Clinical trial NCT03866538
Conditions: Enteropathy Celiac Disease CVID Enteropathy Collagenous Sprue Autoimmune Enteropathy
Sponsor: Mayo Clinic
Start date: 2019-09-10; Completion date: 2021-10-19
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Researchers are trying to determine if withdrawal of budesonide therapy in patients with immune-mediated enteropathies doing well on therapy will result in worsening symptoms, histology, quality of life, and micronutrient/nutritional status when compared to continued therapy.

Detailed description:
This study aims to evaluate patients with small intestinal diseases caused by the immune system (refractory celiac disease type 1, CVID enteropathy, autoimmune enteropathy, and collagenous enteropathy) who have had improvement in symptoms and small intestine healing with oral budesonide.

Patients who meet inclusion criteria and agree to enter the study will be included for 12 weeks or until they choose to discontinue or there are concerns for safety.

At the beginning of the study, patients will undergo questionnaires, blood draw, urine and stool collections, physical exam, and an upper scope (esophagogastroduodenoscopy) with biopsies from the small intestine. They will then be randomized to either continued therapy on their current dose and formulation of budesonide (medication provided by the study) or to withdrawal of the medication over 2 weeks and then no medication during the study. Daily questionnaire on symptoms will be recorded.

Patients will be assessed in the clinical research unit monthly during the study with a questionnaire, physical exam, blood draw, and urine/stool collections.

Finally, at the end of the trial (12 weeks) or at the time of withdrawal from the trial, the patients will complete questionnaires, physical exam, blood collection, urine/stool collection, and upper scope (esophagogastroduodenoscopy) with small bowel biopsies.

Arms: arm 1: Patients in this arm continue budesonide at the dose they were taking at the time of enrollment in the trial arm 2: Patients are weaned off of budesonide over 2 weeks and continued off of the medication for the duration of the trial
Interventions: intervention 1: Withdrawal of Oral Budesonide
Intervention descriptions: intervention 1: The intervention arm will taper and stop budesonide therapy (withdrawal).

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Open-label withdrawal trial of 
budesonide in patients with 
immune mediated 
enteropathies 
 
 NCT03866538 
 
12/16/2019 


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INTRODUCTION 
Study Title: Open-label withdrawal trial of budesonide in patients with immune mediated 
enteropathies 
Synopsis: 
Celiac disease is an immune-mediated enteropathy occurring in genetically susceptible 
patients in response to ingested gluten.1 Other immune mediated enteropathies include 
autoimmune enteropathy, collagenous enteropathy, post-transplant lymphoproliferative 
disorder related enteropathy.  These patients have been     treated with off-label budesonide 
therapy.  In clinical experience with refractory celiac disease, 92% showing improvement in 
symptoms and 89% had improvement of histological changes.5 However, this therapy has 
never evaluated in a randomized, placebo-controlled trial. This is significant as there is no 
approved therapy in patients with RCD or other immune mediated enteropathies, and the 
sequelae of this illness include debilitating symptoms, malnutrition, osteoporosis and 
enteropathy associated T-cell lymphoma.4 Furthermore, physicians and patients have concerns 
regarding the long-term use of budesonide therapy and an appropriate withdrawal strategy is 
not well defined. 
This study aims to evaluate patients with immune mediate enteropathies for changes in 
symptoms and histology after budesonide withdrawal compared to continued therapy.  
Objectives: To determine if withdrawal of budesonide therapy in patients with immune-
mediated enteropathies doing well on therapy will result in worsening symptoms, histology, or 
micronutrient/nutritional status when compared to continued therapy. 
Design and Outcomes 
• 
Design: Open-label withdrawal of budesonide in patients with immune mediated 
enteropathies who have had histological and symptom improvement on oral 
budesonide. 
• 
Outcomes: 
o Primary: Change in histology after withdrawal of budesonide compared to 
continued therapy 
o Secondary: 
 
Change in symptoms after withdrawal of budesonide compared to 
continued therapy 
 
Change from baseline micronutrient and nutritional status after blinded 
withdrawal of budesonide compared to continued therapy 
 
Change in quality of life after blinded withdrawal of budesonide 
compared to continued therapy 
 
Storage of serum and stool for future evaluation of possible non-invasive 
evaluation of bowel injury 
 


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Interventions and Duration 
• 
Intervention: Withdrawal of budesonide therapy compared to continued therapy 
• 
Duration: 12 weeks 
Sample Size and Population 
• 
Sample Size: 10 patients per arm (20 total) 
• 
Population: Adult patients with immune-mediated enteropathies who have had 
histological small bowel improvement and symptom improvement on oral budesonide. 
 
