is possible because attempts to
reestablish contact with the participant have failed).
The participant develops an SAE related to therapy in Phase 1 or 2 of the study.
The participant dies.
The Investigator no longer believes participation is in the best interest of the participant.
Participant Replacement
Enrolled participants who start on the initial dietary protocol and prematurely discontinue/withdraw from the study
will be replaced if they do not reach Week 6 of the study including the EGD. Additional participants will be
enrolled in the same manner as all other participants. Participant numbers will not be re-used. Any enrolled
participant will be included into any intent to treat analysis.
Follow-up after Early Study Withdrawal
Refer to section 9.7.
Study Stopping Rules
The study can be terminated or stopped at the site for reasons including but not limited to:
1. Investigator or sponsor request to withdraw from study participation.
2. Serious and/or persistent noncompliance by the investigator with the protocol or other local applicable
regulatory guidelines in conducting the study.
3. IRB decision to terminate or suspend approval for the investigation or the investigator.
nto any 
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Page 40 of 63
12.SAFETY MONITORING AND REPORTING
Overview
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for
appropriately collecting, grading, recording, and reporting those data. Adverse events that are classified as serious
according to the definition of the FDA must be reported promptly (per Section 12.5.1, Reporting of Serious Adverse
Events and Adverse Events to DAIT/NIAID). Appropriate notifications will also be made to site principal investigators
and the Institutional Review Board (IRB).
Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical Practice, 21CFR Parts 312 and
320, and applies the standards set forth in the National Cancer Institute (NCI), Common Terminology Criteria for
Adverse 
Events 
(CTCAE), 
Version
[enter 
4.0 
or 
correct 
version 
applicable 
to 
trial]
:
http://ctep.cancer.gov/reporting/ctc.html.
Safety will be assessed through documentation of AEs, adverse drug reactions, physical examination findings and vital
signs, and pre- and post-treatment morning cortisol for those patients on SGC in Phase 2.
Definitions
12.2.1 Adverse Event (AE)
the research, whether or not considered r
definition of adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical
Practice) (from OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects
or Others and Adverse Events (1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2 )
For this study, an adverse event will include any untoward or unfavorable medical occurrence associated with:
Study therapy regimen: Topical swallowed steroids
Development of oral thrush
Behavior change
Difficulty sleeping
Bone demineralization
Elevated blood sugar
Hypertension
Eye changes such as glaucoma or cataracts
Potential for adrenal suppression
Potential risk of immunosuppression
w
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Page 41 of 63
12.2.2. Study mandated procedures:
Esophagogastroduodenoscopy (EGD) Biopsies
Bleeding at the site of biopsy collection
Perforation of the stomach, duodenum or esophagus
Allergen Scratch Skin Testing
Prolonged (>24 hours) itching at test site
Swelling (> 10 cm ) at site of test lasting more than 24 hours
Nasal allergic symptoms within 30 minutes of the procedure
Fainting/Vasovagal event within 30 minutes of the procedure
Anaphylaxis
Blood Draws
Fainting/Vasovagal events
Bruising at puncture site larger than 2 cm diameter
Bleeding from puncture site lasting more than 30 minutes
Swelling at puncture site larger than 2 cm
12.2.3 Suspected Adverse Reaction (SAR)
Suspected adverse reaction (SAR) means any adverse event for which there is a reasonable possibility that the
to suggest a causal relationship between the drug and the adverse event. A
suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means
any adverse event caused by a drug (21 CFR 312.32(a)).
12.2.4 Unexpected Adverse Event
GlaxoSmithKline package insert or is not listed at the specificity, severity or rate of occurrence that has been
observed; or is not consistent with the risk information described in the protocol.
also refers to adverse events or suspected adverse reactions that are mentioned in the package insert
as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not
specifically mentioned as occurring with the particular drug under investigation (21 CFR 312.32(a)).
12.2.5 Serious Adverse Event (SAE)
view of either the investigator or
DAIT/NIAID, it results in any of the following outcomes (21 CFR 312.32(a)).
Death: A death that occurs during the study or that comes to the attention of the investigator during the protocol-
defined follow-up period must be reported whether it is considered treatment related or not.
ge insert
e insert o
istent wi
istent wi
o
rse event
even
st a causal r
a causal
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CFR
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Page 42 of 63
A life-
-
or DAIT/NIAID, its occurrence places the subject at immediate risk of death. It does not include an AE or SAR
that, had it occurred in a more severe form, might have caused death.
Inpatient hospitalization or prolongation of existing hospitalization.
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.
Congenital anomaly or birth defect.
Important medical events that may not result in death, be life threatening, or require hospitalization may be
considered serious when, based upon appropriate medical judgment, they may jeopardize the subject and may
require medical or surgical intervention to prevent one of the outcomes listed above.
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol mandated procedures are
not to be reported as an SAE unless hospitalization is prolonged due to complications.
Grading and Attribution of Adverse Events
12.3.1 Grading Criteria
The study site will grade the severity of adverse events experienced by the study subjects according to the criteria
set forth in the National
Common Terminology Criteria for Adverse Events (CTCAE) [Version
4.03, June 14, 2010] This document (referred to herein as the NCI-CTCAE manual) provides a common language
to describe levels of severity, to analyze and interpret data, and to articulate the clinical significance of all adverse
events. The NCI-CTCAE has been reviewed by the Protocol Chair and has been deemed appropriate for the subject
population to be studied in this protocol.
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE
manual:
Grade 1 = mild adverse event.
Grade 2 = moderate adverse event.
Grade 3 = severe and undesirable adverse event.
Grade 4 = life-threatening or disabling adverse event.
Grade 5 = death.
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not limited to, a
radiograph, an ultrasound, an electrocardiogram etc.), a treatment-emergent adverse event is defined as an increase
in grade from baseline or from the last post-
from screening to baseline will also be recorded as adverse events, but are not treatment-emergent. If a specific
event or result from a given clinical or laboratory evaluation is not included in the NCI-CTCAE manual, then an
abnormal result would be considered an adverse event if changes in therapy or monitoring are implemented as a
result of the event/result.
.
se event.
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Page 43 of 63
12.3.2 Attribution Definitions
The relationship, or attribution, of an adverse event to the study therapy regimen or study procedure(s) will initially
be determined by the site investigator and recorded on the appropriate AE case report form. Final determination
of attribution for safety reporting will be determined by DAIT/NIAID. The relationship of an adverse event to
study therapy regimen or procedures will be determined using the descriptors and definitions provided in Table
12.3.2.
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web site:
http://ctep.cancer.gov/reporting/ctc.html.
Table 12.3.2 Attribution of Adverse Events
Code
Descriptor
Relationship (to primary investigational product and/or other concurrent
mandated study therapy or study procedure)
UNRELATED CATEGORY
1
Unrelated
The adverse event is clearly not related:  there is insufficient evidence to suggest a
causal relationship.
RELATED CATEGORIES
2
Possible
The adverse event has a reasonable possibility to be related; there is evidence to
suggest a causal relationship.
