Safety and Tolerability Of Allogeneic Mesenchymal Stromal Cells in Pediatric Inflammatory Bowel Disease
Phase: PHASE1
Conditions: Inflammatory Bowel Diseases
Sponsor: Catherine Bollard

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Safety and Tolerability Of Allogeneic Mesenchymal Stromal Cells in 
Pediatric and Adult Inflammatory Bowel Disease (STOMP) 
 
 
 
SPONSOR 
Catherine Bollard, MD, MBChB 
 
 
PRINCIPAL INVESTIGATOR 
Laurie S. Conklin, MD 
 
 
CO-INVESTIGATORS 
Fahmida Hoq, MBBS, MS 
Sona Sehgal, MD 
Teena Sebastian, MD 
Patrick Hanley, PhD 
 
STATISTICIANS: 
Yunfei Wang, PhD 
 
CENTER 
Children’s National Medical Center 
Center for Cancer and Blood Disorders 
111 Michigan Avenue, NW 
Washington, DC 20010 
(202) 476-5000 
 
 
 
 

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 Emergency Contact Information  
 
Role in Study 
Name 
Email and Telephone Number 
Sponsor 
Catherine Bollard, M.D., 
FRACP, FRCPA 
cbollard@cnmc.org/ 202-476-4776 
Principal Investigator 
Laurie S. Conklin, MD  
 
LConklin@childrensnational.org/ 
(202) 476-3032 
Co-investigators 
Patrick Hanley PhD 
 
 
Fahmida Hoq, MBBS, MS 
 
Sona Sehgal, MD 
 
Teena Sebastian, MD 
PHanley@childrensnational.org/202-
476-6368 
 
fhoq@childrensnational.org/202-476-
3634 
ssehgal@childrensnational.org/202-
476-3032 
tsebasti@childrensnational.org/202-
476-3032 
 
Institutional Review 
Board 
CNMC Institutional Review 
Board 
801 Roeder Road 
Suite 801  
Silver Spring, Maryland, 20910/301-
565-8452 
Study Coordinator 
Nana Ama Afari-Dwamena 
nafaridwam@childrensnational.org 

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Name of Sponsor/Company: 
Catherine Bollard, M.D., FRACP, FRCPA 
 
Title of Study: 
 
Safety and Tolerability of Allogeneic Mesenchymal Stromal Cells in Pediatric and 
Adult Inflammatory Bowel Disease (STOMP trial) 
Study Center(s):  Children’s National Medical Center (CNMC) 
 
Principal Investigator:    Laurie S. Conklin, MD  
 
Co-investigators: Patrick Hanley PhD, Fahmida Hoq, MBBS, MS, Sona Sehgal, MD, 
Teena Sebastian, MD 
 
Objectives:  
 
Primary Objective:  
 
This is a pilot phase 1 study of Mesenchymal Stromal Cells (MSCs) for treatment of 
children and young adult patients with refractory Crohn’s Disease (CD) or ulcerative 
colitis (UC). The primary aim is to evaluate safety and tolerability of the intervention.  
 
Secondary Objectives:  
 
1. Examine the effects of 4 weekly infusions of MSCs on clinical indices, and endoscopic 
scores when available.  
 
2. Examine inflammatory and immunologic effects of MSC infusions on peripheral and 
intestinal mucosal biomarkers including, but not limited to, serum C-reactive protein, fecal 
calprotectin, anti-HLA antibodies, and viral specific T-cell activity before and after 
treatment. 
 
 
 
Study Design:   
 
This study is a pilot phase 1 study of patients with moderately to severely active Crohn 
Disease (CD) and ulcerative colitis (UC) (≥ 18 years, Mayo score: ≥6 or CDAI: ˃ 220; <18 
years, Pediatric Crohn’s Disease Activity Index (PCDAI) :> 30) or Pediatric Ulcerative 
Colitis Activity Index (PUCAI) : >34). [1] [2]   A fixed dose will be studied:  1 x 106 cells/kg 
administered intravenously (IV) weekly for 4 consecutive weeks, with the option of an 
additional 4 weeks of treatment, at the discretion of the principal investigator. The primary 
outcomes are regimen-related toxicity, defined in section 5. Toxicity will be scored as a 
binary variable indicating occurrence or non-occurrence over a monitoring interval from 
the start of MSC therapy to 45 days after the last infusion. Based on the planned 
administration schedule of 4 weeks, the total toxicity monitoring period will have duration 
28 +45 = 73 days. If additional weekly doses are administered, the safety assessment 
phase will be 45 days after the last dose given.  

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Three young adult patients (ages 17≤22 years) will be enrolled, staggered by at least 7 
days, and monitored for toxicity over a period of 73 days.  Infusions are administered 
over the first 28 days, followed by a 45 day monitoring period. If we observe no severe 
(grade 3 or worse) adverse events in the young adult cohort, we will wait a minimum of 
45 days after the last MSC administration before beginning to enroll 3 more patients, 
ages 12≤16 (pediatric cohort).  If we observe a severe (grade 3 or worse) adverse event 
occurring at any time from the start of therapy to 45 days following the last MSC 
administration in the young adult cohort we will stop the study. If we observe no severe 
adverse events attributable to MSCs in the young adult cohort but a severe (grade 3 or 
worse) adverse event occurring at any time from the start of therapy to 45 days following 
the last MSC administration in the pediatric cohort we will stop the study.  A maximum of 
6 patients will be enrolled. Assuming an accrual rate of 3-4 patients per year, it is 
anticipated that it will require at least 18-24 months to accrue all 6 patients.  
Eligibility 
This protocol allows for the treatment of both male and female pediatric and young adult 
patients, between the ages of 12 ≤ 22 years, with active moderate to severe CD or UC, 
who have failed to respond to, or are intolerant of, biologic therapy.  
 
Inclusion  criteria 
 
• 
For the young adult cohort, patients must be ages 17 ≤22 years 
• 
For the pediatric cohort, patients must be ages 12 ≤16 years 
• 
Patients must have moderate-severely active CD or UC (defined in section 2.3), 
and documented active disease on flexible sigmoidoscopy, colonoscopy or MR 
enterography within the preceding 2 months. 
• 
Patients who have failed or are intolerant of biologic therapy.  Specifically, the 
patient will have recurrence or persistence of active disease despite current or 
past treatment with a biologic.  At the time of enrollment, study subjects may be 
currently receiving 5-aminosalicylates, corticosteroids (≤ 20 mg daily or up to 0.5 
mg/kg/day if weight <40 kg), methotrexate, 6MP/azathioprine, or a biologic (either 
as monotherapy or in combination). During the treatment phase, if the treating 
physician thinks that a medication dose should be lowered to avoid side effects, 
this should be recorded. 
• 
Patient or parent/guardian capable of providing informed consent. 
 
Exclusion criteria  
• 
Patients  < 12 years of age or >22 years of age 
• 
Pregnant or breastfeeding. Serum pregnancy test must be negative at screening 
for female subjects of childbearing potential. Urine pregnancy test must remain 
negative at each of 4 infusion visits.  
• 
Patients with toxic mega-colon or intestinal perforation 
• 
Evidence of autoimmune chronic active hepatitis or sclerosing cholangitis. 
• 
Patients with fever > 39° C or clinically significant active infection within 1 week 
(i.e. chronic infections including Hepatitis B/C or HIV or acute infections, including 
urinary tract infection and respiratory tract infection)  
• 
Received an agent not approved by the FDA for marketed use in any indication or 
any small molecule inhibitors (i.e. naltrexone) within 60 days of enrollment.   
• 
Subjects who are taking greater than 20 mg (or if body weight <40 kg, 0.5 mg/kg) 
of prednisone daily.  

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• 
Clinically significant abnormal biochemical and hematological parameters, 
including: 
o Neutrophil count < 1000 cells/mm3 
o Hemoglobin < 8 g/dl 
o Platelet count ≤ 130 cells/mm3 
o Creatinine ≥ 1.2 x the upper limit of normal  
o Alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) ≥ 2x the upper limit of normal 
o Conjugated bilirubin greater than 1.2. mg/dL 
• 
Has active infection with enteric pathogens as evidenced by positive 
microbiological culture of stool or C.difficile toxin PCR.  
• 
Had bowel surgery other than perianal procedures (fistulotomy, seton placement, 
abscess drainage) within 3 months of enrollment. 
• 
Has uveitis 
• 
Has known pulmonary disease, excluding mild intermittent asthma 
 
Primary Endpoints 
 
• 
Safety and tolerability of the intravenous administration of human allogeneic bone 
marrow-derived MSCs to children and young adults with IBD, measured by the 
frequency of any SAEs, AEs and/or early treatment discontinuations.  
 
Secondary Endpoints 
• 
Magnitude of decrease in clinical index (for young adults we will use the CDAI and 
Mayo, and for children the PCDAI and PUCAI) relative to baseline, reporting the 
average decline and 95% confidence limit.  
• 
Changes in biomarkers of inflammation and immunogenicity (i.e. C-reactive protein, 
fecal calprotectin, anti-HLA antibodies, viral-specific T cell activity)  
• 
Where available, magnitude of endoscopic improvement, as assessed by change in 
endoscopic scores (Simple Endoscopic Score Crohn’s Disease [SES-CD] for CD or 
Endoscopic Sub Score within the Mayo Score for UC) relative to baseline, reporting 
the average decline and 95% confidence intervals [3, 4]. 
 