 


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STUDY TEAM MEMBERS 
Principal Investigator:   
Joseph A. Murray, MD 
Consultant and Professor of Medicine 
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA 
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA 
Department of Pediatrics, University of Southern Denmark, Denmark  
 
Co-Investigators:  
, 
 
Fellow 
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA 
 
, 
 
Fellow and Instructor in Medicine 
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA 
 
, 
 
Consultant and Professor of Laboratory Medicine and Pathology 
Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA 
 
, 
 
Clinical Research Coordinator 
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA 
 
 
Clinical Research Coordinator 
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA 
 
 
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA 
 
 
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA 
 
PARTICIPATING STUDY SITES 
Mayo Clinic 
Division of Gastroenterology and Hepatology 
200 First Street Southwest 
Rochester, MN 55905 
 


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STUDY SPECIFICATIONS 
1. Study Objectives/Outcomes 
i. Primary: Change in histology after withdrawal of budesonide compared 
to continuation of budesonide therapy  
II. Secondary: 
i. Change in symptoms after withdrawal of budesonide compared to 
continuation of budesonide therapy 
ii. Change from baseline micronutrient and nutritional status after 
withdrawal of budesonide compared to continuation of budesonide 
therapy 
iii. Change in quality of life after withdrawal of budesonide compared to 
continued budesonide therapy 
iv. Storage of serum and stool for future evaluation of possible non-invasive 
evaluation of bowel injury 
 
2. Background and Rationale for Study 
I. Background 
i. Celiac disease is an immune-mediated enteropathy occurring in 
genetically susceptible patients in response to ingested gluten.1 Other 
immune mediated enteropathies include autoimmune enteropathy, 
collagenous enteropathy, post-transplant lymphoproliferative disorder 
related enteropathy.  Celiac disease prevalence is 0.7% of the United 
States population.2  Less than two percent of patients with celiac disease 
do not respond to a gluten free diet and demonstrate 
recurrent/persistent symptoms and small bowel villous atrophy.3,4  
Refractory celiac disease (RCD) is defined as persistent symptoms and 
histological small bowel changes after at least six months on a gluten 
free diet.4  These patients have been treated with off-label budesonide 
therapy with 92% showing improvement in symptoms and 89% 
showing histological changes.5 However, this therapy has never 
evaluated in a randomized, placebo-controlled trial. This is significant as 
there is no approved therapy in patients with RCD or other immune 
mediated enteropathies, and the sequelae of this illness include 
debilitating symptoms, malnutrition, osteoporosis and enteropathy 
associated T-cell lymphoma.4 Furthermore, physicians and patients have 
concerns regarding the long-term use of budesonide therapy and an 
appropriate withdrawal strategy is not well defined. 
 
II. Rationale for Study  
i. While the benefits of budesonide therapy in refractory, immune-mediated 
enteropathies has been suggested by clinical experience, no study has been 
conducted to determine when and if this therapy can be discontinued.  This 
study aims to evaluate patients with immune mediated enteropathies who 


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have demonstrated symptomatic and histologic improvement on 
budesonide and randomize them to withdraw therapy versus continued 
budesonide.  
 
This question is important as there are systemic effects of long term 
corticosteroid therapy, including budesonide.  Studies have shown that 
adrenal suppression does occur in about 50% of patients on budesonide 6-8. 
The medication is also costly.  
 
3. Study Design 
I. Patients with autoimmune mediated enteropathies (excluding refractory celiac 
disease type 2 and post-transplant lymphoproliferative disorder) on 
budesonide therapy with improvement in symptoms and histological small 
bowel changes will be recruited for a randomized, open-label trial of 
budesonide withdrawal.  After recruitment and consent, subjects would record 
CDSD surveys daily for one week. For those individuals who are unable to travel 
to Rochester for that visit, CDSD will be activated and completed prior to 
consent under the assumption that the data can only be used if future written 
consent is obtained  Then, on the day of randomization, the subjects undergo 
esophagogastroduodenoscopy (EGD) with biopsies taken from the duodenum, 
serum evaluation of micronutrient status, blood count, and creatinine will be 
assessed, and serum will be stored for future evaluation of non-invasive 
evaluation of bowel inflammation.  At enrollment, stool test for gluten exposure, 
CDSD questionnaire and CD-QOL quality of life questionnaire will be 
administered.   Subjects will record symptoms on CDSD daily during the study.  
Subject will be randomized to either withdrawal or continued budesonide 
therapy.  Subjects in the withdrawal arm will be weaned off of budesonide over 
a period of two weeks.  Those continued on therapy will continue at their 
current maintenance dose and dosing scheme.  At 4 weeks,  individuals will 
have laboratory studies drawn locally through a kit that will be mailed to them 
containing testing for blood count, creatinine, albumin, and CRP.  Additionally, 
they will complete a phone interview with a study investigator to fill out the CD-
QOL survey, to screen for adverse events, and to review study exclusion criteria.  
This would be repeated at 8 weeks.  At 12 weeks, the subject will undergo 
repeat EGD with biopsies, serum assessment, QOL questionnaire, one week of 
CDSD symptom questionnaire, and stool gluten testing.   
 
