Prospective Evaluation of the Clinical Utility of Budesonide for the Prevention of Esophageal Strictures After Endotherapy
Phase: PHASE2
Conditions: Esophageal Stricture
Sponsor: Mayo Clinic

 
 
Prospective Evaluation of the 
Clinical Utility of Budesonide 
for the Prevention of 
Esophageal Strictures after 
Endotherapy 
 
NCT# NCT02069847  
 
12/11/2013 

Minimal Risk Protocol Template [IRB 10429.004] 
 
Effective August 28, 2012 
 
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IRB Minimal Risk Protocol Template 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Study Information 
 
Principal Investigator:      Dr. Michael Wallace  
 
 
 
 
 
 
 
 
Study Title: Prospective Evaluation of the Clinical Utility of Budesonide for the Prevention of Esophageal 
Strictures after Endotherapy 
 
 
Protocol version number and date:     13-009467    Version 1, 12/11/2013 
 
Purpose 
 
Hypothesis:  
Oral budesonide prevents esophageal stricture formation in patients who underwent radical EMR or ESD for 
advanced premalignant esophageal lesions or superficial esophageal cancers. 
 
Aims, purpose, or objectives:  
1. The aim of this study is to prospectively record our experience with budesonide for the prevention of 
esophageal stricture formation after endotherapy (mucosal resection, submucosal dissection) as part of 
routine medical care. 
Note: If this study establishes a human specimen repository (biobank) for research 
purposes, do not use this template. Use the Mayo Clinic Human Specimen Repository 
Protocol Template found on the IRB home page under Forms and Procedures at 
http://intranet.mayo.edu/charlie/irb/ 
 
First-time Use: Use this template to describe your study for a new IRB submission. 
1. Complete the questions that apply to your study. 
2. Save an electronic copy of this protocol for future revisions.    
3. When completing your IRBe application, you will be asked to upload this template to the protocol 
section. 
Modification:  To modify this template after your study has been approved: 
1. Open your study in IRBe. Click on the study ‘Documents’ tab and select the most recent version of the 
protocol. Save it to your files. 
2. Open the saved document and activate “Track Changes”..  
3. Revise the protocol template to reflect the modification points , save the template to your files 
4. Create an IRBe Modification for the study and upload the revised protocol template. 

Minimal Risk Protocol Template [IRB 10429.004] 
 
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2. The data will be compared with outcomes with well-annotated historical controls that underwent similar 
procedure with similar follow up but without budesonide exposure.  
3. If sufficient efficacy is seen, these data will be used to plan a prospective controlled clinical trial. All 
patients in the study group will receive standard medical care and no experimental interventions will be 
performed.  
 
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.):   
Surgery has been historically the standard of care for advanced pre-malignant lesions and early esophageal 
cancers (EEC). However, esophagectomy is associated with significant morbidity and mortality [1]. With the 
technological advances of the current flexible platforms in recent years, there has been a growing interest in 
multiple minimally invasive endoscopic techniques for these esophageal disorders. Endoscopic mucosal 
resection (EMR), often in conjunction with mucosal ablative techniques, has been increasingly used for the 
treatment of dysplastic Barrett’s esophagus (BE) and EEC [2], with long-term outcomes similar to traditional 
surgical intervention [3]. Traditionally highly focal EMR is performed of target lesions (e.g. nodules) followed 
by ablation, however some patient have large, or even diffuse nodularity that cannot be treated effectively with 
these methods. Wide spread radical EMR (defined as > 50% circumference resection) and more recently, 
endoscopic submucosal dissection (ESD), a technique initially developed in Japan, have been adopted as 
alternative treatments for the management of advanced pre-malignant and EEC [4-6]. ESD has the advantage 
over mucosal ablative techniques and EMR in that it permits en bloc resection of lesions, irrespective of size; 
thus, permitting a more precise histological evaluation and possibly a lower risk of recurrence [7,8].  
 