Exploratory Endpoints 
Blood, urine, saliva, and stool will be collected for evaluation of biomarkers 
 
Accrual Period: Estimated accrual of 3-4 patients per year for 18-24 months 
 
Study Duration:       Approximately 48 months, including follow up 
 
 

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TABLE OF CONTENTS 
1 
BACKGROUND AND RATIONALE ............................................................................... 8 
1.1 
Inflammatory Bowel Disease: ...................................................................................... 8 
1.3 
Description of the Study Agent/Intervention .............................................................. 9 
1.4 
Scientific Rationale and Clinical Justification .......................................................... 11 
1.4.1 
Rationale for the study of BMSCs in Pediatric IBD ........................... 11 
1.4.2 
PLAN OF STUDY: ................................................................................. 13 
1.4.3 
Rationale for the Dosage and Treatment Period ............................... 14 
2 
STUDY OBJECTIVES AND DESIGN .......................................................................... 15 
2.1 
Study Objectives: ......................................................................................................... 15 
2.1.1 
Primary Objective: ................................................................................ 15 
2.1.2 
Secondary objectives: ......................................................................... 15 
2.2 
Study Design ................................................................................................................ 15 
2.2.1 
Primary Endpoint ................................................................................. 17 
2.2.2 
Secondary Endpoints .......................................................................... 17 
2.2.3 
Exploratory Endpoint ........................................................................... 17 
2.3 
Study Population .......................................................................................................... 17 
2.4 
Recruitment Plan ......................................................................................................... 18 
2.5 
Informed Consent ........................................................................................................ 18 
2.6 
Eligibility criteria ........................................................................................................... 19 
2.6.1 
Subject Inclusion Criteria .................................................................... 19 
2.6.2 
Subject Exclusion Criteria ................................................................... 19 
3 
Study Agent ...................................................................................................................... 20 
3.1 
Preparation Administration, and Dosage ................................................................. 20 
3.2 
Assessment of Subject Compliance ......................................................................... 21 
3.3 
Concomitant Medications and Procedures .............................................................. 22 
3.4 
Prohibited Medications and Procedures .................................................................. 22 
3.5 
Study Schedule ............................................................................................................ 22 
3.6 
Table 1: Protocol of Events ........................................................................................ 22 
3.7 
Baseline assessment/screening ................................................................................ 25 
3.8 
Treatment Phase (Day 0, 7, 14, 21) ......................................................................... 25 
Safety Monitoring Phase (Day 28, 45, 56, 73) +/- 3 days ................................................ 25 
3.9 
Study Procedures ........................................................................................................ 25 
3.9.1 
Phlebotomy ........................................................................................... 25 
4 
Potential Risks and Benefits .......................................................................................... 26 
4.1 
Allogeneic BMSC Infusion .......................................................................................... 26 
4.2 
Phlebotomy ................................................................................................................... 26 
4.3 
Possibility of Direct Benefit ........................................................................................ 26 
5 
DRUG TOXICITY AND/OR ADVERSE REACTIONS (AEs) .................................... 26 
5.1 
ADVERSE EVENT ...................................................................................................... 27 
5.2 
SERIOUS ADVERSE EVENT ................................................................................... 27 
5.3 
UNEXPECTED ADVERSE EVENT .......................................................................... 28 
5.4 
OTHER ADVERSE EVENT ....................................................................................... 28 
5.5 
RELATIONSHIP TO TREATMENT .......................................................................... 28 
5.7 
Severity Assessment .................................................................................................. 30 

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6 
Off TREATMENT AND OFF STUDY CRITERIA........................................................ 31 
7 
Statistical Considerations ............................................................................................... 32 
7.1 
Statistical Analysis Plan .............................................................................................. 32 
8 
RECORDS TO BE KEPT ............................................................................................... 32 
8.1 
Data Handling and Record Keeping ......................................................................... 33 
8.1.1 
Data Management Responsibilities .................................................... 33 
8.1.2 
Data Capture Methods ......................................................................... 33 
8.1.3 
Types of Data ........................................................................................ 33 
8.1.4 
Source Documents and Access to Source Data/Documents ........... 33 
8.1.5 
Record Retention ................................................................................. 34 
9 
REPORTING REQUIREMENTS .................................................................................. 34 
9.1 
Adverse Event Reporting ........................................................................................... 34 
9.2 
Reporting to the IRB .................................................................................................... 35 
9.3 
Pregnancy Reporting .................................................................................................. 35 
9.4 
IND Annual Report to the FDA .................................................................................. 35 
9.5 
Final Report .................................................................................................................. 36 
9.6 
Reporting to the FDA .................................................................................................. 36 
10 
CLINICAL TRIAL OVERSIGHT AND MONITORING ................................................ 36 
10.1 
Safety monitoring ..................................................................................................... 36 
10.2 
Data Review Committee (DRC) ............................................................................. 36 
11 
APPENDIX 1: ................................................................................................................... 38 
11.1 
PCDAI ........................................................................................................................ 38 
12 
APPENDIX 2: ................................................................................................................... 41 
12.1 
PUCAI: ....................................................................................................................... 41 
13 
APPENDIX 3: ................................................................................................................... 43 
13.1 
CDAI .......................................................................................................................... 43 
14 
APPENDIX 4: ................................................................................................................... 44 
14.1 
MAYO SCORE .......................................................................................................... 44 
15 
APPENDIX 5: ................................................................................................................... 45 
15.1 
SES-CD SCORE......................................................................................................... 45 
 
 
 

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1 
BACKGROUND AND RATIONALE 
 
1.1 Inflammatory Bowel Disease: 
 
The purpose of this protocol is to study the safety and tolerability of MSCs for the 
treatment of pediatric and young adult patients with moderate to severe Inflammatory 
Bowel Disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), which 
is unresponsive to conventional therapy. CD and UC are chronic inflammatory diseases 
characterized by relapsing inflammation of the gastrointestinal tract. There is no known 
cure for these lifelong conditions. CD affects the full thickness of the bowel wall, and 
may affect the different areas of the small and large intestine.  Conversely, UC affects 
only the large intestine.   
 
IBD in children profoundly affects nutrition, growth, education, employment, and social 
well-being.  The prevalence of CD in people < 20 years of age is 43 per 100,000 and for 
UC is 28 per 100,000 in the US.  Overall, the cost associated with IBD care is greater in 
children than in adults.  This likely reflects the high number of incident cases in children, 
but also likely reflects the increased severity of IBD in children. [5]   Though a much 
lower prevalence is found in other areas of the world, IBD appears to be emerging in 
areas such as China, South Korea, India, and Iran, correlating with industrialization and 
westernization.  [6]  Twenty-five to 30% of all patients with CD and 20% of those with 
UC are diagnosed before age 20. [7]  [8]  
 
Although exact details of the disease pathogenesis are unknown, the generally 
accepted hypothesis is that IBD occurs as an exaggerated and dysregulated mucosal 
immune response to environmental factors, including intestinal microbiota, in a 
genetically susceptible host.  The hallmark of IBD is an infiltration of innate immune 
cells (neutrophils, macrophages, dendritic cells, and natural killer T cells) and adaptive 
immune cells (B cells and T cells) into the intestinal lamina propria. Innate immune cells 
provide a rapid response to microbes via sensors (i.e. toll-like receptors) which 
recognize microbial and nonmicrobial triggers and initiate inflammatory responses.  In 
CD, failure of dendritic cells to induce tolerogenic regulatory CD4+ T cells leads to a 
cascade of intestinal inflammation. [9] CD is characterized by an imbalance of elevated 
pro-inflammatory effector T cells (Th17 and Th1 cells secreting cytokines interleukin-17 
and 22, interferon γ and TNF α) and decreased inflammatory-suppressing regulatory T 
cells. [10, 11] Th2 cytokines secreted by natural killer T cells are implicated in UC. [12] 
[10]   
 
1.2 Current Standard IBD Treatment: 
Treatment goals in pediatric IBD include improving quality of life, maximizing growth and 
nutrition, and preventing complications, such as toxic megacolon, anemia, intra-
abdominal abscess, intestinal obstruction, intestinal perforation, growth failure and 

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pubertal delays.   In spite of advances in IBD therapeutics, a significant number of 
patients continue to have symptoms while on conventional medications. Moderate to 
severe IBD is treated with systemic corticosteroids, immunomodulators (6-
mercaptopurine for CD and UC, methotrexate for CD), and biologics (i.e. infliximab, 
adalimumab, certolizumab). These medications are variably effective and have potential 
for severe complications and side effects.  From the first introduction of corticosteroids, 
20% of patients do not respond, and 35% of the responders develop steroid 
dependency. [13, 14] 6-mercaptopurine and its parent drug azathioprine possess well-
known immunosuppressive and lymphocytotoxic properties. [15] While 50% of patients 
will achieve a clinical response after 4 months of therapy,  only 40-65% of patients 
maintain remission, and the onset of these drugs is slow. [16, 17]  Methotrexate is 
effective in about a third of patients with CD, although experience with methotrexate in 
pediatric IBD literature is scant and retrospective. [18] Toxicities, particularly 
teratogenicity in females, limit its use. Methotrexate may also cause nausea, bone 
marrow suppression, infections, and liver injury.  
 
Biologic therapies are widely used for treating both UC and CD.  Established and 
emerging therapies for IBD are directed toward the destruction or deterrence of 
activated effector T cells, or blockade of Th1-driving cytokines. Trials with anti-cytokine 
therapy, in particular anti-TNF α medications, have been successful for patients with 
refractory disease.  There are 4 anti-TNF monocolonal antibodies currently FDA 
approved for use in adults with IBD: infliximab, a chimeric IgG1 antibody; adalimumab, a 
fully humanized IgG1 antibody; certolizumab and golimumab, both PEGylated 
humanized Fab’ fragments. [19] However, there are fewer options for pediatric patients, 
as only infliximab is FDA approved for pediatric UC, while both adalimumab and 
infliximab are indicated for treatment of pediatric CD.  Despite these advances, one third 
of patients do not respond to these medications, and an additional third subsequently 
lose response or become intolerant. [20, 21]  
 
Safety data from the use of TNF inhibitors highlight concerns regarding risk of 
infections, such as tuberculosis, listeria, pneumocystis, and invasive fungal organisms.  
It is known that concomitant use of immunomodulators improves clinical efficacy of 
infliximab in adults. [22, 23]  However, serious risks are associated with infliximab and 
immunomodulators. In addition to infection, include infusion/injection reactions, 
hepatitis, and an otherwise extremely rare and almost uniformly fatal hepatosplenic T-
cell lymphoma in pediatric and young adult CD patients receiving the combination of 
infliximab and 6MP or azathioprine.[24, 25]  Thus, a need for new therapies for 
refractory pediatric IBD exists, particularly the need for safely modulating the immune 
system to reduce or reverse the abnormal inflammatory cascade.  
 
