Clinical trial NCT02324699
Conditions: Crohn's Disease
Keywords: Vedolizumab Corticosteroids Prednisone Crohn's disease
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2016-04-01; Completion date: 2018-02-08
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Use of co-induction with corticosteroid therapies may accelerate the remission rate when used with vedolizumab. Further, this may lead to higher rates of response and remission at week 10 than would be seen with vedolizumab monotherapy.

Detailed description:
This study will examine prednisone co-induction with vedolizumab in patients with Crohn's disease. To address questions regarding the effect of co-induction on mucosal healing, the study will include colonoscopic assessment of mucosal healing. Finally, colonic biopsies in this study will allow to elucidate further the mechanism of action of vedolizumab in Crohn's disease through immune phenotyping studies.

Arms: arm 1: Prednisone 40 mg/day starting at week 0 for 2 weeks, tapered by 10 mg weekly to achieve 0 mg by end of week 5 arm 2: Identical placebo taper
Interventions: intervention 1: Prednisone intervention 2: Placebo intervention 3: Vedolizumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: 300mg IV over 30 minutes. Both arms will receive vedolizumab at weeks 0, 2, and 6.

Protocol documents:
Prot_SAP_000.pdf: 
Corticosteroids as Co-Induction Agents With Vedolizumab in Crohn's 
Disease: a Double-blind Placebo Controlled Randomized Trial  
PI: Dr. Bruce Sands
NCT02324699
Document Date: 10-26-2016


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CLINICAL RESEARCH PROTOCOL 
Icahn School of Medicine at Mount Sinai 
 
DATE: October  26, 2016, Amendment 1, version 1.2 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
TITLE: Corticosteroids as co-Induction agents with Vedolizumab In Crohn's disease:  a 
double-blind placebo controlled randomized trial 
 
ABBREVIATED TITLE:  CIVIC 
IDENTIFYING WORDS: Crohn’s disease, vedolizumab, anti- α4β7 integrin 
 
PRINCIPAL INVESTIGATOR:  
Bruce E. Sands, MD, MS 
Professor of Medicine 
Division of Gastroenterology 
Icahn School of Medicine at Mount Sinai 
One Gustave L. Levy Place  
New York, NY 10029 
 
CO-INVESTIGATOR: 
 
Jean-Frederic Colombel, MD, Professor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Saurabh Mehandru, MD, Assistant Professor, Division of Gastroenterology and The 
Immunology Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy 
Place, New York, NY 10029 
 
 
Steven Itzkowitz, MD, Professor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Judy Cho, MD, Senior Faculty, Division of Gastroenterology, Icahn School of Medicine 
at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
James Marion, MD, Senior Faculty, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Elana Maser, MD, Assistant Professor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Thomas Ullman, MD, Associate Professor, Division of Gastroenterology, Icahn School 
of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Asher Kornbluth, MD, Clinical Instructor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 


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Ashish Atreja, MD, Assistant Professor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Pace, New York, NY 10029 
 
Ari Grinspan, MD, Assistant Professor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Benjamin L. Cohen, MD, Assistant Professor, Division of Gastroenterology, Icahn 
School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York 10029 
 
James George, MD, Clinical Instructor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Peter Legnani, MD, Clinical Instructor, Division of Gastroenterology, Icahn School of 
Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Steven Naymagon, MD, Assistant Professor, Division of Gastroenterology, Icahn School 
of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Robert Hirten, MD, Fellow, Division of Gastroenterology, Icahn School of Medicine at 
Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 
 
Shailja Shah, MD, Fellow, Division of Gastroenterology, Icahn School of Medicine at 
Mount Sinai,  One Gustave L. Levy Place, New York, NY 10029 
 
Ryan Ungaro, MD, Assistant Professor, Division of Gastroenterology, Icahn School of 
Medicine, One Gustave L. Levy Place, New York, NY 10029  
 
Seymour Katz, MD, NYU Langone Long Island Clinical Research Associates, 1000 
Northern Boulevard , Suite 160, Great Neck, NY 11021 
 
Simon Lichtiger, MD, Columbia University Medical Center, 622 West 168th Street, New 
York, NY 10032 
 
Chester Maxson, MD, Jupiter Medical Center, 1210 South Old Dixie Highway, Bldg. 
1000, Suite R-4, Jupiter, Florida 33458 
 
David Hudesman, MD, Assistant Professor, NYU Langone Gastroenterology Associates, 
240 East 38th Street, 23rd Floor, New York, NY 10016 
 
 
 
CONSULTANTS: None 
 
 
ESTIMATED DURATION OF STUDY: 2 Years 
NUMBER AND TYPE OF PATIENTS: 123 ambulatory patients with acute, moderate to 
severe Crohn’s disease starting vedolizumab therapy 
 


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SUBJECTS OF STUDY: 
 
Number 
123 patients 
Sex 
 
Male & Female 
 
Age Range 
above 18 years 
 
PROJECT USES IONIZING RADIATION: No 
PROJECT USES “DURABLE POWER OF ATTORNEY”: No 
OFF-SITE PROJECT: Yes 
 
MULTI-INSTITUTIONAL PROJECT: Yes 
 
 