3
Definite
The adverse event is clearly related.
Collection and Recording of Adverse Events
Adverse events (including SAEs) will be collected from the time of consent until a subject completes study
participation or until 30 days after he/she prematurely withdraws (without withdrawing consent) or is withdrawn
from the study.
12.4.1 Collecting Adverse Events
Adverse events (including SAEs) may be discovered through any of these methods:
Observing the participant.
Interviewing the participant
Receiving an unsolicited complaint from the participant.
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an adverse event,
as defined in Section 12.3, Grading and Attribution of Adverse Events.
12.4.2 Recording Adverse Events
Throughout the study, the investigator will record adverse events and serious adverse events as described
previously (Section 12.2, Definitions) on the appropriate AE/SAE CRF regardless of the relationship to study
therapy regimen or study procedure.
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end of study
participation, or until 30 days after the subject prematurely withdraws (without withdrawing consent)/or is
withdrawn from the study, whichever occurs first.
mplaint f
mplaint f
value
alue or
or re
.3, Grad
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from 
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Page 44 of 63
Reporting of Serious Adverse Events and Adverse Events
12.5.1 Reporting of Serious Adverse Events to Sponsor DAIT/NIAID
This section describes the responsibilities of the site investigator to report serious adverse events to the sponsor
via SAE CRF. Timely reporting of adverse events is required by 21 CFR and ICH E6 guidelines.
Site investigators will report to the DMCC (USF) and DAIT/NIAID all serious adverse events (see Section 12.2.4,
Serious Adverse Event), regardless of relationship or expectedness within 24 hours of discovering the event.
For serious adverse events, all requested information on the AE/SAE CRF will be provided. However, unavailable
details of the event will not delay submission of the known information. As additional details become available,
the AE/SAE CRF will be updated and submitted. AE/SAE reports should be reviewed by the investigator.
Upon entry of a SAE, the DMCC created Adverse Event Data Management System (AEDAMS) will immediately
notify the Study Chair, site PIs, the Medical Review Officer, and any additional agencies (if applicable- industry
sponsor, CTEP, etc.) of any reported adverse events via email.
Serious adverse events: The NIH appointed Medical Review Officer (MRO) determines causality (definitely not
related, probably not related, possibly related, probably related, definitely related) of the adverse event. The MRO
[and, if applicable, sponsor] may request further information if necessary and possibly request changes to the
protocol or consent form as a consequence of the adverse event. A back-up notification system is in place so that
any delays in review by the MRO beyond a specified period of time are forwarded to a secondary reviewer. The
Adverse Event Data Management System (AEDAMS) maintains audit trails and stores data (and data updated)
and communication related to any adverse event in the study.
Non-serious expected adverse events: Except those listed above as immediately reportable, non-serious expected
adverse events that are reported to or observed by the investigator or a member of his/her research team will be
submitted to the DMCC in a timely fashion (within 20 working days). The events will be presented in tabular form
and given to the MRO and RDCRN DSMB on an [observational-
-
Local site investigators are also required to fulfill all reporting requirements of their local institutions.
The DMCC will post aggregate reports of all reported adverse events for site investigators and IRBs.
12.5.2 Reporting to the FDA
The study PI, Dr. Marc E. Rothenberg, MD, PhD, holds the IND for this study. Each site will report SAEs in the
DMCC system as defined above in section 12. The DMCC adverse event notification system will notify the IND
sponsor. SAEs will be reported to regulatory authorities per 21 CFR 312.32 and institutional policy. All AEs will
tabulated by the DMCC and available to the IND sponsor on a monthly basis. Adverse events will be reported by
the IND holder, in summary form, at the time of continuing annual review to the IRB, FDA, DSMB and the NIAID.
12.5.3 Annual Reporting
Dr. Marc Rothenberg (the IND holder) will include in the annual study report all adverse events classified as:
Serious, expected, suspected adverse reactions (see Section 12.2.2, Suspected Adverse Reaction, and Section
lso requ
so requ
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Page 45 of 63
12.2.3, Unexpected Adverse Event).
Serious and not a suspected adverse reaction (see Section 12.2.2, Suspected Adverse Reaction).
Pregnancies not reported as serious adverse events.
Note that all adverse events (not just those requiring 24-hour reporting) will be reported annually.
12.5.4 Expedited Safety Reporting
This option, with 2 possible categories, applies if the adverse event is classified as one of the following:
Category 1: Serious and unexpected suspected adverse reaction [SUSAR] (see Section 12.2.2, Suspected
Adverse Reaction and Section 12.2.3, Unexpected Adverse Event and 21 CFR 312.32(c)(1)i).
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The DAIT/NIAID
shall report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal
relationship between the study drug and the adverse event, such as:
A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g.,
angioedema, hepatic injury, or Stevens-Johnson Syndrome);
One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise
uncommon in the population exposed to the drug (e.g., tendon rupture);
An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying
disease or condition under investigation or other events that commonly occur in the studypopulation independent
of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent
or historical control group.
Category 2: Any findings from studies that suggests a significant human risk
The sponsor must report any findings from other epidemiological studies, analyses of adverse events within the
current study or pooled analysis across clinical studies or animal or in vitro testing (e.g. mutagenicity,
teratogenicity, carcinogenicity) that suggest a significant risk in humans exposed to the drug that would result in a
safety-related change in the protocol, informed consent, investigator brochure or package insert or other aspects
of the overall conduct of the study.
Dr. Marc Rothenberg (the IND holder) shall notify the appropriate health authorities, the FDA, central IRB and all
participatinginvestigators ofexpedited SafetyReports within 15 calendar days; unexpected fatal or immediately life-
threatening suspected adverse reaction(s) shall be reported as soon as possible or within 7 calendar days.
12.5.5 Reporting of Adverse Events to IRBs/IECs
Adverse events, including expedited reports, will be reported by CCHMC, in a timely fashion to the central IRB
in accordance with applicable regulations and guidelines.
12.5.6 Pregnancy Reporting
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Page 46 of 63
The investigator shall be informed immediately of any pregnancy in a study subject. A pregnant subject shall be
instructed to stop taking study medication. The investigator shall counsel the subject and discuss the risks of
continuing with the pregnancy and the possible effects on the fetus. Monitoring of the pregnant subject shall
continue until the conclusion of the pregnancy.
The investigator shall report to the Data Management and Coordination Center (DMCC) and DAIT/NIAID all
pregnancies within 1 business day of becoming aware of the event using the CRF. All pregnancies identified during
the study shall be followed to conclusion and the outcome of each must be reported. The Pregnancy CRF shall be
updated and submitted to the Data Management and Coordination Center (DMCC) when details about the outcome
are available.
Information requested about the delivery shall include:
Gestational age at delivery
Birth weight, length, and head circumference
Gender
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, and
24 hours after birth, if available
Any abnormalities.
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and medically
indicated abortion - an SAE shall be submitted to the Data Management and Coordination Center (DMCC) and
DAIT/NIAID using the SAE reporting procedures described above.