 
 
 
1.3 Description of the Study Agent/Intervention 
 

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Human Mesenchymal Stromal Cells (MSCs) - “Universal Stem Cells”  
 
MSCs are undifferentiated, non-hematopoietic, pluripotent cells that give rise to 
mesodermal tissue types, including bone, cartilage, tendon, muscle, and fat. [26] MSCs 
provide support for the growth and differentiation of hematopoietic progenitor cells in 
bone marrow microenvironments and, in animal models, promote engraftment of 
hematopoietic cells. [27] These cells may be isolated from most human tissues, usually 
bone marrow, and expanded ex vivo. [28, 29] MSCs do not express the hematopoietic 
markers CD45, CD34, and CD14, or the co-stimulatory molecules B7-1, B7-2, CD40, 
CD40 ligand, CD80 and CD 86 and probably therefore do not activate alloreactive T 
cells. [30-32]. Minimal classification criteria has been defined as positive for CD146, 
CD90, and human leukocyte antigen (HLA) class 1 and negative for hematopoietic cell 
markers. [33] MSCs constitutively express HLA class I molecules, but do not express 
class II molecules on the cell surface.  In the presence of inflammatory cytokines, i.e. 
IFN γ and TNF𝛼𝛼, the surface expression of class I is increased and class II expression 
is induced. [32] However, mesenchymal tissues, such as bone and cartilage have been 
successfully transplanted without the need for donor-recipient MHC matching, and the 
incidence of acute rejection of these tissues is low.  Thus, the mesodermal origin of 
BMSCs, along with lack of co-stimulatory molecules necessary to activate T cells, 
suggests low immunogenicity of these cells.  MSCs isolated from humans and other 
mammalian species do not elicit a proliferative T cell response from allogeneic 
lymphocytes. [34, 35] 
 
MSCs have been shown to possess immunomodulatory properties, following the initial 
observation that bone marrow-derived MSCs suppressed T cell proliferation. [36]  As 
expected, MSCs suppress proliferation of allogeneic T cells in a dose-dependent, non-
HLA-restricted manner. [30, 32, 37] MSCs inhibit the division of stimulated T cells by 
preventing their entry into the S phase of the cell cycle and by mediating irreversible 
B0/G1 phase arrest. [38]  MSCs interact with other immune cells and are capable of 
altering immune cell responses.  MSCs can inhibit the differentiation of monocytes into 
immature dendritic cells.[39] MSCs also impair the ability of DCs to express co-
stimulatory molecules, produce cytokines, and stimulate T cells. [40] MSCs can 
decrease the pro-inflammatory potential of dendritic cells by inhibiting their production of 
tumor-necrosis factor (TNF) and IFN-γ.[41]  MSCs increase production of IL-10, thereby 
limiting T cell expansion. [41]  Suppression of T cell responses is in part mediated by 
incompletely defined soluble factors, and MSCs may also suppress T cell reactivity by 
inducing T regulatory cells. [42] 
 
A critical benefit of MSCs is that they do not seem to induce immunological memory in 
the recipient even when they are completely HLA mismatched, to the point of avoiding 
rapid rejection.  [43] Given the goal of healing intestinal mucosa, another possible 
benefit of MSCs is that they have been shown to promote tissue repair and healing after 
radiation injury. Infused MSCs improve the outcomes of acute renal, neural, and lung 
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at the site of injury. [44]  Thus, much research has been focused on the potential use of 
MSCs for the treatment of chronic wounds, degenerative diseases, autoimmune 
diseases, and graft-versus-host disease. [45-48]  The vast majority of studies of MSCs 
have been performed in adults.  
 
 
1.4 Scientific Rationale and Clinical Justification 
 
1.4.1 Rationale for the study of BMSCs in Pediatric IBD 
 
Pediatric IBD is a chronic, life-long condition beginning in childhood, characterized by 
relapsing inflammation of the gastrointestinal tract.  Inflammation is thought to be 
mediated by T cells, macrophages, and dendritic cells that produced downstream 
cytokines.  Despite the many therapeutic advances in the treatment of IBD, many 
patients still suffer with refractory disease.  Children with IBD are typically exposed to 
multiple medications over years, and many suffer with associated serious side effects.  
 
According to 2009 US Census data, inflammatory bowel diseases (IBD) (i.e. Crohn's 
disease and ulcerative colitis) affect about 1.2 million Americans. Of these, 62,000 are 
children (38,000 CD and 23,000 UC).  Thus, 5% of all IBD cases in the USA are of 
pediatric age (<20 years). This qualifies drugs to treat pediatric UC and pediatric CD as 
orphan indications.   
(http://www.accessdata.fda.gov/scripts/opdlisting/oopd/OOPD_Results_2.cfmIndex_Nu
mber=340911) Further, while there are options for the treatment of IBD in adults, other 
than corticosteroids, infliximab (Remicade) and adalimumab (Humira) are FDA-
approved for the treatment of moderate to severe pediatric CD.  Infliximab has orphan 
drug designation to treat pediatric UC.  Certolizumab pegol, methotrexate, 6MP, and 5-
ASA products are NOT FDA approved for use in children with UC or CD.  
(http://www.accessdata.fda.gov/scripts/cder/drugsatfda/) 
 
The scientific rationale for investigating the use of MSCs in IBD patients is based on 
known properties of inflammatory and immune modulation and enhancement of tissue 
repair.  This is not a first-in-human study and there is now a sizable body of evidence 
that this intervention is safe when used in people ≥ 18 years of age.  However, the 
safety of MSCs has not been yet demonstrated in children with IBD.  While children 
cannot be treated as “small adults”, this is not an intervention that is expected to have 
substantially different impact on children than adults because metabolic differences are 
not a concern for this intervention.   CD and UC are considered similar enough that 
efficacy in children has been extrapolated from adults in past trials of drugs used to treat 
IBD.   
 
Therefore, there is an urgent medical need to evaluate novel therapies such as MSCs in 
pediatric IBD since:  
1). Children with refractory IBD have few well-studied treatment options. 
2). MSC therapy has already been evaluated in adults  

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3). There is not only the potential for benefit when using MSC in IBD but also the high 
likelihood that the allogeneic MSC will not cause the systemic immune suppression 
seen with other investigational therapies for this disease. 
 
The MSCs that we propose using are different because they are passaged fewer times 
(up to 4 passages). One of the limitations when expanding MSCs is the time, labor, 
necessary space and costs associated with the expansion of these cells.  For example, 
to generate 500 million MSCs using standard T-175cm2 flasks requires four-five 
passages and as many as 200 flasks by the final passage. One way to circumvent 
these limitations is to use a functionally-closed, automated bioreactor that expands a 
large number of cells in a short period of time, such as the Quantum Cell Expansion 
system. Besides being a closed system (which limits the chance of contamination), the 
bioreactor requires only about 20% of the labor that the normal flask-based expansion 
requires and manufactures the cells 1-2 weeks sooner. In addition, the Quantum can 
produce 200-400% more cells during the same time period. In Dr. Hanley’s preliminary 
pre-clinical studies, >500 million MSCs can be expanded after only two passages with 
the potential to generate over 1 billion MSCs by passage two, and over 2.5x1010 MSCs 
by passage three. In these same studies, cells obtained from the Quantum had a similar 
phenotype to those expanded in flasks. We are one of the few centers with a Quantum 
system.  Dr. Hanley is an established expert in the manufacturing of MSCs for phase 1 
trials, as well as the Director of the GMP facility at CNHS.  [49, 50]     
Our cell therapy product consists of allogeneic mesenchymal stromal cells 
manufactured from an eligible normal donor.  We have a CNMC IRB-approved protocol 
(Pro00006717) that provides a mechanism for the use of excess bone marrow obtained 
from healthy donor bone marrow harvests. Up to 100 mL of marrow will be obtained 
from Lonza (Walkersville, MD) under informed consent and transported to Children’s 
National Health System in a validated process at 2-8°C. The donor will meet the 
eligibility requirements as described in 21 CFR parts 1271 Subpart C. Testing (Table 1) 
will be performed using FDA-approved, cleared and/or licensed kits by Lonza within 7 
days of collection of the marrow for manufacturing. Manufacturing will commence within 
24 hours of marrow collection. Risk factors will be assessed by taking a clinical history, 
clinical examination, and by use of a standard questionnaire for blood donors.  
 
 
 
 
This would not be a first-in-human 
study and there is now a sizable body 
of evidence that this intervention is 
safe when used in people ≥ 18 years 
of age.  However, the safety of MSCs 
has not been yet demonstrated in 
Table 1:                      Test 
Chagas Disease 
Hepatitis B Surface Antigen 
Hepatitis B Core 
Hepatitis C Core 
HIV 1 and 2 
TAQ Screen MPX (HBV, HCV, HIV-1 group M RNA, 
HIV-1 Group O) 
NAT HCV 
NAT West Nile Virus 
Serological Test for Syphilis 
CMV 
HTLV-1 

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children with IBD.  Safety and dosing may not be extrapolated from adult studies, as 
classic pharmacokinetic monitoring to document equivalent exposure-response is not 
feasible with cell therapies. 
 
1.4.2 PLAN OF STUDY:  
 
This is a pilot phase 1 treatment protocol for subjects with moderate to severe CD or UC 
who have failed or are intolerant of one biologic.  Subjects must have had a flexible 
sigmoidoscopy or colonoscopy or MR enterography within 2 months of enrollment, 
demonstrating active inflammatory bowel disease.  Subjects with moderate to severe 
CD are defined differently in children and adults.  In patients <17 years of age, 
moderate to severe CD will be defined as having a  Pediatric Crohn Disease Activity 
Index (PCDAI) score of > 30 (range 0-100) and subjects with moderate to severe UC 
are defined as a patients with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score 
of >34 (range 0-85).  In patients ≥ 18 years of age, moderate to severe CD will be 
defined as a CDAI of ≥ 220 (range 0-600), and moderate to severe UC defined as a 
Mayo score of ≥ 6 (range 0-12).  In our study, at the specification of the FDA IND 
review, a young adult cohort will be enrolled first and monitored for toxicity.  A pediatric 
cohort will only begin to enroll if there are no serious adverse events observed in the 
young adult cohort. Subjects will be closely monitored both by the study team to detect 
and evaluate adverse events (AEs), serious adverse events (SAEs), and toxicity 
requiring discontinuation of the intervention.   
Three young adult patients (ages 17 ≤ 22  years) will be enrolled, staggered by at least 
7 days.  A fixed dose will be studied:  1 x 106 cells/kg administered intravenously (IV) 
weekly for 4 consecutive weeks.  Infusions are administered over the first 28 days, 
followed by a 45 day monitoring period.  Our chosen dose (1 x 106 cells/kg weekly for a 
duration of 4 weeks) is within the dosing parameters of previous trials.  In trials of MSCs 
in pediatric GvHD, doses as high as 8 x 106 cells/kg/dose were given up to twice per 
week for four weeks. [51] The rate of administration (for patients < 35 kg, total infusion 
over 60 minutes, and for ≥ 35 kg, 4-6 ml/minute via infusion pump) is also consistent 
with prior pediatric administration in patients with GvHD. [51]   
In our study, toxicity will be scored as a binary variable indicating occurrence or non-
occurrence over a monitoring interval from the start of MSC therapy to 45 days after the 
last infusion. Based on the planned administration schedule, the total toxicity monitoring 
period will have duration 28 +45 = 73 days.    If we observe no severe (grade 3 or 
worse) adverse events in the young adult cohort, we will wait a minimum of 45 days 
before beginning to enroll 3 more patients, ages 12≤16 years (pediatric cohort).  If we 
observe a severe (grade 3 or worse) adverse event occurring at any time from the start 
of therapy to 45 days following the last MSC administration in the young adult cohort we 
will stop the study. If we observe no SAEs attributed to MSC administration in the young 
adult cohort but an SAE (grade 3 or worse) occurring at any time from the start of 
therapy to 45 days following the last MSC administration in the pediatric cohort, we will 
stop the study. If patients with active disease do not have >grade 2 toxicity attributed to 