All subjects in the control arm will continue budesonide formulation and dosing 
scheme. Those noted on the budesonide open capsule regimen will continue this 
regimen as listed below.  
 
If a subject has had a clinical EGD with biopsies within three months of 
randomization and the histology slides are available, this will serve as the 
baseline biopsy. In this case, no frozen biopsy for microbiology or biopsy in RNA 
later will be collected.  
 
II. Open capsule budesonide regimen5: Oral budesonide 3 mg three times daily.  


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• 
First capsule is to be opened, emptied onto applesauce, stir, grind 
medication with teeth, and swallow with a glass of water.  
• 
Second capsule is to be opened, emptied onto applesauce, stir, and 
swallow with glass of water. 
• 
Third capsule is to be swallowed whole. 
• 
Rationale: Deliver of the budesonide to the entire small bowel, given EC 
budesonide is pH dependent and intended to be released in the distal 
small bowel.  
• 
This differs from the prescribing information from the enteric coated 
budesonide, but has been shown to be efficacious for refractory immune-
mediated enteropathies5.  
 
4. Selection and Enrollment of Participants 
I. Inclusion Criteria 
i. Adult patients with immune mediated enteropathies who have had 
improvement in symptoms and histology on oral budesonide therapy. 
II. Exclusion Criteria 
i. Age <18 years 
ii. Positive stool gluten testing in patients with refractory celiac disease 
iii. Small bowel malignancy or history of small bowel malignancy 
iv. Refractory celiac disease type 2 
v. Post-transplant lymphoproliferative disorder associated enteropathy 
vi. No prior improvement in symptoms and histology with budesonide therapy 
vii. Discontinuation of budesonide therapy prior to the trial 
viii. Other concurrent systemic corticosteroids 
ix. Other immune mediating medications, for example but not limited to 
azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, anti-TNF 
monoclonal antibodies, alpha-4 beta-7 integrin inhibiting monoclonal 
antibody, interleukin 12/23 inhibiting monoclonal antibody, JAK inhibitors. 
 
5. Study Interventions 
I. Interventions 
i. Screening period: 
• 
Review of inclusion/exclusion criteria 
• 
Consent documentation and discussion 
a. This may be conducted after the 7 day electronic run in 
questionnaire of symptoms have been completed.  If written 
isn’t obtained, questionnaire data will be deleted.  This will 
be in those instances where subjects cannot travel to 
Rochester multiple times due to cost and availability because 
of the distance to Rochester. 
b. For consents obtained in person, written or iPad consent 
through the PTRAX system will be used for electronic 
consent. 


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• 
Randomization to continued budesonide therapy or withdrawal  
• 
Daily CDSD for seven days leading to start of study period 
ii. Study Period 
• 
Withdrawal Arm: Titration off budesonide as outlined 
• 
Budesonide Arm: Continuation on current therapy and dosing scheme 
• 
Esophagogastroduodenoscopy with biopsies at day 0 and day 84 (or 
withdrawal from the study). 
a. If clinical EGD with biopsies within three months of 
randomization with histology slides available, this will serve 
as baseline biopsy. 
• 
Blood draws as outlined at initiation of the trial, day 28, day 56 and day 
84 
a. The blood draws on day 28 and day 56 will be drawn at the 
patient’s local lab in order to minimize travel requirements 
for subjects who live a distance from Rochester, Minnesota.  
Kits will be mailed to the subjects with the appropriate blood 
tests. 
• 
Stool collection at day 0 and day 84 (or withdrawal from the study) 
• 
Urine collection at day 84 (or withdrawal from the study). 
• 
Daily CDSD survey collected weekly  
• 
Monthly CD-QOL survey 
• 
Meeting with study team for consent/enrollment and at days 0, and 84 
(or withdrawal from the study) 
II. Withdrawal Arm Titration for Patients Previously on Budesonide EC 
i. Patients randomized to the withdrawal arm will be titrated off of 
budesonide over two weeks 
ii. For days 1-7, they will receive 6 mg of budesonide, one opened, chewed 
capsule, one opened and granules mixed with applesauce. 
iii. For days 8-14, they will receive 3 mg of budesonide, one opened, chewed 
capsule. 
iv. For days 15-84, the will receive no budesonide 
III. Withdrawal Arm Titration for Patients on Compounded Budesonide  
i. For days 1-7, subject will receive 6 mg of budesonide 
ii. For days 8-14, subject will receive 3 mg of budesonide 
iii. For days 15-84, subject will receive no budesonide 
6. Study Procedures 
I. Schedule of Evaluation 
i. Screening and Consent 
• 
Patients will either meet in person with study member to discuss 
inclusion and exclusion criteria, study design, and consent, or this 
conversation will be held over the phone in those cases where patients 
live a distance from Rochester, Minnesota 