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TABLE OF CONTENTS 
1) INTRODUCTION .................................................................................................................................. 6 
2) BACKGROUND AND RATIONALE ................................................................................................... 6 
3) SPECIFIC AIMS ..................................................................................................................................... 8 
4) OVERALL STUDY DESIGN ................................................................................................................. 8 
4.1) STUDY TIMEFRAME ......................................................................................................................................... 8 
5) STUDY METHODS ............................................................................................................................... 8 
5.1) RECRUITMENT ................................................................................................................................................. 8 
5.2) INFORMED CONSENT ...................................................................................................................................... 9 
5.3) INCLUSION CRITERIA ...................................................................................................................................... 9 
5.4) EXCLUSION CRITERIA .................................................................................................................................. 10 
5.5) PLAN FOR WOMEN AND MINORITIES ....................................................................................................... 10 
5.6) CROHN’S DISEASE MANAGEMENT ............................................................................................................. 10 
5.7) SUBJECT DISCONTINUATION ...................................................................................................................... 11 
6) SAMPLE COLLECTION AND STORAGE ...................................................................................... 11 
6.1) BLOOD SAMPLE COLLECTION..................................................................................................................... 11 
6.2) BLOOD SAMPLE LABELING ......................................................................................................................... 11 
6.3) BLOOD SAMPLE STORAGE ........................................................................................................................... 11 
6.4) BLOOD SAMPLE PREPARATION ................................................................................................................. 12 
6.5) MEASUREMENT OF DISEASE ACTIVITY MARKERS .................................................................................. 12 
6.6) TISSUE SAMPLE COLLECTION..................................................................................................................... 13 
6.7) STOOL SAMPLE COLLECTION ..................................................................................................................... 13 
7) STUDY DRUG / ADDITION AGENT…................................................................................14 
    7.1) PREDNISONE / PLACEBO...............………………………………………………… 14 
    7.2) VEDOLIZUMAB……………………………………………………………………..14 
8) STUDY-RELATED ASSESSMENTS ................................................................................................ 14 
8.1) SCREENING VISIT #1 ................................................................................................................................... 14 
8.2) SCREENING VISIT #2 ................................................................................................................................... 16 
8.3) RANDOMIZATION ......................................................................................................................................... 16 
8.4) WEEK 0: VEDOLIZUMAB DOSE #1 ............................................................................................................ 17 
8.5) WEEK 2: VEDOLIZUMAB DOSE #2 ............................................................................................................ 17 
8.6) WEEK 6:  VEDOLIZUMAB DOSE # 3 ........................................................................................................... 18 
8.7) FINAL STUDY VISIT AT WEEK 10………………………. ………………………………..19 
9)  PLAN FOR DATA COLLECTION & MANAGEMENT……..…………………………..…..20 
10) STATISTICAL CONSIDERATIONS AND SAMPLE SIZE ........................................................ 20 
10.1) SAMPLE SIZE .............................................................................................................................................. 20 
10.2) STUDY ENDPOINTS .................................................................................................................................... 20 
10.3) STATISTICAL ANALYSIS ............................................................................................................................ 21 
11) DATA MONITORING PLAN ......................................................................................................... 21 
12) HAZARDS AND DISCOMFORTS ................................................................................................. 22 
APPENDIX 1. PATIENT ACTIVITY FLOWCHART ........... ERROR! BOOKMARK NOT DEFINED. 
APPENDIX 2. CROHN’S DISEASE ACTIVITY INDEX ...... ERROR! BOOKMARK NOT DEFINED. 
APPENDIX 3. SIMPLIFIED ENDOSCOPIC SCORE FOR CROHN’S DISEASE................... ERROR! 
BOOKMARK NOT DEFINED. 
APPENDIX 4. BUDGET ......................................................................................................................... 29 


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APPENDIX 5. SUBSTUDY OF PHENOTYPING PERIPHERAL BLOOD AND 
GASTROINTESTINAL IMMUNE SUBSETS USING MASS CYTOMETRY (CYTOF)  ................ 30 
 


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1) Introduction 
Crohn’s disease (CD) is a chronic inflammatory disorder of the alimentary tract.  
Treatment with TNFα antagonists has substantially improved the care of patients with 
CD that are refractory to other conventional treatments such as azathioprine, 6-
mercaptopurine, methotrexate, corticosteroids, and mesalamine.  However, a majority of 
patients will still not be in remission at 1 year after initiation of TNF antagonists (1, 2).  
Further, TNF antagonists have a higher risk of several serious infections including 
tuberculosis and may increase the risk of certain malignancies. 
The GEMINI 2 study was a randomized controlled trial that established the 
efficacy and safety of vedolizumab induction and maintenance therapies.  GEMINI-3 
focused on use of vedolizumab in anti-TNFα failures.  Both of these studies showed 
promise of vedolizumab for induction and maintenance of patients with active Crohn’s 
disease (3, 4).  However, the rate of clinical remission at week 6 was only 15.2% in those 
given vedolizumab and 12% in those on placebo (p=0.433)(4).  In both studies, benefits 
became more apparent by week 10. 
 