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cells and fail to rapidly progress with disease requiring urgent therapy or surgery, and at 
the discretion of the principal investigator, 4 additional weekly doses may be 
administered.  Subjects are eligible to receive up to 4 additional doses of MSCs at 
weekly intervals, each of which will consist of the same cell number (1 x 106 cells/kg). 
The safety assessment period will be 45 days from the last dose administered. A 
maximum of 6 patients will be enrolled. Assuming an accrual rate of 3-4 patients per 
year, it is anticipated that it may require at least 18- 24 months to accrue all 6 patients. 
With the additional 24 months of follow up to evaluate longer-term safety and efficacy 
endpoints, the anticipated trial duration will be about 48 months.   
The primary study endpoint is safety and tolerability of the administration of human 
allogeneic bone marrow-derived MSCs to children and young adults with IBD, 
measured by the frequency of any SAEs, AEs and/or early treatment discontinuations. 
Secondary endpoints will include: 1) magnitude of change in clinical indices CDAI, 
Mayo, PCDAI and PUCAI) relative to baseline, reporting the average decline and 95% 
confidence limit;  2) changes in biomarkers (i.e. C-reactive protein, fecal calprotectin, 
anti-HLA antibodies and viral specific T-cell activity.) and 3) where available, magnitude 
of endoscopic improvement, as assessed by change in endoscopic scores (Simple 
Endoscopic Score Crohn’s Disease [SES-CD] for CD or Endoscopic Sub Score within 
the Mayo Score for UC) relative to baseline, reporting the average decline and 95% 
confidence intervals [3, 4]. 
We will collect serum, saliva, peripheral blood mononuclear cells, stool, and urine for 
study of known and potential biomarkers of disease response. A potential concern 
regarding this therapy is the effect upon T cell-mediated immunity. Thus, we will assess 
peripheral viral-specific T cell activity before and after therapy.    
 
The trial has been registered at clinicaltrials.gov (#NCT02150551). The IND has been 
reviewed and approved at the Center for Biologics Evaluation and Research at the FDA 
(IND#15902).   
 
Safety and dosing may not be extrapolated from other populations, and classic 
pharmacokinetic monitoring is not feasible with cell therapies. A young adult cohort will 
be enrolled and monitored for toxicity.  A pediatric cohort will only begin to enroll if there 
are no serious adverse events observed in the young adult cohort. Subjects will be 
closely monitored both by the study team and an independent DRC to detect and 
evaluate adverse events, serious adverse events, and toxicity requiring discontinuation 
of the intervention.  Participants will be followed closely with weekly follow-up and 
assessment during the treatment protocol, and a subsequent 45 day follow up period 
after last MSC infusion. Laboratory and clinical data will be collected per protocol.  
 
 
1.4.3 Rationale for the Dosage and Treatment Period 
 
Our chosen dose1 x 106 cells/kg weekly x 4weeks is within the dosing parameters of 
previous trials.  In trials of MSCs in pediatric GVHD, doses as high as 8 x 106 
cells/kg/dose were given up to twice per week for four weeks. [51] The rate of 

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administration (for patients < 35 kg, total infusion over 60 minutes, and for children ≥ 35 
kg, 4-6 ml/minute via infusion pump) is also consistent with prior pediatric administration 
in patients with GVHD. [51]   
 
2 
STUDY OBJECTIVES AND DESIGN  
 
2.1 Study Objectives:  
 
2.1.1 Primary Objective:  
 
The primary objective is to examine the safety and tolerability of infusions of fresh bone 
marrow-derived MSCs in the treatment of children and young adults with moderate to 
severe IBD.   
 
2.1.2 Secondary objectives:  
 
 
1. Examine the effects of 4 infusions of MSCs on clinical measures of disease activity in 
patients, using clinical indices, as well as endoscopic scores (if applicable), histologic 
scores, and MR enterography when available.  
 
2. Examine inflammatory and immunologic effects of MSC infusions on peripheral and 
intestinal mucosal biomarkers including, but not limited to serum CRP, fecal 
calprotectin, anti-HLA antibodies, and viral specific T-cell activity before and after 
treatment. 
 
2.2 Study Design 
 
This study is a pilot phase 1 treatment protocol for subjects with moderate to severe CD 
or UC who have failed to respond to or are intolerant of a biologic. Patients must have 
had a flexible sigmoidoscopy, colonoscopy or MR enterography within 2 months of 
enrollment, demonstrating active inflammatory disease.  
 
Two types of patients will be enrolled:  
 
- Moderate to severely active CD subjects (defined in Section 2.4) 
- Moderate to severely active UC subjects (defined in Section 2.4)  
 
At the beginning of the trial, a history and physical examination will be obtained, and 
documentation of baseline co-variates[52]: 
CD:  
o age  
o gender  

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o ethnicity  
o history of abdominal surgery  
o duration of time with diagnosis  
o age at diagnosis  
o disease location 
o  history of failed biologic use  
o history of stricturing/penetrating disease  
o positive family history of IBD  
o history of perianal disease  
o severity and phenotype (Montreal classification for adults, or Paris classification 
for children) 
 
UC:  
o age  
o gender  
o ethnicity  
o age at diagnosis 
o history of failed biologic use  
o duration of time since diagnosis  
o positive family history of IBD)     
 
During the course of the patient’s treatment with MSCs, standard of care will be 
administered by the treating physician, at his/her discretion. There are no specific or 
“antidotal” therapies.  Thus, any toxicity that arises during a patient’s participation in this 
treatment will be managed with supportive measures at the discretion of the treating 
physician.    
 
Three young adult patients (ages 17≤22 years) will be enrolled, staggered by at least 7 
days between patients, and each monitored for toxicity over a period of 73 days.  A 
fixed dose will be studied:  1 x 106 cells/kg administered intravenously (IV) weekly for 4 
consecutive weeks.  Infusions are administered over the first 28 days, followed by a 45 
day monitoring period.  The primary outcome is regimen-related toxicity, defined in 
section 5.  Toxicity will be scored as a binary variable indicating occurrence or non-
occurrence over a monitoring interval from the start of MSC therapy to 45 days after the 
last infusion. Based on the planned administration schedule, the total toxicity monitoring 
period will have duration 28 +45 = 73 days.    
If we observe no severe (grade 3 or worse) adverse events in the young adult cohort, 
we will wait a minimum of 45 days before beginning to enroll 3 more patients, ages 
12≤16 years (pediatric cohort).  If we observe a severe (grade 3 or worse) adverse 
event occurring at any time from the start of therapy to 45 days following the last MSC 
administration in the young adult cohort we will stop the study. If we observe no severe 
adverse events attributable to MSC administration in the young adult cohort but a 

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severe (grade 3 or worse) adverse event occurring at any time from the start of therapy 
to 45 days following the last MSC administration in the pediatric cohort we will stop the 
study.  A maximum of 6 patients will be enrolled. Assuming an accrual rate of 3-4 
patients per year, it is anticipated that it will require at least 18 – 24 months to accrue all 
6 patients. With the additional 24 months of follow up to evaluate efficacy endpoints 
noted in Section 2, the anticipated trial duration will be about 48 months.   
 
 
2.2.1 Primary Endpoint 
 
Safety and tolerability of the administration of human allogeneic bone marrow-derived 
stromal cells to children and young adults with IBD, measured by the frequency of any 
SAEs, AEs and/or early treatment discontinuations.  
 
2.2.2 Secondary Endpoints  
 
 
Magnitude of change in PCDAI, PUCAI, CDAI to baseline, reporting the average 
decline and 95% confidence limit.  
• 
Changes in laboratory parameters indicating inflammation or immunogenicity(i.e. 
C-reactive protein, fecal calprotectin, anti-HLA antibodies, and viral specific T-cell 
activity))  
• 
When available, magnitude of endoscopic improvement, as assessed by change 
in endoscopic scores (Simple Endoscopic Score Crohn’s Disease [SES-CD] for 
CD or Endoscopic Sub Score within the Mayo Score for UC) relative to baseline, 
reporting the average decline and 95% confidence intervals.  
 
2.2.3 Exploratory Endpoint 
 
• 
Blood, urine, saliva, and stool will be collected for evaluation of biomarkers 
 
2.3 Study Population 
 
This treatment protocol allows for the treatment of both male and female young adults 
and children between the ages of 12 years and 22 years with a diagnosis of moderate 
to severe CD or UC who have failed or are intolerant of biologic therapy.  
 
Subjects with moderate-to-severe CD are defined as patient with a PCDAI score > 
30 with visually active CD at the time of endoscopy/colonoscopy, or signs of 
inflammation on MR enterography, within 2 months of enrollment. 
 
Subjects with moderate-to-severe active UC are defined as a patient with a PUCAI 
score >34, and visually active mucosal disease by colonoscopy or flexible 
sigmoidoscopy within past 2 months. 

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2.4 Recruitment Plan 
 
Subjects will be recruited from the IBD Program at Children’s National Medical Center, 
and from other sites via provider communication. The trial will be listed at 
clinicaltrials.gov.  
 