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• 
Age, sex, height, weight, date of diagnosis, medication reconciliation and 
physical exam.  This information will be collected on day zero.. 
• 
Daily CDSD for 7 days leading to start of the trial. This may be done with 
patients who live a distance from Rochester, MN prior to written consent 
under the assumption that the data collected can only be used if consent 
is obtained on Day 0. 
ii. Day Zero: EGD with duodenal biopsies, collection of serum and stool. CD-
QOL and CDSD surveys. Randomization occurs. 
• 
Age, sex, height, weight, date of diagnosis, medication reconciliation and 
physical exam if consent and screening was performed over the phone.  
• 
Serum Studies: Complete blood count with differential, sodium, 
potassium, creatinine, albumin, tissue-transglutaminase IgA, total IgA, 
ferritin, serum iron, total iron binding capacity, zinc, copper, vitamin 
B12, 25-OH vitamin D, serum folate, c-reactive protein. 
• 
Stool Studies: Gluten assessment in RCD1 patients, stool storage for 
future study and microbiology 
• 
Urine Studies: Urine stored for future study 
• 
Duodenal biopsies for histology and for microbiology 
iii. Days 1-7:  
• 
Withdrawal Arm: Budesonide 6 mg daily  
• 
Budesonide Arm: Continued pre-study dose and frequency. 
• 
All subjects daily CDSD. 
iv. Days 8-14: 
• 
Withdrawal Arm: Budesonide 3 mg daily  
• 
Budesonide Arm: Continued pre-study dose and frequency.  
• 
All subjects daily CDSD. 
v. Days 15-84: 
• 
Withdrawal Arm: No budesonide 
• 
Budesonide Arm: Continued pre-study dose and frequency. 
• 
All subjects daily CDSD. 
vi. Day 28 +/- 3 days: 
• 
Laboratory assessment including CBC with differential, sodium, 
potassium, creatinine, albumin, c-reactive protein performed locally via 
a kit that will be mailed to subjects. 
• 
Phone visit to review CD-QOL, to gather information on weight 
measurement, to evaluate for adverse events, and to review exclusion 
criteria 
vii. Day 56 +/- 3 days:  
• 
Laboratory assessment including CBC with differential, sodium, 
potassium, creatinine, albumin, c-reactive protein performed locally via 
a kit that will be mailed to subjects. 


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• 
Phone visit to review CD-QOL, to gather information on weight 
measurement, to evaluate for adverse events, and to review exclusion 
criteria 
viii. Day 84:  
• 
Physical exam. 
• 
EGD with duodenal biopsies, collection of serum, urine, and stool. CD-
QOL and CDSD surveys. 
• 
Serum Studies: Complete blood count with differential, sodium, 
potassium, creatinine, albumin, tissue-transglutaminase IgA, total IgA, 
ferritin, serum iron, total iron binding capacity, zinc, copper, vitamin 
B12, 25-OH vitamin D, serum folate, c-reactive protein. 
• 
Stool Studies: Gluten assessment in RCD1 patients, stool storage for 
future study 
• 
Urine Studies: Urine stored for future study 
• 
Duodenal biopsies for histology and microbiology 
• 
Subjects return to pre-study budesonide dosing schedule. 
ix. Early Withdrawal-Safety or Elective 
• 
If the subject requires early withdrawal due to safety concerns or 
elective withdrawal but agrees to final testing. 
• 
EGD with duodenal biopsies, collection of serum, urine, and stool. CD-
QOL and CDSD surveys. 
• 
Serum Studies: Complete blood count with differential, sodium, 
potassium, creatinine, albumin, tissue-transglutaminase IgA, total IgA, 
ferritin, serum iron, total iron binding capacity, zinc, copper, vitamin 
B12, 25-OH vitamin D, serum folate, c-reactive protein. 
• 
Stool Studies: Gluten assessment in RCD1 patients, stool storage for 
future study 
• 
Urine Studies: Urine stored for future study 
• 
Duodenal biopsies for histology and microbiology 
• 
Subject prescribed budesonide 9 mg daily, open capsule scheme and 
recommend follow up with primary gastroenterologist. 
 