12.5.7 Reporting of Other Safety Information
An investigator shall promptly notify the study sponsor (Dr. Rothenberg) as well as the DMCC and DAIT/NIAID
reportable as an adverse event. The DMCC will notify the central IRB.
12.5.8 Review of Safety Information
12.5.9 Medical Monitor Review
The DAIT/NIAID Medical Monitor shall receive monthly reports from the DMCC compiling new and
accumulating information on AEs, SAEs, and pregnancies recorded by the study site(s) on appropriate CRFs.
In addition, the Medical Monitor shall review and make decisions on the causality and relatedness of the SAE and
pregnancy reports received by the DMCC (See Sections 12.5.1, Reporting of Serious Adverse Events to
DAIT/NIAID and 12.5.6, Pregnancy Reporting).
12.5.10 DSMB Review
The DMCC will provide the DSMB with listings of all SAEs on an ongoing basis, including quarterly reports of
all SAEs. Furthermore, the DSMB will be informed of expedited reports of SAEs.
12.5.10.1 Planned DSMB Reviews
The NIAID Data Safety Monitoring Board (DSMB) shall review safety data at least yearly during planned DSMB
Data Review Meetings. Data for the planned safety reviews will include, at a minimum, a listing of all reported
Monit
Moni
on AEs, S
on AEs, S
Moni
Mon
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(Dr. R
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Page 47 of 63
AEs and SAEs.
The DSMB will be informed of an Expedited Safety Report in a timely manner. An SAE which the Medical
Monitor determines to be an unexpected safety risk will be sent to the DSMB immediately.
12.5.10.2 Ad hoc DSMB Reviews
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called upon for
ad hoc reviews. The DSMB will review any event that potentially impacts safety at the request of the protocol
chair or DAIT/NIAID. In addition, any occurrence of meeting one of the study stopping rules as described in
Section 11.5 will trigger an ad hoc comprehensive DSMB Safety Review. After review of the data, the DSMB will
make recommendations regarding study conduct and/or continuation.
12.5.10.3 Temporary Suspension of Enrollment for ad hoc DSMB Safety Review
A temporary halt in enrollment will be implemented if an ad hoc DSMB safety review is required.
13.STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
Overview
The primary objective of this proposal is to conduct a prospective, non-blinded randomized trial comparing rates
of remission of novel empiric elimination dietary therapies in eosinophilic esophagitis (EoE) in order to assess the
therapeutic viability of empiric elimination diets. Moreover, we aim to assess response to topical swallowed
steroids in non-responders to empiric dietary therapy regimens. Participants aged 18 to 60 years with active EoE
will be enrolled and the primary efficacy outcome will be the rate of histologic remission assessed using esophageal
biopsies obtained following a six week randomized trial of one of two empiric diets. During the screening process,
active EoE will be confirmed by histologic evaluation of esophageal biopsies obtained during an
esophagogastroduodenoscopy (EGD) in subjects with a history consistent with EoE.
Endpoints/Outcomes
The primary efficacy endpoint will assess and compare the percentage of patients achieving remission by following
the two diets. Pre- and post-therapy peak eosinophil counts per hpf and percentages of patients that attain histologic
remission (<15 eosinophils/hpf) will be reported.
A variety of secondary endpoints, including more detailed histologic and endoscopic scores, novel biomarkers,
and several Patient Reported Outcome (PRO) measures will also be assessed. In addition, we will assess the
possible value of a variety of clinical characteristics and biomarkers in terms of predicting response to therapy.
This study will provide significant novel information. This will be a prospective dietary therapy trial using these
empiric elimination diets. As part of our secondary aims, we will also be utilizing a number of novel potential
biomarkers to assess their ability in predicting and assessing response to therapy as well as a number of PRO
metrics.
Measures to Minimize Bias
Patients will be randomized using a 1:1 scheme to 1FED or 6FED within each investigative site. Study staff will
remain blinded to the randomization plan so they do not know the upcoming treatment assignment will be for a
patient until after the patient has been assigned. Study personnel who will perform the histologic assessments will
be blinded to treatment assignment for the slides they are evaluating. The CRPC will not be told which diet a
apy
ap
hpf) will 
hpf) will
endpoints, 
ndpoints
ported O
ported O
be the
th
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we aim
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mens. Par
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Page 48 of 63
participant has been assigned to, and they will not receive any information or documentation indicative of dietary
assignment. The slides and/or images of slides provided to the CRPC will not contain any information that reveals
which diet the participant is on. Knowledge of dietary assignment will be limited to study staff who need to know
which diet a participant has been assigned to (i.e. dietitians).
Analysis Plan
13.4.1 Analysis Populations
The analysis population for the primary and key secondary endpoints will be the intent-to-treat population. All
patients that have been randomized will be included in this analysis. Patients for which the primary endpoint of
histological remission cannot be determined will be imputed as treatment failures.
13.4.2 Primary Analysis of Primary Endpoint(s)/Outcome(s)
The primary endpoint for this study will be histologic remission (<15 eosinophils/hpf) determined at the end of
Phase 1 and will be compared between the two treatment groups. The formal statistical hypothesis for the primary
endpoint is:
H0: p1FED = p6FED
H1: p1FED
6FED
where
p1FED=percentage of patients in histologic remission (<15 eosinophils/hpf) on the 1FED diet at end of Phase 1
p6FED=percentage of patients in histologic remission(<15 eosinophils/hpf) on the 6FED diet at end of Phase 1
This hypothesis will be tested using the generalized linear mixed effects model with the logit link (for binary
outcome) that accounts for the clustering within sites. Important covariates to be included in this model are sex,
presence of atopy and duration of disease.  All t
The mixed effects model is planned in order to include the site as a random effect in the model. This approach
assumes the sites included in this trial are representing a sample of sites about which we wish to make inferences
and therefore will include site as a random effect instead of a fixed effect that implies we are only making
inferences about those specific sites in the study.
13.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s)
Sensitivity analyses will be conducted to assess the robustness of the results. A chi-square test without covariate
adjustment will be performed to compare the histologic remission rates at the end of Phase 1 between the two
groups. As a second sensitivity analysis, additional covariates will be included in the generalized linear mixed
effects model described above including PPI use at baseline, race and/or ethnicity and anthropomorphic measures.
Forest plots displaying differences in remission rates along with two-sided 95% confidence intervals for subgroups
defined by categorical covariates will be provided to visually examine the consistency of results among subgroups.
As an additional sensitivity analysis, multiple imputation (MI) for patients who are missing the primary outcome
measure will be performed. The missing data mechanism will be investigated to determine if the data are missing
this tri
this tr
e site as a
e site as a
pecific si
pecific s
n(<15 eosin
<15 eos
neralized lin
ralized 
within sites
thin sit
ase.  All t
e.  All t
ed in order
d in ord
al are 
l
hp
hp
istical
stica h
eosinophil
osinophil


Page 49 of 63
at random. In addition, a complete cases analysis will be conducted to investigate consistency of the conclusions
from those who complete the study in comparison to conclusions from the intent to treat population with imputed
All sensitivity analyses will be conducted at the nominal two-
13.4.4 Analyses of Secondary and Other Endpoint(s)/Outcome(s)
Following are the secondary objectives of the study:
To extend Phase 1 of this study with a prospective non-blinded trial that determines the rate of remission
following SGC in the 6FED non-responders and the rate of remission following 6FED in the 1FED non-
responders (Phase 2).