2.5 Informed Consent 
 
The informed consent process will be conducted in a private room to respect subject 
privacy. Following the briefing of the research study, the coordinator or designee will 
provide the subject with ample time to read the consent, and will answer any of their 
questions regarding the document. No study procedures will occur before the subject 
gives informed consent. To minimize any possible coercion, supervisors or anyone in a 
dominant position will not be permitted to consent the subject. The treating physician is 
responsible for ensuring that written informed consent, including written authorization for 
use and disclosure of PHI and appropriate signatures and dates, is obtained from each 
patient before any protocol-related procedures, including any pre-treatment procedures, 
are performed.  All patients who are <18 years of age will require a parental or legal 
guardian signature of informed consent. In addition, all patients between the ages of 12 
and 17 years will require a signature of assent.  
 
Prior to the subject’s participation in any trial procedures, the investigator or designee 
will ensure that the potential participant understands the research study and their role in 
the study.  The written informed consent will be signed and dated by the subject and by 
the person who conducted the informed consent discussion. A signed copy of the 
consent form will be placed in the subject’s trial chart and a photocopy will be given to 
the subject. Informed consent will be obtained in accordance with the Code of Federal 
Regulations (CFR) 21 CFR 50.25, 32 CFR 219, 45 CFR 46 and 15-2, ICH Harmonized 
Tripartite Guidance for Good Clinical Practice, and the Belmont Report. Also included in 
the consent process, Health Insurance Portability Accountability Act (HIPAA) 
authorization will be obtained before any study procedure is undertaken. 
 
If subject decides to take part in the research study, their protected health information 
will not be given out except as allowed by law. Study personnel will work hard to keep 
this information private. The results of the data from the study may be published. 
However, subject will not be identified by name. 
 
Subjects may change their mind and withdraw from the study any time they want.  
 
If they decide to stop taking part in the study or if they are removed from the study, they 
may decide that they no longer allow protected health information that identifies them to 
be used in this research study. The study staff will respect the subject's decision to 

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decline access to their medical records and biological samples. Subject decision will be 
available in their records. 
 
If subject agrees to participate in this research study, the research team (PI, co-
investigators, Clinical Research Manager, statistician, Clinical Research Coordinator, 
Quality Assurance coordinator, and Research Nurse), the research sponsor (when 
applicable) and the sponsor's representatives, may use coded study data. The coded 
study data does not include subject name, address, telephone, or social security 
number. Instead, the researcher assigns a code to the data. The research team or the 
research sponsor may share the coded study data with others to perform additional 
research, place it into research databases, share it with researchers in the U.S. or other 
countries, or use it to improve the design of future studies. They may also publish it in 
scientific journals, or share it with business partners of the sponsor and to file 
applications with U.S. or foreign government agencies to get approval for new drugs or 
health care products. 
 
The research team would store personal health information collected from the study in a 
database in a password protected computer for future research. The database is 
maintained by Children’s National Medical Center in the division of Blood and Marrow 
Transplantation. 
 
2.6 Eligibility criteria 
 
2.6.1 Subject Inclusion Criteria 
• 
For the young adult cohort, patients must be ages 17 ≤22 years 
• 
For the pediatric cohort, patients must be ages 12 ≤16 years 
• 
Patients must have moderate-severely active CD or UC (defined in section 2.3), and 
documented active disease on flexible sigmoidoscopy, colonoscopy or MR enterography 
within the preceding 2 months. 
• 
Patients who have failed or are intolerant of biologic therapy.  Specifically, the patient will 
have recurrence or persistence of active disease despite current or past treatment with a 
biologic.  At the time of enrollment, study subjects may be currently receiving 5-
aminosalicylates, corticosteroids (≤ 20 mg daily or up to 0.5 mg/kg/day if weight <40 kg), 
methotrexate, 6MP/azathioprine, or a biologic (either as monotherapy or in combination). 
During the treatment phase, if the treating physician thinks that a medication dose 
should be lowered to avoid side effects, this should be recorded. 
• 
Patient or parent/guardian capable of providing informed consent. 
• 
 
 
2.6.2 Subject Exclusion Criteria 
 
• 
Patient <12 years of age or >22 years of age 
• 
Pregnant or breastfeeding. Serum pregnancy test must be negative at screening 
for female subjects of childbearing potential. Urine pregnancy test must remain 
negative at each of 4 infusion visits.  

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• 
Patients with toxic mega-colon or intestinal perforation 
• 
Evidence of autoimmune chronic active hepatitis or sclerosing cholangitis. 
• 
Patients with fever > 39° C or clinically significant active infection within 1 week 
(i.e. chronic infections including Hepatitis B/C or HIV or acute infections, 
including urinary tract infection and respiratory tract infection)  
• 
Received an agent not approved by the FDA for marketed use in any indication 
or any small molecule inhibitors (i.e. naltrexone) within 60 days of enrollment.   
• 
Subjects who are taking greater than 20 mg (or if body weight <40 kg, 0.5 mg/kg) 
of prednisone daily.  
• 
Clinically significant abnormal biochemical and hematological parameters, 
including: 
o Neutrophil count < 1000 cells/mm3 
o Hemoglobin < 8 g/dl 
o Platelet count ≤ 130 cells/mm3 
o Creatinine ≥ 1.2 x the upper limit of normal  
o Alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) ≥ 2x the upper limit of normal 
o Conjugated bilirubin greater than 1.2 mg/dL 
• 
Has active infection with enteric pathogens as evidenced by positive 
microbiological culture of stool or C.difficile toxin PCR.  
• 
Had bowel surgery other than perianal procedures (fistulotomy, seton placement, 
abscess drainage) within 3 months of enrollment. 
• 
Has uveitis 
• 
Has known pulmonary disease, excluding mild intermittent asthma 
 
3 
STUDY AGENT 
 
3.1 Preparation Administration, and Dosage 
 
 On the day of each infusion, the following procedures/assessments will be performed: 
 
• MSCs will be thawed,  harvested, counted, the viability will be determined, and 
appropriate samples will be sent for other release testing (including sterility).Vital 
signs (heart rate, blood pressure, respiratory rate, and temperature) will be 
measured within 15 minutes prior to the infusion (time 0) and then every 5 
minutes during the infusion.  If vital signs are normal after three 5-minute checks, 
they will be checked every 15 minutes during the remainder of the infusion, and 
then at 30 and 60 minutes after the infusion for 1 hour.  
• Patients will be monitored according to institutional standards for administration 
of blood products and at a minimum will be monitored according to below: 
o Patients should remain in the clinic for at least one hour  
o Patients should remain on continuous pulse oximetry for at least 30 
minutes  

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o Vital signs should be monitored at the end of the infusion then at 30 and 
60 minutes  
• Per institutional guidelines, pre-medication, consisting of oral acetaminophen 
(10-15 mg/kg/dose, max 650 mg) and diphenhydramine (0.5-1 mg/kg/dose, max 
50 mg), will be administered at least 30 minutes prior to the infusion. 
• No other medications should be given during the infusion, unless determined 
medically necessary by the treating physician.  
• Supplemental oxygen will be kept by the bedside at all times.  
• MSCs suspended in Plasmalyte A (multiple electrolyte injection) will be given as 
an IV infusion using weight-based dosing.  We plan to infuse 1-4x106 cells per 
mL, not to exceed 240 mL. With a mean weight of 40 kg, the infusion volume 
would be 40-120 mL. 
• Cells will be infused on Day 0 followed by repeat infusions weekly over a total of 
4 weeks.  An additional 4 weekly doses may be infused at discretion of physician. 
An attempt will be made to administer repeat infusions from the same initial 
donor, but administration of MSCs from another donor is permitted if same-donor 
cells are unavailable. Tracking of donor sample identification information will be 
performed for each sample. 
• MSC’s will be administered intravenously via a 18 gauge needle at a controlled 
rate of 4-6 ml/minute via infusion pump for patients weighting 35 kg or more. For 
patients under 35 kg in weight, the infusion will run in over 60 minutes at a rate 
no greater than 4-6 ml/minute.  A syringe in combination with syringe pump can 
be used for administration in smaller patients.   
• During the administration, the infusion must be stopped for any of the following 
reasons: 
o If the patient has symptoms or signs of respiratory difficulty, including but 
not limited to tachypnea, cyanosis, complains of shortness of breath, even 
if the pulse oximeter reading is normal.  If the symptoms resolve within 30 
minutes after standard supportive oxygen therapy, the infusion may be 
resumed at half the initial rate and the infusion must be completed within 2 
hours of starting the infusion.  If the symptoms recur, then the infusion will 
be stopped and will not be resumed.   
o If SaO2 decreases to ≤ 90% over a continuous period of ˃ 3 minutes, 
whether or not the patient has symptoms of respiratory distress.  If the 
SaO2 is ≤ 90% in the absence of symptoms or signs, the accuracy of the 
pulse oximeter reading should be confirmed by using another machine, 
relocating the sensor, or testing the device on another patient.  
o Infusion may be stopped at the discretion of the treating physician if there 
is another AE that the treating physician believes is related to the infusion, 
or if there is an issue with the infusion, or if the patient withdraws consent. 
 
3.2 Assessment of Subject Compliance 
 

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All infusions are given under the direct supervision of the clinical study team, so study 
agent compliance is insured. 
3.3 Concomitant Medications and Procedures 
 
All prescription medications, over-the-counter medications, non-prescription 
medications (including herbal medications), and concomitant surgical or interventional 
procedures will be recorded for up to 45 days after last MSC infusion.   At the time of 
enrollment, study subjects may be currently receiving mesalamine, corticosteroids (≤ 20 
mg daily, if body weight < 40 kg, up to 0.5 mg/kg/day), immunomodulators, or biologics. 
If the treating physician thinks that a medication dose should be lowered to avoid side 
effects, this should be recorded.    
 
3.4 Prohibited Medications and Procedures 
 
Concomitant non-steroid anti-inflammatory (NSAID) medications will not be permitted 
during study participation.  Other medications used to treat IBD are prohibited other 
than those outlined in the eligibility criteria.  Subjects required rescue IBD therapy 
before the day assessment will be considered treatment failures.  Medications used to 
treat medical conditions other than IBD are permitted after review and approval of the 
Principal Investigator. Systemic immunosuppressant for conditions other than IBD is not 
permitted.  
 
3.5 Study Schedule  
 
Please see below table for detailed schedule of study procedures and assessments 
(table 1). 
  