1.1) Hypothesis:  
Use of co-induction with corticosteroid therapies may accelerate the remission 
rate when used with vedolizumab.  Further, this may lead to higher rates of response and 
remission at week 10 than would be seen with vedolizumab monotherapy. 
 
2) Background and Rationale 
Vedolizumab has been shown to be effective as an inductive agent in Crohn's 
disease.  The rate of clinical remission at week 6 after vedolizumab 300 mg IV at weeks 0 
and 2 is 14.5% vs. 6.8% for placebo in GEMINI 2, a population comprising 50% of 
patients with TNFα antagonist failure (3).  In GEMINI 3, the rate of clinical remission at 
week 6 in the TNFα antagonist failure population was 15.2% compared to 12.1% 
assigned to placebo, while the TNFα antagonist naive subgroup achieved 31.4% clinical 
remission at week 6 with vedolizumab and 12.0% with placebo (4).  By contrast, at week 
10 (after a 3rd induction dose at week 6), 26.6% of TNFα antagonist failure patients and 
35.3% of TNFα antagonist naive patients assigned to vedolizumab achieved clinical 
remission, compared to 12.1% and 16.0% assigned to placebo respectively.  These 
findings suggest that a third inductive dose of vedolizumab and/or additional passage of 


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time are helpful in increasing the inductive efficacy of vedolizumab in Crohn's disease 
patients, and particularly so among TNFα antagonist experienced patients.  Vedolizumab 
has been shown as well to be effective in maintaining remission among patients with 
Crohn's disease who achieve clinical response at week 6.  However, these relatively long 
induction periods and relatively low rates of clinical remission suggest the need to 
explore other inductive therapies as a co-inductive strategy in Crohn's disease.  If 
successful, identifying such a co-inductive therapy might ultimately increase the long 
term success of vedolizumab therapy by enhancing the proportion of patients achieving 
clinical remission and accelerating time to remission. 
 
Corticosteroids have long been used with success as inductive agents in Crohn's 
disease.  No agents yet studied, including anti-TNFα antagonists, demonstrate a faster 
time to response.  One study of prednisone co-induction with infliximab noted higher 
than anticipated rates of remission than had been observed historically with infliximab 
alone (5).  Systematic review and meta-analysis in Crohn's disease demonstrate rates of 
clinical remission with inductive corticosteroids between 43 and 83% (6).  This 
experience suggests that a strategy of corticosteroid co-induction with vedolizumab might 
increase the proportion and rapidity of clinical remission in Crohn's disease.  On the other 
hand, corticosteroids are associated with well-known side effects even with short term 
use.  Furthermore, there is some evidence that corticosteroids may inhibit mucosal 
healing, raising the possibility that with corticosteroid co-induction, short term clinical 
remission might be achieved at the expense of mucosal healing and longer term disease 
outcomes (7, 8).  Finally, much has yet to be learned about the mechanism of action of 
vedolizumab in Crohn's disease in order to account for the apparently longer time to 
achieve clinical remission than in UC, and the effects on mucosal immunity. 
 
To address these concerns, we propose to study a strategy of prednisone co-
induction with vedolizumab in patients with Crohn's disease.  To address questions 
regarding the effect of co-induction on mucosal healing, we propose to include 
colonoscopic assessment of mucosal healing in this study.  Finally, the opportunity to 
obtain colonic biopsies in this study will allow us to elucidate further the mechanism of 
action of vedolizumab in Crohn's disease. 
 


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3) Specific Aims 
1. To determine whether a prednisone taper, when added as co-inductive therapy, 
increases the proportion of patients with Crohn's disease who achieve clinical remission 
at week 6 after induction therapy with vedolizumab 300 mg IV at weeks 0 and 2, as 
compared to placebo co-induction. 
 
2. To determine if the rate of endoscopic response, defined as decrease from baseline 
SES-CD by 50%, at week 10 is higher with prednisone vs. placebo co-induction in 
conjunction with vedolizumb given at weeks 0, 2 and 6. 
 
3. To describe the mucosal and peripheral immunophenotypic changes with vedolizumab 
therapy in Crohn's disease both with and without prednisone co-induction. 
 
4) Overall Study Design 
This is a prospective, blinded, interventional, placebo-controlled study designed 
to define the impact of co-intervention with prednisone when offering induction therapy 
with vedolizumab in Crohn’s disease.  The interventional component of the study will 
assess remission rates at weeks 6 and 10 of patients who receive a combination of 
prednisone and vedolizumab compared to those who receive vedolizumab monotherapy.  
 
4.1) Study timeframe 
123 patients with moderate to severe Crohn’s disease will be enrolled, with study 
activities expected to last 18 months.  
 
5) Study Methods 
5.1) Recruitment 
Patients will be recruited through the outpatient clinics and personal clinics of the 
study investigators.  Recruitment will also be achieved through the gastroenterology 
practices  affiliated with each recruiting institution.  The faculty or gastroenterology 
fellows at the participating institutions will identify eligible patients from the ambulatory 
or inpatient setting.  Patients identified in the IBD ambulatory clinics with moderate to 
severe Crohn’s disease and needing treatment with vedolizumab will be screened for 
eligibility during the ambulatory visit.  The gastroenterology fellow  involved in the study at 


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each site will send weekly email reminders to the gastroenterologists to encourage recruitment.  
Additionally, recruitment for the study will be achieved through the circulation of 
pamphlets and a dedicated website.  Consecutive ambulatory patients with moderate to 
severe Crohn’s disease meeting inclusion/exclusion criteria will be enrolled after written 
informed consent is obtained.   
 