To evaluate the effect of each therapy on histological remission defined by a variety of changes in
eosinophils, including (a) pre- and post-therapy peak eosinophil counts; (b) partial remission (2-14 peak
eosinophils/hpf).
To evaluate the effect of each therapy by utilizing the histology scoring system (HSS) created to express
the severity and extent of other abnormalities in the gastrointestinal (GI) tract that often accompany
eosinophilic inflammation.
To evaluate endoscopic outcomes as assessed by the endoscopy scoring system (EREFS).
To determine the impact of each therapeutic intervention on biomarkers using the EoE Diagnostic Panel
(EDP).
For secondary objective 1, the remission rate for non-responders who proceed to Phase 2 will be summarized
separately depending on the treatment patients received during Phase 1. The 95% two-sided confidence interval
for the rate will be provided. In addition, forest plots that display the estimated remission rate along with two-sided
95% confidence interval will be presented for the subgroups as defined for the primary endpoint. This will provide
a visual representation to assess consistency of rates across subgroups. If the remission rate is missing for patients
in Phase 2, it will be imputed as a treatment failure.
The formal statistical hypothesis for each of the key secondary endpoint is:
H0
1FED
6FED
H1
1FED
6FED
where
1FED=population parameter (e.g. mean, proportion) for patients in histologic remission (<15 eosinophils/hpf) on
the 1FED diet at end of Phase 1
6FED=population parameter (e.g. mean, proportion) for patients in histologic remission(<15 eosinophils/hpf) on
the 6FED diet at end of Phase 1.
To test these hypotheses for each of the secondary objectives 2-5, treatment group comparisons at the end of Phase
1 will be performed using the generalized linear mixed effects model using the link that is appropriate for the
endpoint (i.e. logit for binary, cumulative logit for ordered multinomial categories, identity for continuous). These
models will account for the clustering within sites and will include gender, presence of atopy and duration of
disease as covariates. For continuous data, appropriate transformations will be considered (e.g. log, square root,
eter (e
eter
d d
d
hat displ
disp
subgroups
bgroups a
f rates
tes acros
ac
nt failure.
ailure.
ch of the key
of the 
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system
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onders w
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Page 50 of 63
rank) to satisfy the assumptions of the analyses.  If the remission status for the categorical outcomes is missing, it
will be imputed as a treatment failure. Missing data for continuous outcomes will be imputed using multiple
imputation techniques. Covariates for imputation will include investigative site, gender, presence of atopy and
duration of disease. Each of the secondary outcomes 2-5 will be tested at the two-
multiple testing.
13.4.5 Analyses of Exploratory Endpoint(s)/Outcome(s)
Exploratory objectives are detailed below:
To evaluate the clinical and psychosocial effect of each therapy utilizing surveys to assess EoE symptoms
and problems/feelings related to eating.
To determine if any clinical parameters predict response to therapeutic intervention.
To determine if any biomarkers including serum food specific IgE, CRD, and IgG4 predict response to
therapeutic intervention.
To determine if skin testing, in the form of prick and patch testing, predicts response to therapeutic
intervention.
To determine if milk-driven T cells in the blood positively correlate with milk atopy patch test results and
effectiveness of dietary therapies.
At the start of the trial intake of the allergens will be determined and descriptive statistics will be used to describe
how often/how much of the allergens were consumed as part of the usual diet. During the trial any accidental
exposure will be documented and we can use descriptive statistics to describe how often/how much of the allergens
were consumed accidentally.
To compare treatment groups at the end of Phase 1 for EoE symptoms and problems/ feelings related to eating, the
generalized linear mixed effects model described for the secondary endpoints will be used with the link function
appropriate for the endpoint.  Imputation for missing data will follow that described for the secondary endpoints.
To evaluate the ability of biomarkers to predict response to therapeutic intervention, multivariable logistic
regression analysis will be conducted with remission/no remission as the dependent variable and biomarker levels
as the independent variables. Multi-collinearity of the independent variables will be assessed. The area under the
receiver operating characteristic curve (AUROC) will be estimated along with 95% confidence interval. This
analysis will be conducted based on the remission status at the end of Phase 1. This analytic approach will be used
to determine if skin testing predicts response to therapeutic intervention and to determine if milk-driven T cells
predict response to intervention and to determine if T cells correlate with milk atopy patch test results. All
exploratory analyses will be conducted at the nominal two-sided
13.4.6 Descriptive Analyses
Demographic, patient characteristics, medication use and study completion status will be summarized for the two
treatment groups using mean ± standard deviation or median [interquartile range] for continuous variables and
frequency and percentages for categorical variables. Treatment comparisons will be performed using the two-
sample t-test
nducte
uct
les. Multi
es. Multi
acteristic 
acteristic
d bas
ba
e sta
st
ase 1 for
for EoE
scribed for t
ribed fo
on for missin
for mis
arkers to p
kers to 
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ate with m
ned and des
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part of th
part of th
istics
ics


Page 51 of 63
Additionally, we may perform some exploratory analyses when the two groups in Phase 2 become substantially
imbalanced in their demographics and disease characteristics. Also, wewill perform comparisons the groups who
choose to continue on Phase 2 and those who opt out, in both arms.  Any apparent difference will be noted.
Interim Analyses
No interim for efficacy nor futility analyses are planned for this study.
Interim data summaries will be provided to the DSMB in accordance with the DSMB charter. Data presentation
by study arm will be provided in a blinded fashion with no indication of actual treatment assignment, unless
specifically requested by the DSMB to facilitate their review.
13.5.1 Interim Analysis of Efficacy Data
N/A
13.5.2 Interim Analysis of Safety Data
N/A
13.5.3 Futility Analysis
N/A
13.5.4 Statistical Hypotheses
See above
Sample Size Considerations
The sample size was based on the primary endpoint of the percent of patients in histologic remission (<15
eosinophils/hpf) at the end of Phase 1. Based on preliminary data, it is assumed that the remission rate for the
1FED population is 45%.16 We assume that the remission rate in the 6FED population will be increased to 70%. A
sample size of 60 patients per group (120 total patients) will provide at least 80% power to detect a difference in
rates between groups of 25% at the two-sided
This calculation is based on a likelihood ratio test statistic for
comparing proportions. To allow for a potential approximate 15% drop-out, the sample size will be increased to
68 patients per group (136 total patients). This calculation was performed using the PASS vers. 12 software. The
following table displays the robustness of the sample size under various response rate and drop-out rate scenarios.