3.6 
Table 1: Protocol of Events 

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Visits/Procedures 
Screening 
visit 
Treatment and Safety Monitoring phase  
Follow-up Phase 
Visit Day 
Day -30 to -1 
Day 0 
(Dose#1) 
Day 7 
(Dose 
#2) 
Day 14 
(Dose 
#3) 
Day 21 
(Dose 
#4) 
Day 28 
Day 45 
Day 56 
aDay 73 
Day 180 
Day 360 
Day 720 
Visit Window 
Day -30 to -1 
± 1 dayb 
± 3 
days 
± 3 
days 
 ± 3 days 
 ± 3 days 
 ± 3 days 
 ± 3 
days 
±3days 
±28 days 
±28 days 
±28 days 
Physical Examination  
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Medical & Surgical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Active disease on 
sigmoidoscopy, 
colonoscopy, or MR 
enterography 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (temp, HR, RR, 
BP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
SaO2 via pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AEs/SAEs  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Eligibility Criteria  
 
X 
 
 
 
 
 
 
 
 
 
 
Collection of serumc, 
saliva, urine, stool for 
research 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Urine pregnancy test 
(before each infusion) 
X 
X 
X 
X 
 
 
 
 
 
 
 
MSC infusion 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Disease activity 
assesseda 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Routine Labs 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Electrolytes, liver 
enzymes, urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Quantitative CRP, fecal 
calprotectin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

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aDisease activity assessed using: PCDAI, PUCAI, CDAI, Mayo, SES-CD   
bOnly applies to routine labs and pregnancy test 
cWe will draw up to 40 ml of blood at 9 time points for research studies (at baseline before the first infusion, before each subsequent infusion, and at the 45 day 
safety follow up).

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3.7 Baseline assessment/screening  
 
During the assessment visit, which will occur during the one month period prior to MSC 
administration, a discussion of the informed consent and signing of the consent will be 
completed prior to the initiation of study procedures.  Medical and surgical history, 
physical examination and labs will also be performed.  To satisfy enrollment criteria, a 
colonoscopy or flexible sigmoidoscopy, or MR enterography, must have been performed 
within the preceding 2 months for clinical purposes to document active inflammation. If 
possible, endoscopic assessment using the SES-CD for CD and the Mayo Score (see 
appendix 4) will be performed.  An upper endoscopy with biopsies may also be 
performed if the physician deems this necessary for clinical assessment. These 
procedures may be done for clinical purposes at an outside facility, in which case 
endoscopic scores may not be available.  
 
3.8 Treatment Phase (Day 0, 7, 14, 21) 
 
On Days 0, 7, 14, and 21, subjects will arrive at the hospital for infusion of study drug, 
eligibility criteria, laboratory assessments, assessment of AEs/SAEs, collection of 
serum, saliva, urine and stool, and assessment of clinical indices.  
 
Safety Monitoring Phase (Day 28, 45, 56, 73) +/- 3 days 
 
During this visit, the patient will return to Children’s National, or be seen by a local 
physician for a follow-up visit, physical exam, laboratory assessments, AEs/SAEs 
assessment, assessment of clinical indices, bloodwork, saliva, urine and stool collected 
for fecal calprotectin. Assessment of symptoms and screening for adverse events may 
be done by telephone if necessary.   
 
Follow-up Phase (Day 180, 360, 720) +/- 28 days 
Subjects will return to Children’s National, or be seen by a local physician, for a physical 
examination and assessment of clinical indices.  If physical examination is obtained by a 
local physician, reports will be emailed or faxed to the study investigator.  Assessment 
of symptoms and screening for adverse events may be done by telephone if necessary.   
 
3.9 Study Procedures 
 
Any procedures performed during this study, such as endoscopy, colonoscopy, or MR 
enterography, will be done for clinical purposes.   
3.9.1 
Phlebotomy  
 

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Research blood will be drawn during screening visit, treatment phase, and safety 
monitoring phase but will not exceed 2 cc/kg or a maximum of 40 ml per blood draw.[53]  
Blood tests run (CBC, CMP, CRP) are considered standard of care.  However, 
additional tissue specimens (urine, saliva, blood, and stool) may be collected and 
banked, if the subject provides consent.  
Any remaining specimens that will be stored for future research will be stored safely and 
securely in a research specimen storage laboratory at the CETI Laboratory at CNMC. 
 
4 
POTENTIAL RISKS AND BENEFITS 
 
4.1 Allogeneic BMSC Infusion 
 
To date, serious complications or side effects from MSC infusions have not been 
described.  In the trial by Forbes, et al., of MSCs in the treatment of adults with luminal 
CD, there was one SAE reported: a subject diagnosed with sigmoid adenocarcinoma at 
the day 42 endoscopy.   The patient was subsequently found to have had low-grade 
dysplasia on sigmoid mucosal biopsy specimen from the entry endoscopy and there 
had been a previous recommendation for colectomy because of mucosal atypia within a 
known proximal rectal stricture. [54] Reported infusion side effects are mild and include 
headache, hives, fever, congestion, and dysguesia (altered taste).  Transfusion 
reactions and allergic reactions have not been reported in published Phase 1 and II 
trials.  
 
 
4.2 Phlebotomy 
 
Blood draws may cause pain and bruising. Sometimes drawing blood causes people to 
feel lightheaded, and very occasionally causes fainting. 
 
 
4.3 Possibility of Direct Benefit 
 
Subjects may or may not receive any direct benefit from participating in this study.  
Subjects may potentially have a decrease in active IBD symptoms, possible induction of 
remission, and possible improved quality of life.  Study medications and study-related 
routine clinical monitoring tests will be provided free of charge.  Results of any 
specialized tests done as part of the study will be made available to interested study 
subjects, their parents, and their healthcare providers.  
 
 
5 
DRUG TOXICITY AND/OR ADVERSE REACTIONS (AES) 
 
Adverse events will be collected as per SOP BMT_SOP003_AE Routine and serious 
adverse events will be collected and reported as per SOP BMT_SOP_004_SAE 
Report.   
 
 

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5.1 ADVERSE EVENT  
 
An AE, as defined by the ICH guideline for GCP, is: 
 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment.  
 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, "reasonable possibility means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug." 
 
An AE is considered to be any adverse change or exacerbation from a baseline 
condition which occurs following the initial administration of an investigational product 
whether or not the event is considered to be related to the investigational product. 
Examples of this include but are not limited to the following: 
 
• 
Adverse changes including new signs and symptoms, intercurrent illness 
modifying the clinical course, or the worsening of a baseline condition including 
the increased frequency of an event or an increased intensity of a condition  
• 
Concomitant disease with onset or increased severity after the start of study 
product administration 
• 
A new pattern in a pre-existing condition, occurring after the receipt of 
investigational product that may signal a clinically meaningful change 
• 
Clinically significant changes in laboratory values 
 
5.2 SERIOUS ADVERSE EVENT 
 
As defined by the Code of Federal Regulations (CFR), a serious adverse event (SAE) is 
any adverse drug experience occurring at any dose that results in any of the following 
outcomes: 
 
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
Congenital anomaly/birth defect.  
 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 

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immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
5.3 UNEXPECTED ADVERSE EVENT 
 
As defined by 21 CFR 312.32 (a), an unexpected adverse drug experience is: 
 
“An adverse event or suspected adverse reaction is considered "unexpected" if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or available, 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended.  For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if 
the investigator brochure referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed only cerebral 
vascular accidents. "Unexpected," as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation.” 
5.4 OTHER ADVERSE EVENT 
 
Other adverse events will be identified by the PI during the evaluation of safety data.  
Significant adverse events of particular clinical importance, other than SAEs and those 
AEs leading to discontinuation of the subject from the study, will be classified as other 
adverse events.  For each, a narrative may be written and included in the clinical study 
report. 
 
5.5 RELATIONSHIP TO TREATMENT 
 
The PI or Sub-I must assign a relationship of each AE to the receipt of the 
investigational product.  The investigator will use clinical judgment in conjunction with 
the assessment of a plausible biologic mechanism, a temporal relationship between the 
onset of the event in relation to receipt of the investigational product, and identification 
of possible alternate etiologies including underlying disease, concurrent illness or 
concomitant medications.  The occurrence of adverse events will be monitored at each 

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visit.  The following guidelines should be used by investigators to assess the 
relationship of an AE to study product administration:   
 
Not related: No relationship to study treatment.  Applies to those events for which 
evidence exists that there is an alternate etiology.  For example, events 
that are clearly related to another medical condition (i.e. diabetes), are 
related to an outside circumstance (i.e. trauma), or that are not temporally 
related to administration of the treatment.  
 
Unlikely: 
Likely unrelated to the study treatment.  Likely to be related to factors 
other than study treatment, but cannot be ruled out with certainty.  The 
need for medical or surgery related to progressive IBD, or known 
symptoms directly related to IBD such as diarrhea, perianal disease, intra-
abdominal or perianal abscess, intra-abdominal fistula, rectal bleeding, 
and weight loss are unlikely to be related to the study treatment.  This also 
includes patients with known history of extraintestinal manifestations 
related to IBD (such as arthralgias, arthritis, uveitis, erythema nodosum, 
pyoderma gangrenosum, or mouth ulcers) who experience such 
symptoms during the treatment period.   
  
Possible: 
An association between the event and the administration of study 
treatment cannot be ruled out.  There is a reasonable temporal 
association, but there may also be an alternative etiology such as the 
subject’s clinical status or underlying factors including other therapy. This 
includes known potential risks of IBD and treatments that the patient is 
receiving, such as infection and lymphoma 
 
Probable: 
There is a high degree of certainty that a relationship to the investigational 
product exists.  There is a reasonable temporal association, and the event 
cannot be explained by known characteristics of the subject’s clinical state 
or factors including other therapy. 
 
Definite: 
An association exists between the receipt of investigational product and 
the event.   An association to other factors has been ruled out. 
 
5.6 INFUSION-RELATED ALLERGIC REACTIONS 
 
The investigators should ensure that appropriate best clinical practices and treatment 
are initiated should an event indicating an allergic or hypersensitive reaction occur. 
Each event will be recorded as an AE or SAE, depending on which criteria are met by 
the event. The start and stop/restart times must be recorded in the CRF. 
 
Should an infusion-related allergic reaction occur the infusion will be stopped 
immediately and the subject closely monitored until stable. An infusion-related allergic 
reaction may appear as flushing, sudden rash, or shortness of breath or difficulty 
breathing. 