5.2) Informed Consent 
We will follow Mount Sinai’s “SOP HRP-090 Informed Consent Process for 
Research” and “SOP HRP-091 Written Documentation of Consent.”  Potential 
participants will be presented with the opportunity to participate in the study.  Those 
interested in participating will be introduced to the study procedures and will be given the 
opportunity to have their questions answered.  Potential participants will also be 
counseled about who may have access to their medical and other personal information so 
as to remain in compliance with HIPAA standards.  Patients agreeing to participate will 
provide written consent during the screening ambulatory visit.  The consent process will 
be executed by one of the investigators or one of the trained research staff.  No research 
data or labs will be collected prior to obtaining written informed consent.  The signed 
original consent form will be retained in the research files in the research office, in a 
locked file cabinet in a locked office.  A copy of the signed consent form will be provided 
to the subject.  Non-English speaking patients will be excluded from the study. 
 
5.3) Inclusion Criteria 
1. Age at entry 18 to 70 
2. CDAI score ≥220 and ≤ 450 
3. Concomitant azathioprine, methotrexate, or mercaptopurine permitted if dose has 
been stable for > 8 weeks.  Prior anti-TNFα antibody use permitted but must be 
discontinued (>2 weeks from last dose) prior to initiation of vedolizumab.  
Concomitant oral antibiotics for Crohn’s disease therapy are permitted if dose has 
been stable for ≥ 2 weeks.  Concomitant rectal therapies (suppositories or enemas) 
are permitted if dose has been stable ≥ 2 weeks.  Prior use of cyclosporine and 
natalizumab is permitted if last use is at least 3 months prior to the initiation of 
vedolizumab.   
4. Screening colonoscopy SES-CD score ≥ 7 or ≥ 4 if isolated ileal disease. 


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5. Able to provide written informed consent. 
 
5.4) Exclusion Criteria 
1. Concurrent use of anti-TNFα antibodies. 
2. Corticosteroids within prior 3 months (other than budesonide controlled ileal release 
and budesonide extended release tablets) 
3. Stoma at the time of enrollment 
4. Absolute contraindication to systemic corticosteroid use such as hypersensitivity to 
any part of the formulation, systemic fungal infection, or recent administration of 
live or live attenuated vaccine within prior two weeks. 
5. Pregnant women or plans for pregnancy within 3 months of study inclusion 
6. Presence of stoma, more than three small-bowel resections, or documented history of 
short bowel syndrome 
7. Intestinal stricture requiring surgery 
8. Abdominal abscess 
9. Inability or unwillingness to provide informed consent 
10. Any other condition, which, in the opinion of the investigators would impede 
competence or compliance or possibly hinder completion of the study 
 
5.5) Plan for Women and Minorities 
All consecutive subjects at a site consenting to the study, including women and 
minorities, will be enrolled. Subjects will not be excluded because of gender or race. 
 
5.6) Crohn’s disease Management 
This is an interventional study of co-administration of corticosteroids with 
vedolizumab.  Management of Crohn’s disease outside the scope of this will be at the 
discretion of the treating gastroenterologist based on their clinical judgment.  Examples 
of management at the discretion of the treating physicians include continuing concurrent 
use of other IBD medications (i.e. 5-ASA drugs or immunomodulators). 
 


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5.7) Subject Discontinuation 
Subjects may withdraw their consent at any time during the study by informing 
one of the investigators or the study coordinator of the decision.  Subjects who withdraw 
consent will not undergo any further study procedures. 
The sponsor may terminate the study at any time for any reason, including but not 
limited to unsatisfactory accrual or data collection. 
 
6) Sample Collection and Storage 
6.1) Blood Sample Collection 
Regardless of whether blood is drawn from an intravenous line or by separate 
venipuncture, standard sterile methods will be utilized.  The following sample types will 
be collected during the study: 
- 
Serum (SST vials): Immune phenotyping markers, C-reactive protein (CRP), 
comprehensive metabolic panel, and albumin will also be collected in SST 
vials at specified time points. 
- 
Whole blood (EDTA Spray-dried vials):  Complete blood count with 
differential and immune phenotyping markers will be collected at specified 
time points. 
Blood samples will be collected using a 21 gauge butterfly needle to avoid backflow as 
the collection vials contain chemical additives.  Blood samples will be drawn in the 
following order: 1) SST collection vial(s); 2) EDTA spray-dried collection vial(s); 3) 
EDTA collection vial(s).  
  
 
6.2) Blood Sample Labeling 
Specimens will be labeled with the donor’s study number and the date that the 
specimen was collected. 
 
6.3) Blood Sample Storage 
All blood and tissue specimens may be stored for up to two years for analyses.   
Blood samples will be stored under appropriate conditions in the  locked laboratory of 
Dr. Saurabh Mehandru at the Icahn School of Medicine at Mount Sinai. 
 