Sample
Size
per
group
Difference to detect
with 80% power if
1FED rate is 45%
Difference to detect
with 80% power if
1FED rate is 50%
Difference to detect
with 80% power if
1FED rate is 55%
56
26%
24%
24%
60
25%
23.5%
23.5%
64
24%
23%
23%
68
24%
23%
22%
p
robustne
obustn
Diff
Di
oint of the
nt of th
n preliminar
prelim
he remission 
remiss
total patient
al pati
sided
ded
or a potentia
or a potenti
atients). Th
ents). T
ss of
ss


Page 52 of 63
14.IDENTIFICATION AND ACCESS TO SOURCE DATA
Source Data
Source documents and source data are considered to be the original documentation where subject information,
visits consultations, examinations and other information are recorded. Documentation of source data is necessary
for the reconstruction, evaluation and validation of clinical findings, observations and other activities during a
clinical trial.
Access to Source Data
The site investigators and site staff will make all source data available to the DAIT/NIAID, the DMCC and their
representatives, as well as to relevant health authorities. Authorized representatives as noted above are bound to
maintain the strict confidentiality of medical and research information that may be linked to identify individuals.
15.PROTOCOL DEVIATIONS
Protocol Deviation Definitions
15.1.1 Protocol Deviation
The investigators and site staff will conduct the study in accordance to the protocol; no deviations from the protocol
are permitted. Any change, divergence, or departure from the study design or procedures constitutes a protocol
deviation. As a result of any deviation, corrective actions will be developed by the site and implemented promptly.
15.1.2 Major Protocol Deviation (Protocol Violation)
A Protocol Violation is a deviation from the IRB approved protocol that may affect the subject's rights, safety, or
well-being and/or the completeness, accuracy and reliability of the study data. In addition, protocol violations
include willful or knowing breaches of human subject protection regulations, or policies, any action that is
inconsistent with the NIH Human Research Protection
serious or continuing noncompliance with federal, state, local or institutional human subject protection regulations,
policies, or procedures.
15.1.3 Non-Major Protocol Deviation
A non-major protocol deviation is any change, divergence, or departure from the study design or procedures of a
research protocol that does not have a major impact on the subject's rights, safety or well-being, or the
completeness, accuracy and reliability of the study data.
15.1.4 Reporting and Managing Protocol Deviations
The study site principal investigator has the responsibility to identify, document and report protocol deviations as
directed by the study Sponsor. However, protocol deviations may also be identified during site monitoring visits or
during other forms of study conduct review.
lian
ian
r Protoc
r Proto
atat
ons wil
wi
col Violatio
Violat
IRB approv
RB appr
curacy and r
racy and
s of human 
of hum
Research Pr
Research Pr
ce with
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Upon determination that a protocol deviation (major or minor) has occurred, the study staff will a) notify the site
Principal Investigator, b) notify the DMCC and c) will complete a Protocol Deviation form. The Protocol Deviation
form will document at a minimum the date PD occurred, the date PD identified, a description of event, whether
the deviation resulted in SAE/AE, the signature of PI, report to central IRB, and documentation of a corrective
action plan. The DMCC and DAIT/NIAID may request discussion with the PI to determine the effect of the
protocol deviation on the study participant and his/her further study participation, the effect of the protocol
deviation on the overall study, and corrective actions. The PI will complete and sign the Protocol Deviation form
and submit it to the DMCC and to the central IRB, per IRB regulations. Major protocol deviations will be reported
to the DSMB by the NIAID Medical Monitor at the Medic
16.ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD
CLINICAL PRACTICE
Statement of Compliance
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for
Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the criteria specified in this
study protocol. Before study initiation, the protocol and the informed consent documents will be reviewed and
IRB), which will serve as the
central IRB for the study. Any amendments to the protocol or to the consent materials will also be approved
by the CCHMC IRB before they are implemented.
Informed Consent Process
The consent process will provide information about the study to a prospective participant and will allow
adequate time for review and discussion prior to his/her decision. The principal investigator or designee listed
on the delegation log will review the consent and answer questions. The consent designee must be listed on the
delegation log, have knowledge of the study and received training (from the local IRB, PI, or study coordinator)
in the consent process The prospective participant will be told that being in the trial is voluntary and that he or
she may withdraw from the study at any time, for any reason. All participants (or their legally acceptable
representative) will read, sign, and date a consent form before undergoing any study procedures. Consent
primary language. A copy of the signed consent form will be given
to the participant.
This study will be conducted in compliance with ICH E6 GCP: Consolidated Guidelines pertaining to informed
consent. At the first visit, prior to initiation of any study-related procedures, participants will give their written
consent to participate in the study after having been informed about the nature and purpose of the study,
participation/termination conditions, and risks and benefits. If the participant is unable to provide written
by institutional specific guidelines. The informed consent document must be signed and dated by the
participant, or the particip
informed consent document must be provided to the participant or the
legally authorized
representative. Signed
study file and be available for
representative provides written consent, participants will also give their written assent to participate in the
study as approved by institutional specific obtaining assent.
The consent form will be revised when important new safety information is available, the protocol is amended,
and/or new information becomes available that may affect participation in the study.
n, and
an
bout the stu
ut the st
o his/her dec
his/her d
t and
nd answe
an
udy and
and recei
ve participan
particip
y at any tim
at any t
d date a
da
), as delin
, as deli
ording to th
rding to t
consent do
consent do
to the con
to the con


17.INVESTIGATOR REQUIREMENTS
Protocol Adherence
The investigator must adhere to the protocol as detailed in this document and agree that the Sponsor and the IRB
must approve any change to the protocol. The investigator will be responsible for enrolling only those participants
who have met the protocol screening and study entry criteria.
Case Report Forms
The CRFs will be used for the recording of all information and study data as specified by this protocol. The CRFs
must be completed by the research personnel. The principal investigator is responsible for ensuring that accurate
CRFs are completed in a timely manner. Collected data will be entered into online electronic case report forms.
Electronic case report forms will be developed in collaboration with the Data Management and Coordinating
Center that contain the requisite data fields.
Source Document Maintenance
Source documents are defined as the results of original observations and activities of a clinical investigation.
Source documents may include, but are not limited to, study progress notes, e-mail correspondence, computer
printouts, clinical laboratory data, and recorded data from automated instruments. All source documents produced
in this study will be maintained by the investigator and made available for inspection by regulatory authorities.
The original signed dated informed consent form for each participating participant shall be filed with records kept
by the investigator and a copy given to the participant. The patient outcome questionnaires will be recorded directly
on the paper forms and will be considered as source data.
Data Quality and Monitoring Measures
As much as possible data quality is assessed at the data entry point using intelligent on-line data entry via visual
basic designed screen forms. Data element constraints, whether independent range and/or format limitations or
assess data quality post-data entry. As we note, data quality begins with the design of the data collection forms and
procedures and incorporates reasonable checks to minimize transcription and omission errors. Of the more
important quality assurance measures are the internal validity checks for reasonableness and consistency.
Data Monitoring: The RDCRN DMCC identifies missing or unclear data and generates a data query to the
consortium administrator contact.
Data Delinquency Tracking: The Data Management and Coordinating Center will monitor data
delinquency on an ongoing basis.