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Definitions and grading will follow the current NCI-CTCAE criteria. Current definition and 
suggested treatment plan for infusion-related allergic reaction: 
 
Grade 1: Mild transient reaction 
1. Stop infusion and evaluate for severity. If reaction remains a grade 1 then restart 
at reduced rate. 
2. Reduce infusion rate by 50%,  
3. Treat subject per good clinical practice (suggest antihistamines, corticosteroids, 
etc. as medically indicated) and monitor for worsening condition. 
4. If the reaction persists or worsens the infusion will be discontinued. 
 
Grade 2: Readily responds to clinical treatment (e.g., antihistamines, corticosteroids); 
should consider prophylactic treatment for ≤24 hours. 
1. Stop infusion for up to 3 hours (product should not be infused after 4 hours).  
2. Administer clinical treatment for allergic reaction as medically indicated. 
3. Resume infusion at 50% of previous rate once reaction has decreased to Grade 
1 in severity. Monitor closely for any worsening. 
4. If the reaction reoccurs, stop infusion. Study treatment is to be discontinued. 
 
Grade 3: Prolonged or severe reaction (e.g., not rapidly responsive to treatment or a 
recurrence of reaction after an initial improvement of a Grade 1 or Grade 2 reaction. 
1. Discontinue infusion immediately. Study treatment is to be discontinued 
2. Administer clinical treatment for allergic reaction as medically indicated. 
3. Report as a SAE 
 
Grade 4: Characterized as life-threatening AE; urgent intervention indicated to maintain 
hemostasis. 
1. Discontinue infusion immediately. Study treatment will be discontinued. 
1. Administer clinical treatment for allergic reaction as medically indicated. 
2. Report as a SAE 
 
 
5.7 Severity Assessment 
 
All AEs will be assessed for severity by the investigator. Inherent in this assessment is 
the medical and clinical consideration of all information surrounding the event including 
any medical intervention required. Each event will be assigned one of the following 
categories: mild, moderate, severe, or life-threatening. The criteria below may be used 
for any symptom not included in the grading scale. Any grade 4 (life-threatening) AE 
must be reported as an SAE. 
 
Mild 
                               Grade 1   
Does not interfere with routine activities 
                                                                Minimal level of discomfort  
Moderate 
                    Grade 2          Interferes with routine activities 
                                                                 Moderate level of discomfort  

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Severe 
                     Grade 3         Unable to perform routine activities 
                                                                Significant level of discomfort  
Potentially life-threatening Grade 4       Hospitalization or ER visit for potentially 
                                                                life-threatening event  
 
FDA guidelines for toxicity will be followed; however, if a subject is evaluated in an 
emergency room for nonlife threatening illness or symptoms (i.e., visits emergency 
department on weekend for mild problems because the physician’s office is closed), the 
information from that visit will be reviewed and severity of the adverse event will be 
assessed according to the subject’s clinical signs and symptoms. 
 
 The term “severe” is often used to describe intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself however, may be of 
relatively minor medical significance (such as severe headache). This is not the same 
as “serious”, which is based on subject/event outcome or action criteria usually 
associated with events that pose a threat to a subject’s life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
6 
OFF TREATMENT AND OFF STUDY CRITERIA 
 
Off Treatment Criteria for an Individual Subject  
 
All patients, regardless of reason for withdrawal, will be asked to continue in the follow-
up phase of the study.  An individual subject may be withdrawn from the study for any of 
the following criteria: 
 
• 
An individual subject’s decision (the Investigator will attempt to determine the 
reason for the subject’s decision).  
• 
Non-compliance with the study medication and procedures to the extent that it is 
potentially harmful to the subject or to the integrity of the study data. 
• 
Worsening of IBD symptoms as defined by a PCDAI greater than 50 or PUCAI 
greater than 65. 
• 
Subjects requiring rescue treatment for IBD  
• 
Any clinical AE, laboratory abnormality, or other medical condition or situation 
such that continued participation in the study would not be in the best interest of 
the subject (including changing medication doses due to concern for side 
effects). 
• 
A change in the subject’s baseline condition after enrollment, but prior to start of 
the treatment period so that the subject no longer meets the inclusion/exclusion 
criteria. 
• 
The investigator deems a subject to be no longer fit to participate in the study. 
 
Off Study Criteria for an Individual Subject   
 

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• Completion of study specified procedures. 
• Refusal of further study follow-up by patient or legal 
guardian 
• Lost to follow up 
• Death 
• Physician’s discretion 
• Patient withdrew from study  
• Other  
 
7 
STATISTICAL CONSIDERATIONS 
 
7.1 Statistical Analysis Plan  
 
7.1.1. Sample size and follow up. A maximum of 6 patients will be treated in this pilot 
study. It is anticipated that it will require 18-24 months to accrue 6 patients. With the 
additional 24 months of follow up to evaluate efficacy endpoints noted in Section 2, the 
anticipated trial duration will be 48 months.  
7.1.4. Safety Monitoring and Stopping Rules. For the purpose of safety monitoring, 
“toxicity” will be defined as a probable or definite regimen related severe (grade 3 or 
worse) adverse event occurring at any time from the start of therapy to 45 days 
following the last MSC administration.  If we observe 1 severe (grade 3 or worse) 
adverse event occurring at any time from the start of therapy to 45 days following the 
last MSC administration in the young adult cohort we will stop the study.  If we observe 
no attributable severe adverse events in the young adult cohort, but do observe 1 
severe (grade 3 or worse) adverse events occurring at any time from the start of therapy 
to 45 days following the last MSC administration in the pediatric cohort, we will stop the 
study.  
7.1.3. Future Trials. If the trial is not stopped early, then the toxicity and efficacy data 
will be used to plan a future trial of MSC cell therapy in pediatric patients with either CD 
or UC, including (i) blinded placebo-controlled phase II trials optimizing dose or 
administration schedule, or (ii) randomized comparison to standard therapies.  
 
8 
RECORDS TO BE KEPT  
 
The CETI Research Office will maintain a password protected, restricted access 
database documenting the dates and doses of therapy as well as clinical chemistries 
and hematologic parameters. The clinical status and occurrence of any adverse events 
and subsequent interventions are to be kept on all patients. 
o Imaging reports 
o Surgical summaries 
o Autopsy summaries, where appropriate 

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o Informed consent documents 
All required clinical evaluation records will be the responsibility of Principal Investigator 
who will also be responsible for analysis of the clinical outcome and toxicity. 
The laboratory evaluation of immunological efficacy will be the responsibility of Principal 
Investigator.  
 
8.1 Data Handling and Record Keeping 
 
8.1.1 Data Management Responsibilities 
 
The Investigator is responsible for assuring that the data collected are complete, 
accurate, and recorded in a timely manner.  Source documentation (the point of initial 
recording of information) should support the data collected in the electronic data system 
and must be signed and dated by the person recording and/or reviewing the data.  All 
data should be reviewed by the Investigator and signed as required with electronic 
signature.  
 
8.1.2 Data Capture Methods 
 
Data Collection: The OpenClinica database, a 21CFR11.10 compliant database, will be 
used for data capture. Access to the system will be limited to the study members only. 
The OpenClinica database will be used to capture data as per the protocol required 
assessments (see Table 4.2.2).  
 
All required clinical evaluation records will be the responsibility of principal Investigator 
who will also be responsible for analysis of the clinical outcome and toxicity. 
The laboratory evaluation of immunological efficacy will be the responsibility of Principal 
Investigator.  
 
 
 
8.1.3 Types of Data 
 
Source documents include, but are not limited to, the subject’s medical records, 
laboratory reports, ECG tracings, biopsy reports, clinic notes, pharmacy records, and 
any other similar reports or records of procedures performed during the subject’s 
participation in the study.  
 
8.1.4 Source Documents and Access to Source Data/Documents 
 
Source documents include all recordings of observations or notations of clinical 
activities, and all reports and records necessary for the evaluation and reconstruction of 
the clinical trial.  Data will be collected directly from subjects during study visits and 
telephone calls, or will be abstracted from the subjects’ medical records.  The subject’s 
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(with doses and frequency) or other medical interventions or treatments administered, 
as well as any AEs experienced during the trial.  
 
8.1.5 Record Retention 
 
The investigator is responsible for retaining all essential documents listed in the ICH 
GCP Guideline.  All essential documentation for all study subjects will be maintained by 
the investigators in a secure storage facility for a minimum of 3 years.  The FDA 
requires study records to be retained for up to 2 years after marketing approval or 
disapproval (21 CFR 312.62), or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational agent for a specific 
indication.  These records will also be maintained in compliance with IRB, state and 
federal medical retention requirements, whichever is the longest.  All stored records will 
be kept confidential to the extent required by federal, state, and local law.  Destruction 
of research records will not proceed without permission of the IRB.  
 
The FDA requires that the Investigator must retain study files for a period of at least 5 
years after study completion or 2 years following the date that a marketing application is 
approved for the indication in which the study agent is being investigated (whichever is 
later). 
 
9 
REPORTING REQUIREMENTS  
 
• Discuss all patients with CNMC Research Nurse 
• Enter/Register all patients after calling Principal Investigator. The following forms  
should be completed: 
 
 Eligibility checklist 
 On study form 
 Drug Toxicity and/or Adverse Reactions 
 Adverse events will be collected as per SOPs (BMT_SOP003).  
 Serious adverse events will be collected and reported as per SOP (BMT 
_SOP004).  
 
9.1 Adverse Event Reporting 
 
Reporting of patient serious adverse events (SAEs) will be consistent with standard 
BMT SOP (BMT _SOP004_SAEReport).  Unexpected, grades 4-5AEs must be reported 
within 24 hours of knowledge of the event.  Unexpected, grade 3 AEs must be reported 
within three business days of knowledge of the event. All other unanticipated problems 
will be reported to the IRB within seven (7) business days of knowledge of the problem. 
The Data Review Committee (DRC) Board will receive summary reports of all adverse 
experiences on at least an annual basis. 
 