7. Safety Assessments 
I. Specifications of Safety Parameters  
i. Serious Adverse Events 
• 
Hospitalization for dehydration, malnutrition, or severe diarrhea 
• 
These would result in withdrawal from the study. If possible, patients 
would undergo laboratory assessment, EGD with biopsies and 
questionnaires. 
ii. Adverse Events-Meeting any of the following would result in withdrawal 
from the study with reassessment of serologies, EGD with biopsies, as 
outlined in the withdrawal portion of the protocol. 
• 
Loss of greater than or equal to 5% of body weight 


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• 
Hemoglobin decrease by >2 grams without other clear etiology 
• 
Albumin decrease by more than 1 g/dL as this was a predictor of greater 
mortality9. 
• 
CDSD Symptom of >6 bowel movements per day for 3 days in a week. 
II. Methods and Timing for Assessing, and Recording Safety Parameters 
i. Subjects would be able to contact our study office at any point during the 
trial to report adverse events. 
ii. Formal assessment of laboratory parameters, weight parameters, and CDSD 
scores would occur at monthly visits. 
III. Reporting of Adverse Events 
i. Reporting of serious adverse events to the independent safety monitor 
would occur immediately. 
ii. Reporting of adverse events not included as serious adverse events would 
be reported and reviewed quarterly by the independent safety monitor. 
IV. Independent Safety Review 
i. A gastroenterologist, independent of the study, will review serious adverse 
events and other adverse events as outlined above. She or he has the 
authority to abort the study at any point. 
V. Follow up for adverse events 
i. If the subject develops the predetermined adverse events requiring 
withdrawal from the trial, he or she will be started on 9 mg of budesonide 
open capsule formulation and scheduled for follow up with primary 
gastroenterologist. 
 
8. Interventional Discontinuation 
I. Completion of the Trial 
i. At the completion of the trial, all subjects will resume budesonide dose and 
scheme they were prescribed prior to the trial. 
ii. Subjects will be encouraged to follow up as scheduled with primary 
gastroenterologist. 
II. Withdrawal from Trial 
i. Safety/Adverse Events: If withdrawal from trial was due to safety or adverse 
events. The reassessment of disease with EGD and duodenal biopsies, 
serologies, urine and stool collection, and questionnaires will be completed 
if able. 
• 
Subjects will be prescribed budesonide 9 mg daily utilizing open capsule 
formulation 
• 
Follow up will be arranged with primary gastroenterologist 
ii. Elective Withdrawal: If withdrawal is elective and not related to symptoms 
or adverse effects, the subjects will resume budesonide dose and frequency 
as to that before the trial. 
• 
Subjects will be offered repeat EGD with duodenal biopsies, serologies, 
collection of urine and stool, and questionnaires. 


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• 
If there are concerns for worsening symptoms, the subject will be placed 
on budesonide 9 mg daily utilizing open capsule formulation with 
instructions to follow up with his/her primary gastroenterologist. 
9. Statistical Considerations 
I. General Design 
i. Randomized, open-label withdrawal of budesonide therapy in patients with 
immune-mediated enteropathies who have had improvement in symptoms 
and small bowel histology with budesonide therapy. 
II. Sample Size and Randomization 
• 
Sample Size: Aim is 10 patients per arm (20 total) 
• 
Power Analysis:  Based on the fact that these are rare diseases, there is 
limited knowledge of what constitutes meaningful histologic change and 
recruitment may be limited.  A decrease in villous height to crypt depth ratio 
from baseline of .8 (SD = .6) was used as the non-inferiority margin based on 
prior literature11.  Assuming the expected change from baseline between 
the two groups is the same, 10 subjects are needed in each arm to achieve 
the target power of 0.80 using an alpha of 0.05 and a one-sided test. 
• 
 Randomization: Block randomization based on underlying immune-
mediated enteropathy, either refractory celiac disease type 1 or other. 
• 
Treatment Assignment Procedures: Block randomization will occur as 
above by computer generated randomization. 
• 
Statistical Analysis: The primary aim in this study is to determine if subjects 
can safely be removed from budesonide therapy. The change of villous 
height to crypt depth ratio from baseline to 12 weeks (calculated as the 
difference of baseline and 12 weeks post treatment) between the 
randomized groups (withdraw versus continued therapy) will be assessed 
with a Wilcoxon rank-sum one-sided test. Analyses will be conducted in SAS 
statistical software (SAS Institute Cary, NC) and R statistical package (R 
Foundation for Statistical Computing, Vienna, Austria). An alpha level of .05 
will be used to determine statistical significance.  
 