Registration
Registration of participants on this protocol will employ an interactive data system in which the clinical site will
attest to the
eligibility as per protocol criteria and obtain appropriate informed consent. IRB approval
for the protocol must be on file at the DMCC before accrual can occur from the clinical site.
The DMCC will use a system of coded identifiers to protect participant confidentiality and safety. Each participant
enrolled will be assigned a local identifier by the enrollment site.
This number can be a combination of the site
Page 54 of 63
measure
measur
The
The RDCR
RDCR
inistrator
inistrator
Tra
Tr
a.a.
easures
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Page 55 of 63
identifier (location code) and a serial accession number. Only the registering site will have access to the linkage
between this number and the personal identifier of the subject. When the participant is registered to participate in
the study, using the DMCC provided web-based registration system, the system will assign a participant ID
number. Thus each participant will have two codes: the local one that can be used by the registering site to obtain
personal identifiers and a second code assigned by the DMCC. For all data transfers to the DMCC both numbers
will be required to uniquely identify the subject. In this fashion, it is possible to protect against data keying errors,
digit transposition or other mistakes when identifying a participant for data entry since the numbers should match
to properly identify the participant.  In this fashion, no personal identifiers would be accessible to the DMCC.
Laboratory Data Flow
The DMCC will provide laboratories with on-line forms and/or electronic data exchange mechanisms - depending
on their capabilities and needs - to enter, update and obtain relevant data. Online forms exist to verify specimen
receipt, report specimen issues and submit test results for specimens. The preferred method to exchange data
electronically is through the Specimen Management System Web Service. The Web Service allows laboratories
to obtain specimen shipment information, receive individual specimens or specimen shipments, report specimen
issues and communicate specimen aliquots in a secure manner (test result submission is planned). The DMCC
will also support uploading of files electronically.  All transactions are logged and validated for both methods.
Study Completion
Before a study can be considered completed or terminated, the investigator must have the following data and
materials:
Clinical laboratory findings, clinical data, and all special test results from screening through the EOT
visit (to 30 days after the last dose of study agent).
CRFs properly completed by appropriate study personnel and reviewed and approved by the
investigator.
Copies of protocol amendment(s) and IRB approval/notification if appropriate.
A summary of the study prepared by the principal investigator (an IRB/IEC summary letter is
acceptable).
Audits and Inspections
The principal investigator will permit study-related monitoring, audits, IRB review, and regulatory inspections
by providing direct access to CRFs and source data/documents.
Institutional Review Board Approval
This protocol, the informed consent document, and all relevant supporting data must be submitted to the IRB for
approval. IRB approval of the protocol, informed consent document, study materials and any advertisement (if
applicable) used to recruit study participants must be obtained before the study may be initiated. This study will
tral
IRB for the study.
The principal investigator (PI) is responsible for keeping the IRB advised of the progress of the study and of any
changes made to the protocol as deemed appropriate, but in any case, at least once a year. The PI is also responsible
for notifying the IRB of any unanticipated AEs that occur during the study in accordance with local
nspect
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Page 56 of 63
IRB policies. Recent guidance from the USA FDA suggests that the following AEs should be reported to the
Any AE that, even without detailed analysis, represents a serious unexpected AE that is rare in the absence
of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome).
A series of AEs that, on analysis, is both unanticipated and a problem for the study. There would be a
determination that the series of AEs represents a signal that the AEs were not just isolated occurrences and
were significant to the rights and welfare of participants.
An AE that is described or addressed in the IB/package insert, protocol, or informed consent documents,
or is expected to occur in study participants at an anticipated rate (e.g., expected progression of disease,
occurrence of events consistent with background rate in participant population), but occurs at a greater
frequency or at greater severity than expected.
Anyother AE that would cause the sponsor to modify the investigator brochure, study protocol, or informed
consent form, or would prompt other action by the IRB to assure protection of human participants.
It will be the responsibility of the investigator to assure that the essential documents are available at the investigator
site. Any or all of these documents may be subject to, and should be available for, audit by CCHMC or Sponsor
auditor and inspection by the regulatory authorities as defined in the monitoring plan.
18.ETHICS
Ethics Review
The investigator will obtain approval to conduct the study from the appropriate regulatory agency in accordance
with any applicable country and local-specific regulatory requirements prior to initiating the study.
Ethical Conduct of the Study
This study will be conducted in compliance with the ethical principles of the Declaration of Helsinki, and any
additional national or IRB-required procedures.
The investigato
information that will be presented to potential participants/parents or legal guardians (e.g. advertisements or
information that supports or supplements the informed consent) are reviewed and approved by the IRB. The
investigator agrees to allow the IRB direct access to all relevant documents. The IRB must be constituted in
accordance with all applicable regulatory requirements. The investigator will provide the IRB with relevant
document(s)/data that are needed for approval of the study.
Privacy and Confidentiality
a unique identification number and these numbers rather than names will be used to collect, store, and report
participant information. Site personnel will not transmit documents containing personal health identifiers (PHI) to
the study sponsor or their representatives.
19.DATA HANDLING AND RECORDKEEPING
supple
upp
ow the IRB
ow the IRB
plicable r
plicable 
need
ne
ry r
y 
with the ethi
th the et
ures.
es.
d to poten
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ements
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Page 57 of 63
Inspection of Records
Data generated by this study must be available for inspection by any regulatory authorities and the IRB as
appropriate. At a
request, medical information may be given to his or her personal physician or other
appropriate medical personnel responsible for his or her welfare. Participant medical information obtained during
the course of this study is confidential and disclosure to third parties other than those noted above is prohibited.
Retention of Records
The investigator shall retain records required to be maintained under this part for a period of 2 years.
20.PUBLICATION POLICY
The CEGIR policy on the publication of study results will apply to this trial.


Page 58 of 63
21.REFERENCES
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Straumann A. The natural history and complications of eosinophilic esophagitis. Gastrointest Endosc Clin
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Faubion WA, Jr., Perrault J, Burgart LJ, Zein NN, Clawson M, Freese DK. Treatment of eosinophilic
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Konikoff MR, Noel RJ, Blanchard C, Kirby C, Jameson SC, Buckmeier BK, et al. A randomized, double-
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, ,
rtially ef
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li E, Verma
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ner JP, 
iling.
ing. Gast
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ntiuk S, E
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m (HSS) is S
(HSS)
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(EoE) 
Thomas CS, 
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KF, Putnam PE, Greenler AJ, Greenberg AB, Bryson RA, Davis CM, Olive AP, Gupta SK, Erwin EA, Klinnert
MD, Spergel JM, Denham JM, Furuta GT, Rothenberg ME, & Varni JW (2013) PedsQL Eosinophilic Esophagitis
Module: Feasibility, Reliability and Validity. J Pediatr Gastroenterol Nutr.