Esophageal stricture (ES) formation is a widely recognized adverse event of radical EMR and ESD. 
Indeed, ES is the most common complication of radiofrequency ablation (RFA) for BE, with a reported 
incidence ranging from 5% to 12% [9,10]. A single-center retrospective study reported ES formation in 67% of 
73 patients with EMR of at least 50% of their esophageal circumference [11]. Similarly, the incidence of ES 
development after ESD is between 70-90% when the mucosal defect involves more than three-quarters of the 
esophageal circumference [5,12]. In aggregate, the extent of the esophageal mucosal defect following 
endotherapy appears to be the most consistent predictor of ES formation. 
 
Prevention of ES development following endotherapy can significantly improve a patient’s quality of 
life and possibly reduce the potential risks and costs associated with treatment of ES with repeated endoscopic 
balloon dilations (EBD) [13]. Glucocorticoids have been evaluated as a potential preventive therapy for ES 
based on their anti-inflammatory properties and inhibitory effects on collagen deposition [14,15]. Several 
studies from Japan [16, 17] have evaluated the utility of endoscopic triamcinolone injection (ETI) for the 
prevention of stricture formation after ESD. However, local steroid injection is invasive and can be associated 
with the potential risk of bleeding and perforation at the newly created mucosal defect.  
 
Oral prednisolone has been shown to be effective as a preventive strategy for ES formation [18]. 
However, prolonged use of systemic oral steroids can be associated with multiple adverse effects. Budesonide is 
a synthetic steroid with topical anti-inflammatory properties and high first-pass metabolism; thus, potentially 
less systemic absorption and side effects. A modified swallowed viscous budesonide/sucralose slurry has been 
shown to be safe and effective for treatment of esophageal narrowing due to eosinophilic esophagitis [19]. 
Given these characteristics, oral budesonide has been explored for the prevention of ES [20, 21]. Most recently 
Mayo Clinic Rochester developed a new budesonide capsule formulation. Alike viscous budesonide the 
budesonide capsule can be opened and the powder can be mixed with honey or pancake syrup. A similar 
formulation is currently used in pilot studies for treatment of eosinophilic esophagitis. The advantage of 

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budesonide capsule is the improve taste in comparison to viscous budesonide originating from budesonide 
respules which is unpalatable. 
Subject Information – charts, records, images, or specimens are considered ‘subjects’ 
 
Target accrual: 
We plan to include a total of 50 patients into the study group in setting of a pilot study. As part of a multi-center 
study 25 patients will be recruited at Mayo Clinic Florida into the study group and 25 patients at University of 
Florida, Gainesville. 
The control group will consist of 150 patients (1:3 match) which will be obtained by retrospective chart review 
from all patients who underwent similar procedures between 1/1/2011 and 12/31/2013. Of 150 patients 75 
patients will be provided by Mayo Clinic Florida and 75 patients from University of Florida, Gainesville. 
 
 
Subject population:  
All patients scheduled to undergo EMR or ESD as clinically indicated will be considered for the study. Patients 
with an esophageal mucosal defect involving more than 50% of the esophageal circumference following 
EMR/ESD will be offered to participate in this study.  
 
Inclusion Criteria:  
1. Age 18 years or older 
2. Diagnosis of esophageal lesion treated with ESD or EMR which involves ≥ 50% of the esophageal 
circumference. 
 
Exclusion Criteria:   
3. Locally advanced disease 
4. Prior esophageal surgery 
5. Participation in another research protocol that could interfere or influence the outcome measures of the 
present study.  
6. The subject or legal representative is unable/unwilling to give informed consent. (study group) 
7. Medications or conditions for which there is a contraindication to use of budesonide (see pharmacology 
section below) 
8. Concomitant use of systemic steroids or other immune suppressive medication for a different condition 
9. Pregnant women 
 
Will a Certificate of Confidentiality be obtained? No 
 
Study Design  
 
Methods: Describe, in detail, the research activities that will be conducted under this protocol:   
 
1. Informed Consent: The investigators will explain the nature of the study to each patient scheduled to 
receive budesonide following endotherapy and invite the subject to participate and provide a copy of the 
informed consent form. Each patient will be told prior to their participation that they are free to 
withdraw from the study at any time and that participation in this study will not alter their scheduled 

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medical care. They will read and sign the consent form prior to their participation of the study and they 
will be asked if they have any questions or need clarification after they have read the consent form and 
prior to their signing of the form.  
 