III. Stopping Rules 
i. Stopping rules: Section 7 defines serious adverse events and adverse events 
that would result in subjects being withdrawn from the trial for safety 
• 
The independent safety monitor will determine if the study must be 
stopped early due to concern for safety. Reporting to this monitor is 
outlined in section 7. 
IV. Outcomes 
i. Primary Outcome 
• 
Histology Outcome:  Duodenal histology will be compared from 
initiation of the study to that at completion or withdrawal. Oberhuber-


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Marsh Classification and villous-crypt height ratio and IEL’s will be 
assessed by a masked pathologist. 
ii. Secondary Outcomes 
• 
Symptom Outcome: CDSD score will be monitored throughout the trial 
and evaluated as a continuous variable observing for changes in 
symptoms during treatment versus withdrawal 
• 
Quality Outcome: CD-QOL will be assessed monthly and at 
completion or withdrawal and changes will be evaluated for 
association with withdrawal versus continuation of budesonide. 
• 
Micronutrient/Nutritional Outcome: Nutrient assessment will be 
completed at initiation and completion of the study assessing for 
micronutrient differences between those randomized to withdrawal of 
budesonide compared to continued therapy. Weight will be monitored 
monthly throughout the study and assessed for overall change. 
10. Data Collection and Storage  
I. Data Collection Forms 
i. Forms for data collection are attached as Appendix IV. 
ii. CDSD will be available via daily email link to those with internet and email 
access. Paper copies will be available to those without email or internet 
access. 
II. Data Management 
i. Data will be collected both on paper and electronically throughout the study. 
The data will be securely archived electronically. 
ii. RedCap research database will be formulated to collect and manage data. 
III. Protocol Deviations 
i. All efforts will be made to ensure that the study does not deviate from the 
protocol. 
ii. If changes need to be made for safety or logistics, they will be reviewed by 
the Institutional Review Board prior to any change.  
IV. Monitoring 
i. Safety will be monitored as stated above. 
11. Participant Rights and Confidentiality 
I. Institutional Review Board (IRB) Review 
i. This study, any modifications, consent, and any documentation will be 
reviewed by the Mayo Clinic Institutional Review Board. 
II. Informed Consent Forms 
i. A study member will discuss the attached consent form with the participant 
prior to entry into the trial. This discussion may be performed over the 
phone.  A copy of this will be provided to the participant, including contact 
information for the study team, Mayo Clinic IRB, research billing, and a 
research advocate. 
III. Participant Confidentiality 


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i. Data will be collected and secured electronically.  Any publication will not 
include any identifying information for study participants.   
IV. Study Discontinuation 
i. At the completion of each participant’s time in the study, the protocol 
discussed medication recommendation and follow up. This includes 
completion of the trial and if the subject electively withdraws or the trial is 
stopped for subject safety. 
ii. If the overall trial needs to be stopped due to safety concerns, all subjects 
will be contacted and returned to their prior dose and schedule of 
budesonide. They will receive recommendations to follow up with their 
primary gastroenterologist.  
V. Participant Payment  
i. $250 for each endoscopy completed 
ii. Medication would be provided for the time enrolled in the trial 
12. Ethical Considerations 
I. The study will be conducted in accordance with the International Council on 
Harmonization guideline E6 Good Practice, the Declaration of Helsinki, and with 
local regulations for completion of clinical trials. 
II. The study will be evaluated by the Mayo Clinic Institutional Review Board. 
III. The study will be listed as a registered clinical trial with clinicaltrials.gov. 
IV. It is possible that subjects randomized to budesonide withdrawal may lose future 
effect of budesonide therapy. This will be included as a risk in the consent 
documentation. 
13. Committees 
I. Independent Safety Review Committee as outlined above. 
14. Publication of Research Findings 
I. All findings will be submitted for publication after the completion of the study. 
 
 
 


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15. References 
1.    Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. 
Gut 2013;62:43-52. 
2. Choung RS, Unalp-Arida A, Ruhl CE, Brantner TL, Everhart JE, Murray JA. Less Hidden Celiac 
Disease But Increased Gluten Avoidance Without a Diagnosis in the United States: Findings From the 
National Health and Nutrition Examination Surveys From 2009 to 2014. Mayo Clin Proc 2016. 
3. Leffler DA, Dennis M, Hyett B, et al. Etiologies and predictors of diagnosis in nonresponsive 
celiac disease. Clin Gastroenterol Hepatol 2007;5:445e50. 
4.  Rubio-Tapia A, Murray JA. Classification and management of refractory coeliac disease. Gut 
2010;59:547-57.  
5.  Mukewar SS, Sharma A, Rubio-Tapia A, et al. Open-capsule budesonide for refractory celiac 
disease. Am J Gastroenterol 2017; 112:959-67. 
6.  Greenberg GR, Feagan BG, Martin F, et al. Oral budesonide for active Crohn’s disease. 
Inflammatory Bowel Disease Study Group. N Engl J Med 1994;331:836-841. 
7. Campieri M, Ferguson W, Doe T, et al. Oral budesonide is as effective as oral prednisolone in 
active Crohn’s disease. The Global Budesonide Study Group. Gut 1997;41:209-214. 
8.  Tremaine WJ, Hanauer SB, Katz S, et al. Budesonide CIR capsules (once or twice daily dividided-
dose) in active Crohn’s disease: a randomized placebo-controlled study in the United States. Am J 
Gastroenterol 2002;97:1748-1754. 
9. Rubio-Tapia A, Verbeek WHM, van Wanrooij RLJ, et al. Creation of a model to predict survival in 
patients with refractory coeliac disease using multinational registry. Alimentary Pharmacology and 
Therapeutics 2016;44:704-714. 
 