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BK, Jameson SC, Kaul A, Franciosi JP, Kushner JP, Putnam PE, Abonia JP, & Rothenberg ME (2011) A striking
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vas
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Schedule of Assessment
Dietary Questionnaires
a
b
c
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e

SAP_001.pdf: 


Version 10/14/2019
Statistical Analysis Plan
CCHMC Division of Biostatistics and Epidemiology
Data Management and Analysis Center
Six Food vs One Food Eosinophilic Esophagitis Elimination Diet followed by Swallowed Glucocorticoid Trial
Principal Investigator: Marc Rothenberg, MD, PhD
Statisticians: Lisa Martin, PhD, TBD
Project Sponsor: NCATS, NIDDK, NIAID
Grant Number (if applicable):
CCHMC IRB Number: 2015-3622
IRB Approval Date(s): Initial (6/23/2015); Current (5/21/2019)
________________________________________________________________________
Purpose of Study
The primary objective of this proposal is to conduct a prospective, non-blinded randomized trial comparing rates of remission
of empiric elimination dietary therapies in eosinophilic esophagitis (EoE) in order to assess the therapeutic viability of empiric
elimination diets. Moreover, we aim to assess response to topical swallowed steroids in non-responders to empiric six food
dietary therapy regimens and the response to 6FED in 1FED non-responders. Participants aged 18 to 60 years with active EoE
will be enrolled and the primary efficacy outcome will be the rate of histologic remission assessed using esophageal biopsies
obtained following a six week randomized trial of one of two empiric diets. During the screening process, active EoE will be
confirmed by
local pathology review (histologic evaluation)
of esophageal biopsies obtained during by
esophagogastroduodenoscopy (EGD) in subjects with a history consistent with EoE.
Study design
We will be recruiting a total of 136 participants, between the ages of 18-60. Participants will be enrolled in this study based on
the presence of active eosinophilic esophagitis and adherence to the inclusion and exclusion criteria. We intend to conduct a
prospective non-blinded randomized trial that compares a 1-food elimination diet (1FED) versus a 6-food elimination diet
(6FED) for six weeks (Phase 1). Subsequently, non-responders to 1FED dietary elimination therapy will be treated with 6FED
and non-responders to 6FED will be treated with SGC (swallowed fluticasone at a dose of 880 mcg twice a day) for six weeks
(Phase 2) while on an unrestricted diet, if the participant chooses to continue in to Phase 2. The empiric dietary therapy
interventions are as follows: 1-food elimination diet (1FED)
avoidance of milk vs. 6-food elimination diet (6FED)
avoidance of milk, egg, wheat, soy, fish/shellfish, and peanut/tree nuts, for six weeks. Milk elimination for both 1FED and
schematically in Figure 1 Study Design Flowchart.
In Phase 1, participants will be randomized 1:1 to either 1 food elimination (milk elimination alone, 1FED) or 6 food
elimination (milk, egg, wheat, soy, fish/shellfish, peanut/tree nuts elimination, 6FED) therapeutic diet. At the end of this phase,
an EGD will be performed to assess remission. Attainment of remission (esophageal eosinophil counts <15 eosinophils/high
powered field) after Phase 1 will result in study discontinuation and maintenance ofthe
dietarytherapy. Treatment
non-responders may choose whether or not to continue into Phase 2. Dietary therapy non-responders who were on 6FED in
Phase 1 and continue on to Phase 2 will receive topical swallowed steroids for six weeks (Phase 2) followed by EGD with
esophageal biopsies. These participants will return to an unrestricted diet (i.e. stop 6FED) prior to beginning topical swallowed
steroid therapy. Dietary non-responders in Phase 1 who were on 1FED and continue on to Phase 2 will continue to a 6FED


Version 10/14/2019
therapeutic diet (Phase 2) for six weeks followed by EGD with esophageal biopsies to assess remission.
The instructions for the 1FED and 6FED therapeutic diets will be standardized across sites by providing consensus documents
produced by registered dietitians who are experts in dietary elimination in EoE. There are currently no validated dietary
questionnaires for measuring food allergen intake in adults in the US. Dietary intake and consumption of the allergens will be
measured at the start of the trial and adherence to the dietaryelimination (i.e. avoidance of the allergens) during the trial will
be measured using modified versions of the
usual dietary intake/diet history questionnaires and 3-day food diaries
(http://cancercontrol.cancer.gov). Stool samples may be collected from subjects who consent to stool collection to evaluate the
effect of diet on the microbiome.
Similarly, standardized instructions for using SGC will be provided, based on our prior studies. We have chosen to use
fluticasone propionate (FP) rather than budesonide in this study, given our prior work in this area, and our recent finding that
high-dose fluticasone is well tolerated and highly effective, and our preliminary findings concerning esophageal transcripts
that predict responsiveness to FP therapy. The study design is shown schematically in Figure 1 Study Design Flowchart.
Figure 1 Study Design Flowchart


Analysis Populations
The analysis population for the primary and secondary endpoints will be the intent-to-treat population with
the goal of including patients who have been randomized in the analyses.  However, we will exclude
patients who were inappropriately randomized and never completed the enrollment visit. Patients for which
the primary endpoint of histological remission cannot be determined will be imputed as treatment failures.
To maximize comparability with other studies, we will also perform per protocol analyses, including only
individuals who complete the study phase of interest for all proposed studies.
Variables of Interest
Primary outcome:
1) Remission rate (<15 peak eosinophils/hpf)
Secondary outcomes:
1) Change in eosinophils/hpf from baseline to post treatment
2) Remission status: Patients will be classified into 3 remission categories:  complete histological
-14 peak eosinophils/hpf); no remission
3) Histology Scoring System (HSS): Will include the overall score, grade score, stage score, and the
inflammatory and structural sub-scores. Scores will be reported as distal, proximal, and maximum
4) HSS score by remission status (complete, partial, and no remission).
5) Endoscopy Scoring System (EREFS): Will include the overall score and the inflammatory and
fibrostenotic sub-scores.  Scores will reported as distal, proximal, and maximal score.
6) EoE Diagnostic Panel (EDP):  The summary EoE score (EDP total score) will be a secondary
outcome.
Derived Variables.
1) HSS scores.  Sum of the feature scores divided by the maximum possible score for the biopsy for
grade and stage.   The total score is the sum of the grade and stage scores. Inflammatory sub- scores
include the following features: eosinophils, abscesses, surface layering, and surface necrosis.
Structural sub-scores include basal layer hyperplasia, dilated intercellular spaces, apoptotic
epithelia, and lamina propria fibrosis.
2) HSS remission. HSS remission is defined as a having both a grade and stage total score less than
or equal to 3 and an eosinophil grade score no greater than 1.  This is calculated separately for distal
and proximal biopsies.  When both distal and proximal biopsies are in remission, this is considered
complete remission, when only one of the two biopsies meet these criteria, it is partial remission.
When neither meet these criteria, it is no remission. Analyses will include full remission vs other
and full+partial remission vs no remission.
3) EREFS. Total EREFS score will be calculated by summing the grades for all five of the features.
The inflammatory score contained the sum of the exudate, edema, and furrows scores (this could
range from 0 to 5), and the fibrostenotic score contained the sum of the rings and stricture scores
(this could range from 0 to 4).