2. Study Group: Participants will be instructed to swallow budesonide 3mg twice daily for eight 
consecutive weeks following endotherapy with EMR or ESD. Budesonide will be provided in a capsule 
containing 3mg budesonide only by Mayo Clinic Pharmacy with full 8 weeks supply. The patient will 
require opening the capsule and mixing the budesonide powder in 10ml (2 teaspoons) honey, or pancake 
syrup.  
3. Patients will be instructed not to ingest any solid or liquids for 30 minutes before and after taking the 
budesonide. . For purposes of this study, budesonide is used off-label but according to the same dose and 
efficacy as has been demonstrated in other esophageal inflammatory conditions. [19] Patients will 
receive a handout with exact instructions how and when to take Budesonide gel. (attached) 
 
3. Historical Control Group: Consists of patients who have undergone EMR or ESD for similar indications 
as the study group between 1/1/2011 and 12/31/2013 at Mayo Clinic Florida. The inclusion and 
exclusion criteria for the historical control group are the same as the study group. All data will be 
abstracted by retrospective chart review. Patients will not be contracted by study team. Consent will be 
not obtained from this group. 
 
4. Follow-Up and Endpoints: Esophagogastroduodenoscopy (EGD) and endoscopic balloon or boogie 
dilation (EBD) will be performed on demand for dysphagia score ≥ 1 (scale 0-4) if symptoms cannot be 
attributed to a cause other than esophageal stricture (ES). Dilation will be continued until dysphagia 
score of 0 is reached. Additional ablation will be performed as clinically indicated, typically after 
stricture dilation has achieved luminal diameter of at least 10mm.  For patients with dysphagia, the 
stricture diameter will be measured according to the largest balloon size at which no friction is seen with 
standard endoscopic passage. For patients without dysphagia, the diameter will be estimated base on 
luminal inspection using an open biopsy forceps for reference.  An ES will be defined as inability to 
pass standard endoscope during EGD. Clinical symptoms of dysphagia will be evaluated with validated 
symptom scores (Eckardt and validated dysphagia scores) [22] with phone call at 1, clinic visit at 2 
months and at the time of EGD at 3 months. All patients will undergo a follow-up EGD and barium 
esophagography to evaluate for asymptomatic ES at 12 weeks after endotherapy with EMR/ESD. Patient 
who have severe dysphagia (score 3 or 4 corresponding to ability to swallow liquids only or worse) will 
be offered earlier evaluation as clinically indicated.  
 
5. Additional Data: Patients’ perceptions, compliance and tolerability of Budesonide as treatment for 
prevention of ES will be recorded at 1 and 2 month follow up. Presence of esophageal candidiasis at 
time of EGD. Number of dilations sessions to achieve dysphagia score of 0.  
 
Resources: Describe the available resources to conduct the research (personnel, time, facilities, mentor 
commitment, etc.):  
 
Dr Wallace will be the principal investigator (PI) supervising the study. Dr Wolfesen will be the co-PI. Dr 
Bartel will perform the chart review and will abstract the data into spreadsheets. Drs Wallace, Wolfsen and 

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Bartel will perform the patient requirement and obtain the consent form during the clinic visits prior the 
endotherapy. 
Clinic visits as well as endoprocedures will take place in regular gastroenterological clinic setting. 
 
Check all that apply. If none apply, leave blank: 
 
x  This is a multisite study involving Mayo Clinic and non-Mayo Clinic sites.  
When checked, describe the research procedures/activities being conducted only at Mayo Clinic: 
 
  Mayo Clinic staff will be engaged in research activity at a non-Mayo Clinic site.  When checked, provide 
the location and a detailed description of the Mayo Clinic research staff involvement. 
 
 
  This study is to establish and/or maintain an ongoing database or registry for research purposes only. 
 
  The research involves contact or interaction with subjects, for example, surveys, questionnaires, 
observation, blood draw. 
 