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6.4) Blood Sample Preparation 
The vials will be processed as follows: 
- 
SST collection vials: The vials will be spun in a fixed angle or swing bucket 
type centrifuge, inverted 5X, allowed to stand for 30 minutes (to allow for 
clotting), and then centrifuged for 15 minutes at 1100-1300 x g.  
- 
At baseline and specified time points for assessment of disease activity 5.0 
mL whole blood (EDTA) will be collected. 
- 
At baseline, blood (5X10 ml EDTA and 1X10ml SST tubes). Briefly, PBMC 
will be isolated per density gradient. 5X10^6 PBMC will be used per 
condition (baseline, cultured and stimulated, cultured and unstimulated) for 
CYTOF analyses (described separately). SST tubes (1X10ml) will be 
processed as above for serum collection for assessment of serum cytokines 
and soluble markers of inflammation. 
 
6.5) Measurement of Disease Activity Markers 
Serum (1.0 mL) and whole blood (5.0 mL) will be collected at specified time 
intervals for CRP, CBC with differential or metabolic panel as specified in section 7.1. 
Additional blood (62.5 mL) will be collected at the beginning of treatment and during 
specified time points detailed in the protocol schedule of events (appendix 1) to evaluate 
the phenotype and function of innate and adaptive immune cells.   
Immunophenotypic analyses 
Immunophenotyping of the peripheral blood and GI tissue will be performed on 
60 patients (30 patients on Vedolizumab induction and 30 patients on Vedolizumab plus 
prednisone induction) due to feasibility issues.  Please see accompanying document 
“Phenotyping peripheral blood and gastrointestinal immune subsets using mass 
cytometry (CyTOF)” for details.  The following markers will be assessed: 
a) Phenotypic markers: CD19 (B cells), CD4 and CD8 subsets of T cells, CD16 
(monocytes, NK cells), CD56 (NK cells) CD66 (neutrophils, basophils), CD14 
(monocytes, neutrophils, dendritic cells), BDCA1 (CD1a dendritic cells), CD123 
(plasmacytoid dendritic cells, basophils), BDCA3 (CD141 cross presenting 
dendritic cells) 


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b) Immunological memory markers: CD45 (hematopoietic cells), CD45 RA 
(naïve vs. memory), CD27 and CCR7 (central memory vs. effector memory vs. 
transitional memory) 
c) Cellular activation markers: HLA-DR, CD38 
d) Cytokine production: TNF-a, IFN-g, IL-6, IL-17A, IL-10 
 
Measurement of cytokines will be performed in PMA/ionomycin stimulated cells. 
 
6.6) Tissue Sample Collection 
Colon biopsy specimens will be collected using jumbo biopsy forceps. A total of 
16 colonic biopsies will be collected: eight from the inflamed and eight from uninflamed 
areas. From each set of 8 eight biopsies, 1 each will be sent for histopathology and the 
remainder will be used for analyses of immunophenotypic changes as described below. 
The biopsies will be collected at baseline (screening visit 2) and at week 10. If at week 10 
colonic inflammation is not noted, a total of 16 biopsies will be obtained from the 
previously inflamed area. For analyses by H&E, the biopsies will be obtained in formalin 
and processed by the Department of Pathology at each institution. For immunological 
analyses, all biopsies will be processed in the laboratory of Dr. Saurabh Mehandru at the 
Icahn school of Medicine at Mount Sinai. Briefly, collagenase type IV will be used to 
digest the biopsies using gentle agitation at 1000 rpm for one hour. After extensive 
washing and filtration, mucosal mononuclear cells (MMC) will be obtained as per 
established protocols (9).  Using metal conjugated antibodies, phenotypic and functional 
markers will be examined on the MMC (see additional details re CYTOF).  
 
6.7) Stool Sample Collection 
Stool specimens for calprotectin must be collected in sterile containers.  
Specimens will be collected at baseline, at week 6 and at week 10.  A minimum of 1 
gram of stool is required.  Samples will be labeled with the donor’s study number and 
stored in a -70 freezer in Dr. Saurabh Mehandru’s laboratory at Ichan School of Medicine 
at Mount Sinai. 
 
 
 


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7) Study drug / Additonal agent 
The study drugs/substances used in this study include Prednisone/placebo.  Vedolizumab 
will be given on a standard of care basis as an additional agent. 
 
7.1  Prednisone / Placebo 
 
The research pharmacy at The Icahn School of Medicne at Mount Sinai will 
prepare and dispense 5 weeks supply (98 capsules) of the study drug.   The subject will 
receive all the study medication (prednisone/placebo) in one batch.   
 
Prednisone/Placebo is prepared and dispensed according to the dosing schedule: 
o Week 0: 40 mg daily 
o Week 1: 40 mg daily 
o Week 2: 30 mg daily 
o Week 3: 20 mg daily 
o Week 4: 10 mg daily 
 
 
7.2 Vedolizumab (Additional Agent):  
 
All subjects enrolled in the study will receive Vedolizumab.  Vedolizumab will be 
administered as standard of care at an infusion center agreed upon by the 
Gastroenterologist and the subject.  Subjects will be administered 300mg IV 
Vedolizumab over 30 minutes using standard infusion procedures at Week 0, Week 2 and 
Week 6. 
 