4) Adherence.  Adherence will be dichotomized into mostly adherent vs not-mostly adherent.  The
judgement of adherence will be based on questionnaires about food intake and dietitian input. If
inconsistent, food diaries will be reviewed.  The final adherence call will be provided to the
statistician.
5) Atopy.  Atopy is a multi-faceted disease. Individuals will be defined as atopic if they report a
history of asthma, eczema, allergic rhinitis, allergic conjunctivitis, IgE mediating food allergy


and/or atopic dermatitis.
6) Time since diagnosis will be calculated as the study date at baseline minus the date at diagnosis.
Prior to any hypothesis testing, all variables will be reviewed for plausibility.
Any values which are
considered suspect will be reviewed by the clinical team to ensure accuracy.  Continuous data will be
evaluated for distributional assumptions of normality.  Natural log-transformation will be considered for
right skewed non-normally distributed data (the most typical skew seen in physiologic data).
Demographics/Patients Characteristics
Demographic, patient characteristics, medication use and study completion status will be summarized for
the two treatment groups using median [interquartile range] for continuous variables and frequency and
percentages for categorical variables. Treatment comparisons will be performed for demographics and
Demographics and patient characteristics will be summarized within each Phase1 treatment group between
patients who choose to continue into Phase 2 and those who opt out.  Any apparent difference will be
noted.
Analysis of Primary Outcome
Primary Objective:
1. Determine the rate of remission following 1FED vs. 6FED and evaluate the relative efficacy of these
dietary therapies.
Statistical hypothesis for the primary outcome:
H0: p1FED = p6FED
where p1FED=percentage of patients in histologic remission (<15 peak eosinophils/hpf) on the 1FED diet
at end of Phase 1
p6FED=percentage of patients in histologic remission (<15 peak eosinophils/hpf) on the 6FED diet at end
of Phase 1
This hypothesis will be tested using the generalized linear mixed effects model with the logit link (for
binary outcome) that accounts for the clustering within sites. Covariates to be considered in this model are
sex, current age, baseline esophageal eosinophil count, adherence, presence of atopy, and time since
diagnosis
Analyses of Secondary Endpoint(s)/Outcome(s)
Following are the secondary objectives of the study:
1) To extend Phase 1 of this study with a prospective non-blinded trial that determines the rate of
remission following SGC in the 6FED non-responders and the rate of remission following 6FED
in the 1FED non- responders (Phase 2).
2) To evaluate the effect of each therapy on histological remission defined by a variety of changes
in eosinophils, including (a) pre- minus post-therapy peak eosinophil counts; (b) partial


remission (2-
eosinophils/hpf).
3) To evaluate the effect of each therapy by utilizing the histology scoring system (HSS) created to
express the severity and extent of other abnormalities in the gastrointestinal (GI) tract that often
accompany eosinophilic inflammation.
4) To evaluate endoscopic outcomes as assessed by the endoscopy scoring system (EREFS).
5) To determine the impact of each therapeutic intervention on biomarkers using the EoE
Diagnostic Panel (EDP).
For secondary objectives 1, the remission rate at the 6-week time point for non-responders in Phase 1
who proceeded to Phase 2 will be summarized separately depending on the treatment patients received
during Phase 1. The 95% two-sided confidence interval for the rate will be provided. If the remission
rate is missing for patients that entered Phase 2, it will be imputed as a treatment failure.
To test hypotheses for each of the secondary objectives 2-5, treatment group comparisons at the end of
Phase 1 will be performed using the generalized linear mixed effects model using the link that is
appropriate for the endpoint (i.e. logit for binary, cumulative logit for ordered multinomial categories,
identity for continuous). These models will account for the clustering within sites and will consider sex,
baseline esophageal eosinophil count, adherence, presence of atopy, and time since diagnosis as
covariates. For continuous data, appropriate transformations will be considered (e.g. log, square root,
rank) to satisfy the assumptions of the analyses.  If the remission status for the categorical outcomes is
missing, we will evaluate how to treat the observation.  If the study subject prematurely quit the clinical
trial, then we will consider the observation a treatment failure.  However, if the data was not captured (as
in the case of a biopsy which did not capture both distal and proximal findings then we will consider
imputation. Missing data for continuous outcomes may be imputed using multiple imputation techniques.
Covariates for imputation will include investigative site, sex, presence of atopy and duration of disease.
Secondary outcomes 2-5 will be tested at the two-
Analyses of Exploratory Endpoint(s)/Outcome(s)
Exploratory Variables:
1) Change in Patient Reported Outcome (PRO) metrics (pre- minus post- treatment)
a.
EoE Adult Symptom Score Activity Index (EESAI)
i.
VDQ, AMS, Overall PRO
b.
Adult EoE Quality of Life Score
i.
Social impact, emotional impact, disease anxiety, eating/diet impact,
choking anxiety
c.
PROMIS General Health Questionnaire
2) Clinical parameters
a.
Baseline disease activity measures (peak eosinophil count, EREFS, HSS)
b.
Body mass index (BMI)
c.
Presence of atopy and specific atopic diseases (e.g., is asthma associated with tx
response/non-response)
d.
Demographics (sex, age, race)
3) Biomarkers
a.
Serum food specific IgE


b.
CRD
food specific components for IgE and IgG4
c.
Serum food specific IgG4
d.
EDP score
4) Skin testing results
a.
Skin prick tests to milk, egg, wheat, soy, peanut, shellfish, fish, and 5 tree nuts.
b.
Positive is defined as >= 3mm.
5) Milk driven T-cells
a.
T-cell count
b.
Cytokine levels
Exploratory objectives are detailed below:
1) To evaluate the clinical and psychosocial effect of each therapy utilizing patient reported
outcomes (PROs) to assess EoE symptoms and problems/feelings related to eating.
2) To evaluate factors predicting treatment response including
a)
Clinical parameters
b) Serum food specific IgE, CRD, and IgG4
c)
Skin testing results, in the form of prick and patch testing
d) Milk-driven T cells in blood
To test hypotheses for exploratory objective one, we will compare the treatment arms using general linear
mixed models as described for the secondary outcome measures. To test hypotheses for exploratory
objective 2, we will compare responders to non-responders using the generalized linear mixed effects
model using the link that is appropriate for the endpoint (i.e. logit for binary, cumulative logit for ordered
multinomial categories, identity for continuous). Covariates will be considered as appropriate. For
continuous data, appropriate transformations will be considered (e.g. log, square root, rank) to satisfy the
assumptions of the analyses.
Adverse Events
Adverse events (AE) that occur during Phase 1 and Phase 2 will be summarized within each treatment
group using frequency and percent of patients with at least 1 occurrence and total number of occurrences
(nAEs).   These summaries will be done by SOC/AE level using the CTCAE 4.0 system. The percentage
of patients experiencing at least one occurrence of an AE at the SOC/AE level will be compared using
Software Used (with References) and Specialized Macros (with References)
SAS version 9.4
This SAP has been reviewed and approved by:
Investigator
Date