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9.2 Reporting to the IRB 
 
Following AEs should be considered as unanticipated problems that must be reported to 
the IRB within seven business days of the knowledge of the AE(s): 
Single occurrence of a serious, unexpected, and uncommon event that is strongly 
associated with investigational products exposure 
• 
A single or small number of a serious, unexpected event that is not commonly 
associated with investigational products exposure but is uncommon in the study 
population 
 
• 
Multiple occurrences of an AE that, based on aggregate analysis, is determined 
to be an unanticipated problem. There should be a determination that the series 
of AEs represents a signal that the AEs were not just isolated occurrences and 
involve risk to human subjects  
 
• 
An AE that is described in the investigator’s brochure, protocol, or informed 
consent documents, but occurs at a specificity or severity that is inconsistent with 
prior observations 
 
• 
A serious AE that is described in the investigator’s brochure, protocol, or 
informed consent documents, but for which there is a clinically significant 
increase in the expected rate of occurrence 
 
• 
Any other AE or safety finding, including those based on animal or epidemiologic 
data that would cause the sponsor to modify the investigator’s brochure, protocol, 
or informed consent documents, or would prompt other action by the IRB to 
ensure the protection of human subjects 
 
9.3  Pregnancy Reporting 
 
Each pregnancy must be reported immediately (within 72 hours of identification) by 
reportable event submission system to the CNMC IRB. Subjects who become pregnant 
after Day 0 will be followed to term, and the following information will be gathered for 
outcome, date of delivery, health status of the mother and child including the child’s 
gender, height and weight.  Complications and or abnormalities should be reported 
including any premature terminations. A pregnancy is reported as an AE or SAE only 
when there is suspicion that the treatment may have interfered with the effectiveness of 
contraception or there was a serious complication in the pregnancy including a 
spontaneous abortion or an elective termination for medical rationale. 
 
9.4 IND Annual Report to the FDA 
 
The PI will be responsible for the preparation of a detailed annual synopsis of clinical 
activity, including adverse events, for submission to the sponsor.  Each annual report 

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will summarize IND activity for 1 year beginning approximately 3 months before the IND 
FDA anniversary date.  The sponsor’s representative will notify the PI of the due date 
with sufficient time for the PI to assemble the required information.   
 
9.5  Final Report 
 
A report will be submitted to the FDA in accordance with ICH E3 Guideline “Structure 
and Content of Clinical Study Reports”. A final report will also be submitted to the IRB at 
the time of study closure. 
 
9.6 Reporting to the FDA 
 
Serious adverse events (SAEs) that are unlisted/ unexpected, and at least possibly 
associated to the drug for this study should be reported promptly to the Food and Drug 
Administration (FDA).  Fatal or life threatening SAEs that meet the criteria for reporting 
to the FDA must be reported to the FDA within 7 calendar days after awareness of the 
event by submitting FDA form 3500/MedWatch form.  All other SAEs that meet the 
criteria for reporting to the FDA must be reported to the FDA within 15 calendar days 
after awareness of the event.  A clear description of the suspected reaction should be 
provided along with an assessment as to whether the event is drug or disease related. 
 
 
10 CLINICAL TRIAL OVERSIGHT AND MONITORING 
This protocol will be conducted in accordance with the CNMC BMT Monitoring Plan. 
This protocol will be monitored in accordance with federal regulations and FDA 
guidance documents. 
 
 
The conduct of this clinical trial will be evaluated in accordance with the CNMC BMT 
Quality Assurance Policy and Procedure Plan (SOP: BMT_SOP010_QA). 
 
10.1 Safety monitoring 
 
Safety monitoring will be conducted throughout the study; therefore safety concerns will 
be identified by continuous review of the data by the PI, clinic staff, and Data Review 
Committee (DRC).  
 
10.2 Data Review Committee (DRC)    
 
The Data Review Committee (DRC) is primarily being established to monitor serious 
adverse events which may occur during the trial, complete an annual review of the 
safety data, and to make any recommendations as appropriate. The DRC is required to 
review all unanticipated problems involving risk to subjects or others, SAEs, and all 
subject deaths associated with the protocol and provide an unbiased written report of 

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the event.  The DRC should indicate concurrence or non-concurrence with the details of 
the report provided by the investigator.  Reports for events determined by either the 
investigator or DRC to be related or unrelated to participation and reports of events 
resulting in death should be promptly forwarded to the IRBs. 
 
 

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11 APPENDIX 1: 
11.1 PCDAI 
 
History (Recall, 1 week) 
Abdominal Pain 
 
 
 
0=None 
5= Mild: Brief, does not interfere with activities 
10= Moderate/Severe: Daily, longer lasting, 
affects activities, nocturnal 
 
Patie  It Functioning, General Well-
Being 
 
 
mitation of activities, well 
5=Occasional difficulty in maintaining age-
appropriate activities, below par 
10= Frequent limitation of activity, very poor 
 
As (per day) 
 
 
 
liquid stools, no blood 
5= Up to 2 semi-formed with small blood, or 2-
5 liquid 
10=Gross bleeding, ≥ 6 liquid, or nocturnal 
diarrhea 
 
 
 
 
Laboratory 
HCT 
 
<10 years (male and female) 
 
 
 
11-14 years (Male)  
0= > 34% 
2.5 = 29-33% 
 5 = <29% 
 
 
0 = > 35% 
2.5 = 30-34%  
 
5 = < 30% 
 
 
11-19 years (female) 
 
 
 
 
15-19 years (Male) 
0 = ≥ 34% 
2.5 = 29-33% 
5 = < 29% 
 
0 = ≥ 37% 
2.5 = 32-36% 
 
5 = < 32% 
 
ESR 
0 = < 20 mm/hr  
 
2.5 = 20-50 mm/hr 
 
5 = > 50 mm/hr 
 
Albumin 
0 = ≥ 3.5 g/dL   
 
5 = 3.1-3.4 g/dL  
10 = ≤ 3.0 g/dL 
 

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Examination 
Weight 
0 = Weight gain or voluntary weight 
5 = Involuntary weight stable, 
 
10 = Weight    
stable/loss 
 
 
 
weight loss 1%-9% 
 
 
 
loss ≥ 10% 
 
Height at Diagnosis 
0  = ˂ 1 channel decrease 
5 = ≥ 1, < 2 channel decrease 
 
 
10 = > 2   channel decrease 
 
Height at Follow-Up 
0 = Height velocity ≥ -1 SD 
5 = Height velocity < -1 SD, > 2 SD 
 
10 = height velocity ≤ 2 SD 
Abdomen 
0 = No tenderness, no mass 
5 = Tenderness or mass without tenderness 
10 = tenderness, involuntary 
 
 
 
 
 
 
 
guarding, definite mass 
Perirectal Disease 
0 = None, asymptomatic tags 
5 = 1-2 indolent fistula, scant drainage, 10 = Active fistula, drainage, 
 
No tenderness   
 
 
 
 
 
 
tenderness, or abscess 
 

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Extra-intestinal Manifestations 
Fever ≥ 38.5 for more than 3 days in the past week, definite arthritis, uveitis, E. nodosum, P.gangrenosum 
0 = None 
5= 1 
 
 
 
10= ≥ 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12 APPENDIX 2: 
12.1 PUCAI: 
 
Item 
                                       
                                  Points 
1. Abdominal Pain 
 
No pain 
0 
Pain can be ignored 
5 
Pain cannot be ignored 
10 
 
 
2. Rectal Bleeding 
 
None 
0 
Small amount only, in 
<50% of stools 
10 
Small amount with most 
stools 
20 
Large amount (>50% of 
stool content) 
30 
 
 
3. Stool consistency of 
most stools 
 
Formed 
0 
Partially formed 
5 
Completely unformed 
10 
 
 
4. Number of stools per 
24 hours 
 
0 to 2 
0 
3 to 5 
5 
6 to 8 
10 
>8 
15 
 
 

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5. Nocturnal stools (any 
episode causing 
wakening) 
 
No 
0 
Yes 
10 
 
6. Activity Level 
 
No limitation of activity 
0 
Occasional limitation of 
activity 
5 
Severe restricted activity 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13 APPENDIX 3:   
13.1 CDAI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical or laboratory variable 
Weighting factor 
Number of liquid or soft stools each day for seven days 
x 2 
Abdominal pain (graded from 0-3 on severity) each day for seven days 
x 5 
General well being, subjectively assessed from 0 (well) to 4 (terrible) each day for seven days 
x 7 
Presence of complications 
x 20 
Taking Lomotil or opiates for diarrhea 
x 30 
Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite) 
x 10 
Hematocrit of <0.47 in men and <0.42 in women 
x 6 
Percentage deviation from standard weight 
x 10 
One point each is added for each set of complications: 
●arthralgias or frank arthritis 
●inflammation of the iris or uveitis 
●presence of erythema nodosum, pyoderma gangrenosum, or apthous ulcers 
●anal fissures, fistulae, or abscesses 
●other fistulae 

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14 APPENDIX 4:   
14.1 MAYO SCORE 
Endoscopic findings 
Normal, inactive disease  
0 
  
Mild disease, erythema, decreased vascular pattern, mild friability 
1 
  
Moderate disease, marked erythema, absent vascular pattern, erosions, friability 
2 
  
Severe disease, spontaneous bleeding 
3 
  
  
  
Stool frequency 
Normal for the patient 
0 
  
1-2 more than normal 
1 
  
3-4 more than normal 
2 
  
5 or more stools than normal 
3 
  
  
  
Rectal bleeding 
No blood seen 
0 
  
Streaks of blood with stool less than half the time 
1 
  
Obvious blood with stool most of the time 
2 
  
Blood alone passed 
3 
  
  
  
Physician's Global 
Assessment 
Normal 
0 
  
Mild disease 
1 
  
Moderate disease 
2 
  
Severe disease 
3 
 
 
 
 
 
 

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15 APPENDIX 5:  
15.1 SES-CD SCORE 
 
 
 
 
Score per Segment 
Variable 
0 
1 
2 
3 
Size of ulcers 
None 
Apthous ulcers (0.1-0.5 cm) 
Large ulcers (0.5-2.0 
cm) 
Very large ulcers (> 
2 cm) 
Ulcerated 
surface 
None 
<10% 
10%-30% 
> 30% 
Affected surface  
Unaffected 
segment 
< 50% 
50%-75% 
>75% 
Presence of 
narrowing 
None 
Single, can be passed 
Multiple, can be 
passed 
Cannot be passed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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References: 
 
 
 
1. 
Turner, D., et al., Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. 
Gastroenterology, 2007. 133(2): p. 423-32. 
2. 
Hyams, J.S., et al., Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr, 1991. 12(4): p. 
439-47. 
3. 
Daperno, M., et al., Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. 
Gastrointest Endosc, 2004. 60(4): p. 505-12. 
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