 
Prednisone/Placebo and Vedolizumab must be started on the same day at Week 0. 
 
8) Study-Related Assessments 
Study activities are summarized in appendix 1.  Screening visits 1 and 2, and the 
week 0 assessment will be conducted by one of the investigators or the study coordinator. 
 
8.1) Screening Visit #1 
Screening of all patients with moderate to severe Crohn’s disease will occur in the 
ambulatory clinic.  If a patient is felt suitable for inclusion, during the screening visit the 
following activities will occur: 
1) Obtain informed consent 
 
2) Review inclusion/exclusion criteria 
 


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3) Confirm Crohn’s disease diagnosis 
 
4)  Demographic information collected: 
a. Age/Date of Birth 
b. Gender 
c. Race 
d. Ethnicity 
e. Smoking History 
 
5) Full disease history: 
f. Year of diagnosis 
g. Duration of disease 
h. Prior Crohn’s related surgery 
i. Location of Crohn’s disease 
j. Duration of current flare 
k. Number of draining fistulas, if applicable 
l. Presence of active extra-intestinal manifestations 
 
6) Record past and present use of Crohn’s disease related medications.  The 
following information will be collected for each medication 
 
m. Name 
n. Dose 
o. Route 
p. Frequency 
q. Start date 
r. Stop date 
s. Reason for stopping (i.e. loss of response, intolerance, patient 
preference, etc) 
 
7) Administer and collect disease-related activity indices (See appendix 2) 
a. Current CDAI score (appendix 2) 
 
8) Abstract laboratory data (performed as standard of care) and blood draw 
a. Standard of Care Labs 
i. CBC with diff 
ii. Comprehensive metabolic panel including electrolytes, 
albumin, renal function, and hepatic function 
 
9) Subjects will be provided a kit for collection of stool for measurement of fecal 
calprotectin.  This specimen will be collected at screening visit number 2. 
 
10) Subjects will be given preparation instructions for baseline screening 
colonoscopy to be completed at screening visit number 2. 
 


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11) Subjects will be asked to sign a medical release that will allow us to request 
medical records from on-site and off-site medical providers if necessary.  
Subjects will provide the name(s) and contact information for each physician 
involved in treating his/her Crohn’s disease. 
 
8.2) Screening Visit #2 
The second screening visit will occur at time of the baseline colonoscopy.  
Patients will arrive after taking a preparation for colonoscopy.  During this visit the 
following activities will occur: 
 
1) Collection of fecal calprotectin sample 
2) Abstract laboratory data (performed as standard of care) and blood draw for 
immune phenotyping 
 
a. Research Labs 
 
i. Blood 
1. CRP 
2. Immune subsets and cytokine levels 
 
3) Perform baseline colonoscopy to assess disease severity and distribution 
(performed as standard of care).  The SES-CD tool (appendix 3) will be used 
to quantify and compare inflammatory load.  Biopsies may be taken for 
histopathology as well as for immune phenotyping as mentioned in section 
6.6. 
 
4)   Video recordings of the colonoscopy will be performed to allow for scoring  
the amount of inflammation seen during the procedure.  The video will only be  
from the inside of the colon and not contain any images that would personally  
identify any subject. Additionally, to protect subject’s confidentiality, any unique 
identifierssuch as subject’s name will be removed from the recording. Finally, the 
recording will be stored in an electronic hard drive, under lock and key.   
 
Subject will be given a kit for collection of fecal calprotectin the day prior to the week 6 
visit.  They will be sent a reminder email two days prior to the week 6 visit. 
 
 
 
8.3) Randomization  
1. Randomization into the study will be done through the Research Pharmacy at the 
Icahn School of Medicine at Mount Sinai.  Once a patient is deemed eligible for 
randomization in the study, a Mount Sinai medical record number will be requested 
and assigned to the patient to facilitate drug preparation and dispensation from the 


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pharmacy at the Icahn School of medicine at Mount Sinai.  Patients will be 
randomized in a blinded fashion, 1:1 to one of two groups, in a method that stratifies 
for: 
a) Prior anti-TNFα use 
      b) Concomitant immune modulator use 
 
Group A:  Prednisone 40 mg/day starting at week 0 for 2 weeks, tapered by 10 mg 
weekly to achieve 0 mg by end of week 5 
 
 
Group B:  Identical placebo taper (40 mg/day starting at week 0 for 2 weeks, tapered by 
10 mg weekly to achieve 0 mg by end of week 5 
 
 
Upon randomization, patients will be dispensed all study pills for the arm they are 
randomized to during this study visit. 
 
 
8.4) Week 0: Vedolizumab Dose #1 
The week 0 visit should occur within one week after the screening colonoscopy confirms 
eligibility.  The week 0 activities will be conducted by study personnel or one of the 
study investigators. 
A) Prior to administration of vedolizumab, the following activities will occur: 
1) History and physical examination to assess for signs of active, untreated infection 
 
B) Following the pre-infusion activities, the patient will be administered 300mg IV 
vedolizumab over 30 minutes using standard infusion procedures at Mount Sinai. 
 