16. Appendices 
I. Study Timeline 
II. Informed Consent Form 
III. Esophagogastroduodenoscopy and Biopsy Guideline 
 
 
 
 


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References: 
1. 
Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and 
related terms. Gut 2013;62:43-52. 
2. 
Choung RS, Unalp-Arida A, Ruhl CE, Brantner TL, Everhart JE, Murray JA. Less Hidden 
Celiac Disease But Increased Gluten Avoidance Without a Diagnosis in the United States: 
Findings From the National Health and Nutrition Examination Surveys From 2009 to 
2014. Mayo Clin Proc 2016. 
3. 
Leffler DA, Dennis M, Hyett B, et al. Etiologies and predictors of diagnosis in 
nonresponsive celiac disease. Clin Gastroenterol Hepatol 2007;5:445e50. 
4.  
Rubio-Tapia A, Murray JA. Classification and management of refractory coeliac disease. 
Gut 2010;59:547-57.  
5.  
Mukewar SS, Sharma A, Rubio-Tapia A, et al. Open-capsule budesonide for refractory 
celiac disease. Am J Gastroenterol 2017; 112:959-67. 
6.  
Greenberg GR, Feagan BG, Martin F, et al. Oral budesonide for active Crohn’s disease. 
Inflammatory Bowel Disease Study Group. N Engl J Med 1994;331:836-841. 
7. 
Campieri M, Ferguson W, Doe T, et al. Oral budesonide is as effective as oral 
prednisolone in active Crohn’s disease. The Global Budesonide Study Group. Gut 
1997;41:209-214. 
8.  
Tremaine WJ, Hanauer SB, Katz S, et al. Budesonide CIR capsules (once or twice daily 
dividided-dose) in active Crohn’s disease: a randomized placebo-controlled study in the 
United States. Am J Gastroenterol 2002;97:1748-1754. 
9. 
Rubio-Tapia A, Verbeek WHM, van Wanrooij RLJ, et al. Creation of a model to predict 
survival in patients with refractory coeliac disease using multinational registry. 
Alimentary Pharmacology and Therapeutics 2016;44:704-714. 
 
 


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Version V, Date:   12/16/2019 
Appendix  I: Study Timeline 
 
Consent 
Visit** 
Pre-
Study 
Day 0 
Days 1-7 
Days 8-14 
Days 15-
83 
Day 28 
+/- 3 
Day 56 
+/- 3 
Day 
84 
Safety 
Withdrawal 
Withdrawal 
Arm 
 
 
 
Budesonide 
3 mg BID  
Budesonide 
3 mg  
0 mg 
 
 
Home 
Dose 
9 mg open 
capsule 
regimen 
Drug Arm 
 
 
 
Home Dose 
Home Dose 
Home 
Dose 
 
 
Home 
Dose 
9 mg open 
capsule 
regimen  
Consent 
X 
 
X** 
 
 
 
 
 
 
 
Physical Exam 
X 
 
X** 
 
 
 
 
 
X 
X 
Weight/Height 
X 
 
X 
 
 
 
X 
X 
X 
X 
Vital Signs  
 
 
X 
 
 
 
 
 
X 
X 
Age 
X 
 
X 
 
 
 
 
 
 
 
Sex 
X 
 
X** 
 
 
 
 
 
 
 
Date of 
Diagnosis 
X 
 
X** 
 
 
 
 
 
 
 
EGD with 
biopsies for 
histology and 
microbiology 
 
 
X* 
 
 
 
 
 
X 
X 
CDSD 
 
Daily 
x7 
days 
X 
Daily 
Daily 
Daily 
 
 
X 
X 
CD-QOL 
 
 
X 
 
 
 
X 
X 
X 
X 
Urine 
Pregnancy Test 
 
 
X 
 
 
 
 
 
X 
 
Sodium 
 
 
X 
 
 
 
X 
X 
X 
X 
Potassium 
 
 
X 
 
 
 
X 
X 
X 
X 
Creatinine 
 
 
X 
 
 
 
X 
X 
X 
X 
CBC with diff 
 
 
X 
 
 
 
X 
X 
X 
X 
TTG-IgA 
 
 
X 
 
 
 
 
 
 
 
Total IgA 
 
 
X 
 
 
 
 
 
 
 
Ferritin 
 
 
X 
 
 
 