  The study involves audiotaping or videotaping   
 
 
 
 
 
Blood Collection 
 
If this study involves prospective blood collection by finger, heel, ear stick or venipuncture, complete the 
following:  
 
 
  From healthy, non pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period 
and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) _______ 
 
 
  From other adults and children considering age, weight, and health of subject. For a minimal 
risk application, the amount of blood drawn from these subjects may not exceed the lesser of 50 ml or 3 
ml per kg in an 8 week period, and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.)_______  
 

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Review of Chart, Images, Specimens 
Provide the date range for collection of data and/or specimens that will be included in your research dataset.  
(Example: 01/01/2000 to 12/31/2012)  
Date range: From _1__/_1__/_2011____  to _12__/_31__/_2014____ 
 
Check all that apply: 
 
  This study involves only data and/or specimens that exist at the time this application is submitted to the IRB 
(IRB submission date). No data or specimens will be collected beyond this date.  
 
 
  This study involves only data and/or specimens that will be collected after submission to the IRB. 
 
x  The study involves data and/or specimens that exist at the time of submission to the IRB and data and/or 
specimens that will be collected after submission to the IRB, for example a study that includes collection of 
existing data and prospective collection of specimens. 
 
  Data and/or specimens used in this study are collected under another IRB protocol. When checked, provide 
the IRB number(s) from which the research material will be obtained and check the box below to attest that 
subjects have provided consent for future use of their data and/or specimens, as described in this protocol.  
 
 
IRB Number(s): 
 
 
□Subjects have provided consent for use of their data and/or specimens, as described in this protocol. 
 
  Other data sources will be utilized in this study. When checked, provide all data sources: 
 
 
 
 
Data Confidentiality, HIPAA Subject Identifiers 
 
Review the list of subject identifiers below and, if applicable, check the box next to each subject identifier being 
recorded at the time you are collecting/abstracting data/specimens for use in this study. 
 
Subject Identifiers:  Individually identifiable information, including demographic data, that identifies the 
individual or for which there is reasonable basis to believe it can be used to identify the individual.  NOTE: 
Identifiers apply to subjects enrolled in your study and to the subject’s relatives, household members, 
employers, etc. 

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Internal refers to subject identifiers that will be included in the dataset maintained by the study team. 
External refers to subject identifiers that will be shared with persons outside of the immediate study team, for 
example, sent to an external collaborator or shared with a national registry.  
 
 
SUBJECT IDENTIFIERS 
Check all that apply 
INTERNAL 
IDENTIFIER 
EXTERNAL 
IDENTIFIER 
Name 
x 
 
Social Security number 
 
 
Medical record/patient registration number, lab accession, specimen or 
radiologic image number 
x 
 
Study number, subject ID, or any other unique identifying number, 
characteristic or code that can be used to link the identity of the subject to the 
data 
x 
x 
Dates: All elements of dates [month, day, and year] directly related to an 
individual. Their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
x 
x 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
images and any comparable images 
 
 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
 
 
Phone or fax numbers 
 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
 
If None of the above identifiers will be recorded or maintained in the 
dataset and/or sent outside of the study team, please check “None”. 
 None 
 None 
 
 
Statistical Information 
 
Note: Power analyses and study endpoints are not needed for a pilot or feasibility studies.  
 
 
 No statistical information. If checked, please explain: 
 
 
Statistical Considerations 
 
Power Statement:  pilot study 

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Data Analysis Plan:  
Incidence of esophageal stricture and frequency of required endoscopic balloon dilation will be compared 
between historical control and study groups. Statistical significance of comparisons between the groups will be 
determined by using the Fisher exact test, chi-square test, Student t test, and Mann-Whitney test, as appropriate. 
P values <0.05 will be considered significant. 
 
 
Endpoints 
    
 
Primary:  
 
       
 
 
Measure the incidence of dysphagia following ESD or EMR in both historic control group and study 
intervention group. 
Need for repeat balloon dilation for esophageal stricture after 3 months following ESD or EMR in both historic 
control group and study intervention group. 
 
 
 
 
 
REFERENCES 
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2013;63(4):232-48. 
2. Soetikno R, Kaltenbach T, Yeh R, Gotoda T. Endoscopic mucosal resection for early cancers of the 
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3. Ngamruengphong S, Wolfsen HC, Wallace MB. Survival of patients with superficial esophageal 
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1429. 
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5. Ono S, Fujishiro M, Niimi K, et al. Long-term outcomes of endoscopic submucosal dissection for 
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