 
8.5) Week 2: Vedolizumab Dose #2 
The week 2 visit should occur two weeks after receipt of initial vedolizumab dose.  
The week 2 activities will be conducted by study personnel or one of the study 
investigators. 
A) Prior to administration of vedolizumab, the following activities will occur: 
1) History and physical examination to assess for signs of active, untreated infection 
 
B) Following the pre-infusion activities, the patient will be administered 300mg IV 
vedolizumab over 30 minutes using standard infusion procedures at Mount Sinai 
 


HSM#14-01076/GCO#14-2209   
 
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8.6) Week 6: Vedolizumab Dose #3 
The week 6 visit should occur four weeks after the week 2 visit.  The week 6 
activities will be conducted by study personnel or one of the study investigators. 
A) Prior to administration of vedolizumab, the following activities will occur: 
1) History and physical examination to assess for signs of active, untreated infection.  
Other screening questions will be asked to screen for side effects related to 
prednisone use. 
2) Administer and collect disease-related activity indices  
a. Current CDAI score (appendix 2) 
3) Abstract laboratory data (performed as standard of care) and blood draw for 
immune phenotyping 
 
a. Standard of Care Labs 
i. CBC with diff 
 
b. Research Labs 
 
i. Blood 
1. CRP 
2. Immune subsets and cytokine levels 
 
ii. Stool 
1. Fecal calprotectin (patient will have brought sample 
performed the day previously) 
 
 
B) Following the pre-infusion activities, the patient will be administered 300mg IV 
vedolizumab over 30 minutes using standard infusion procedures at Mount Sinai 
 
C)  Patient will be given a kit for collection of fecal calprotectin the day prior to the week 
10 visit.  They will be sent a reminder email two days prior to the week 10 visit.  
 
D)  Patient will also be given instructions for their colonoscopy to be performed at week 
10. 
 
 
 
8.7) Final study visit at week 10 
The week 10 visit should occur four weeks after the week 6 visit.  The week 10 
activities will be conducted by study personnel or one of the study investigators. 
A) Prior to colonoscopy, the following activities will occur: 


HSM#14-01076/GCO#14-2209   
 
19 
1) History and physical examination to assess for signs of active, untreated infection.  
Other screening questions will be asked to screen for side effects related to 
prednisone use. 
2) Administer and collect disease-related activity indices  
a. Current CDAI score (appendix 2) 
3) Abstract laboratory data (performed as standard of care) and blood draw for 
immune phenotyping 
 
a. Standard of Care Labs 
i. CBC with diff 
 
b. Research Labs 
 
i. Blood 
1. CRP 
2. Immune subsets and cytokine levels 
 
ii. Stool 
1. Fecal calprotectin (patient will have brought sample 
performed the day previously) 
 
B) Perform week 10 colonoscopy to assess disease severity and distribution.  The SES-
CD tool (appendix 3) will be used to quantify and compare inflammatory load with 
baseline colonoscopy.  Biopsies may be taken for histopathology as well as for immune 
phenotyping as mentioned in section 6.6. 
 
C) Video recordings of the colonoscopy will be performed to allow for scoring the 
amount of inflammation seen during the procedure.  The video will only be from the 
inside of your colon and not contain any images that would personally identify you. 
Additionally, to protect your confidentiality, any unique identifiers such as your name 
will be removed from the recording. Finally, the recording will be stored in an electronic 
hard drive, under lock and key. 
 
D) Patient will be provided stipend at this visit to reimburse them for all their study visits.  
This includes $50 for the week 0, 2, and 6 visits.  This also includes $200 for the 
screening visit #2 and week 10 visits.  Payments will only be provided for study visits 
that were completed. 
 
9) Plan for Data Collection and Management 


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The collection and management of the data from all sites will be through an 
online computer website and database at the Icahn School of Medicine at Mount Sinai.    
Hard copies of data collection forms will be completed at each participating institution 
and submitted to the Icahn School of Medicine to be entered in the electronic database.  
Data collection forms will not contain patient names, medical record numbers, or any 
other identifiable information.  Data collection forms will contain an assigned study 
number. Copies of all consent forms and data collection forms will also be kept at the 
individual sites in locked cabinets for secure back-up.  
 
 
10) Statistical Considerations and Sample Size 
10.1) Sample Size 
The primary outcome is clinical remission defined as a CDAI < 150 at week 6.  
Using a conservative estimate of 45% in group A and 19% in group B, 56 patients are 
needed per group for 80% power at a 2-sided alpha of 0.05.  Factoring in an additional 
10% to account for possible dropout, the total number of targeted enrollment is 123 
patients. 
 
Approximately 7000 patients per year are seen at Mount Sinai Hospital for 
Crohn’s disease or ulcerative colitis, many of whom have active symptoms requiring 
change in management.  With a targeting enrollment of 123 patients, we estimate roughly 
10 patients will be enrolled per month, which would allow for completion by 14 months.  
 