 
 
X 
X 
Serum Iron 
 
 
X 
 
 
 
 
 
X 
X 
TIBC 
 
 
X 
 
 
 
 
 
X 
X 
25-OH vitamin 
D 
 
 
X 
 
 
 
 
 
X 
X 
Vitamin B12 
 
 
X 
 
 
 
 
 
X 
X 
Folate, serum 
 
 
X 
 
 
 
 
 
X 
X 
Zinc 
 
 
X 
 
 
 
 
 
X 
X 
Copper 
 
 
X 
 
 
 
 
 
X 
X 
Albumin 
 
 
X 
 
 
 
X 
X 
X 
X 
C Reactive 
Protein 
 
 
X 
 
 
 
X 
X 
X 
X 
Stored Serum 
 
 
X 
 
 
 
 
 
X 
X 
Urine 
Collection-
Storage 
 
 
X 
 
 
 
 
 
X 
X 
Stool gluten (if 
celiac disease) 
 
 
X 
 
 
 
 
 
X 
X 
Urine Gluten (if 
celiac disease) 
 
 
X 
 
 
 
 
 
X 
X 
Stored stool for 
microbiology 
 
 
X 
 
 
 
 
 
X 
X 
(*) If clinical esophagogastroduodenoscopy has been completed within 3 months of randomization 
and slides are available, this will serve as initial biopsy. In this case, no biopsies will be stored for 
microbiology. 
(**) For those patients who cannot travel easily to Rochester, n these cases, certain aspects of the 
screening visit will be obtained at the visit on Day 0, as indicated. 


18 
 
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19 
 
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II. Informed Consent—Attached to IRB application.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


20 
 
Version V, Date:   12/16/2019 
III. Esophagogastroduodenoscopy and Biopsy Guideline 
• 
Subjects will undergo endoscopy at the initiation of the trial and at completion (day 84) or 
after safety withdrawal. 
• 
Initial EGD with biopsy may be omitted if clinical EGD with biopsies were completed within 
3 months of initiation of the trial with histology slides available. Biopsy for microbiology 
will be omitted in this case. 
• 
Moderate conscious sedation will be provided by a licensed Gastroenterologist and 
administered by a nurse. 
• 
Biopsies will be obtained from the duodenum 
o 2 biopsies from the duodenal bulb for histology (2 biopsies per bottle) 
o 4 biopsies from the second portion of the duodenum for histology (2 biopsies per 
bottle) 
o 1 biopsy from the second portion of the duodenum for microbiology will be rapidly 
frozen (not fixed in formalin). 
o 1 biopsy from the second portion of the duodenum will be fixed in RNA later. 
o Tissue obtained for histology will be fixed in formalin and sent to the laboratory for 
sectioning, staining, and interpretation 
o Villous height to crypt depth ratio, Oberhuber-Marsh classification, and 
intraepithelial lymphocyte count will be assessed. 
• 
Endoscopies will occur in the Clinical Research Unit. 
• 
Subjects will be monitored by nursing staff after the procedure until awake and safe for 
dismissal. 
• 
A licensed physician will be available if needed during the recovery period. 
 
 
 
 
 
 
 
 
 
 
 


21 
 
Version V, Date:   12/16/2019 
 
IV: Laboratory Collection, Handling, and Storage 
Urine Studies: 
A urine sample will be collected on days 0 and day 84 (or withdrawal from trial).  This will be tested 
for 33mer gluten immunogenic peptides using the anti-gliadin G12 antibody and lateral flow device 
from GlutenTOX (Bioomedal, Sevilla, Spain).  Once collected, 5 ml will be aliquoted and sent to BAP 
storage at -80 degrees C. This will be requested for gluten exposure testing and the remainder will 
be stored in BAP at -80 degrees C.  
 
Stool Studies: 
Stool will be collected on days 0 and 84 (or withdrawal from trial).  This will be tested for 33mer 
gluten immunogenic peptides by ELISA.  This will be collected in sterile container and 25 ml will be 
aliquoted and sent to BAP for storage at -80 degrees C. This will be requested for 33mer testing and 
the remainder will be stored at BAP at -80 degrees C.  
Stored Serum: 
All labs outlined in the protocol will be drawn and transported to the lab by the CRTU.  Serum for 
storage will be collected.  2 serum gel tubes with silicone coat with clot activator (BD 367986), 5 ml 
each, will be collected, inverted 5 times, stored upright for 2 hours at room temperature. Then 
centrifuged at 2000 g for 20 minutes.  Harvest and freeze within 180 minutes of collection. These 
can be sent to BAP.  This will be available for future cytokine analysis. 
A second tube, either serum gel tube or red top tube, 5 ml, will be collected, centrifuged, aliquoted 
and transported to BAP for storage.