10.2) Study Endpoints 
Primary Endpoint: 
1) Week 6 clinical remission, defined as CDAI < 150, in group A vs. group B 
 
Secondary Endpoints: 
1) Week 10 clinical remission (CDAI < 150) in each group 
2) Week 6 clinical response (decrease in CDAI > 100 from baseline) in each group 
3) Week 10 clinical response (decrease in CDAI > 100 from baseline) in each group 
4) Comparison of the proportion of patients in each group achieving week 10 SES-
CD decrease of > 50% from baseline 
5) Comparison of absolute change from baseline in SES-CD in each group at week 
10 
6) Comparison of absolute change from baseline in CDAI in each group at week 6 
7) Comparison of absolute change from baseline in CDAI in each group at week 10 
8) Adverse events in each group at week 6 
9) Adverse events in each group at week 10 
10) Comparison of absolute change from baseline CRP in each group at week 6 


HSM#14-01076/GCO#14-2209   
 
21 
11) Comparison of absolute change from baseline CRP in each group at week 10 
12) Comparison of absolute change from baseline calprotectin in each group at week 
6 
13) Comparison of absolute change from baseline calprotectin in each group at week 
10 
14) Descriptive analysis related to mechanism of action using peripheral blood and 
intestinal mucosal tissue 
 
10.3) Statistical Analysis 
 
Predictors of the endpoints listed above will be explored.  Potential predictors to 
be assessed include: 
 
1) Age 
2) Gender 
3) Ethnicity 
4) Current smoker (yes/no) 
5) Past smoker (yes/no) 
6) Duration of disease 
7) Duration of current flare 
8) Extent of disease (ileal only, ileocolonic, upper GI tract, colon only) 
9) Concomitant meds 
a. Immunomodulator (yes/no) 
b. 5-ASA (yes/no) 
c. Prior anti-TNFα use (yes/no) 
10) Baseline CDAI score 
11) Baseline CRP 
12) Baseline fecal calprotectin 
13) Research disease activity markers 
 
 
11) Data Monitoring Plan 
Study data will be collected at each site and submitted to the coordinating site 
(ISMMS).  The Investigators and research coordinators of this protocol at each site will 
monitor data and safety regularly at weekly meetings. These meetings are separate from 
regular clinical rounds and consist of review of all study patients including flow sheets of 
major safety and efficacy measurements.   
From a central stand point, bi-monthly conference calls between participating 
sites will take place to monitor the study data.  The principal Investigator will lead the 
conference calls and at least one member of each site team will be present for the call.  
Safety data/Serious adverse events will be submitted to Mount Sinai as they occur.  
Accumulated data and safety information will be evaluated by the Principal monitor and 
the additional monitor at Mount Sinai on a weekly, as outlined in the Protocol Template. 


HSM#14-01076/GCO#14-2209   
 
22 
There is not a DSMB established for this study.  The rationale for not using an 
outside data and safety monitoring committee is that the drug being used is FDA 
approved medication that have been associated with few severe side effects.  All 
measurements and tests are well established in clinical medicine.  All serious adverse 
events will be reported to the Mount Sinai IRB within 2 days. 
 
12) Hazards and Discomforts 
The risks and discomforts of frequent phlebotomy:   
To document changes in levels of biochemical markers of inflammation and to 
monitor the metabolic effects of vedolizumab, frequent blood sampling will be required. 
Patients will have a maximum of 5 venipunctures during the period of evaluation, therapy 
and follow up. Each venipuncture will remove 15 to 50 ml of blood. Blood collection by 
venipuncture is associated with mild discomfort, and the possibility of localized bruising, 
phlebitis, or extravasation. The risk of infection or fainting is extremely small. 
 
The risks and discomfort of colonoscopy: 
A colonoscopy will be performed before commencement of vedolizumab and 
after 10 weeks of treatment.  Preparation for the procedure will involve taking a standard 
preparation for colonoscopy at the discretion of the treating gastroenterologist.  
Commonly used preparation at Mount Sinai Hospital is Polyethylene glycol 3350 – 238 
grams mixed with a clear fluid such as water or Gatorade.  There is a slight risk of 
dehydration with taking colonoscopy preparation.  The procedure itself lasts between 5 
and 20 minutes.  During the procedure the patient may feel pressure and slight cramping 
in the lower abdomen.  Colonoscopy is a safe procedure, but does carry small risks of 
perforation, bleeding, infection, and adverse reaction to conscious sedation if used.  The 
risk of perforation in colonoscopy is approximately 1 in 1400 (10). 
 
Potential Loss of Confidentiality:  
Every effort will be made to protect privacy and confidentiality.  Patient-related 
information (i.e. informed consent, medical records) will be kept in a locked filing 
cabinet in the PI or study coordinator’s office or on a password protected computer.  No 
information related to this research testing will be entered into a computer database that 
identifies the patient by name or any other identifying information.  To minimize the risk 


HSM#14-01076/GCO#14-2209   
 
23 
of misuse of these data, only personnel authorized by the Principal Investigator will have 
direct access to the study database. 
Similarly, only personnel authorized by the Principal Investigator will have direct 
access to the blood storage facilities and samples.  As noted previously, the blood 
samples will not contain the direct identifiers, but will be labeled with a study number 
and date of blood draw. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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