Safety and Tolerability Of Allogeneic Mesenchymal Stromal Cells in Pediatric Inflammatory Bowel Disease

Study Overview
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Brief Summary
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In this trial, investigators will infuse donor bone marrow mesenchymal stromal cells intravenously, as a treatment for pediatric Crohn's disease or ulcerative colitis that has not responded to conventional therapies. The goals of this study are to test the safety and tolerability of donor mesenchymal stromal cells in children with Inflammatory Bowel Disease. Mesenchymal stromal cells support the development of blood cells within the bone marrow. When isolated from a donor and infused into an animal or human, they have been demonstrated to travel to areas of inflammation, to alter immune responses, to decrease pro-inflammatory cytokines, and to promote tissue repair. Infusion of these cells does not lead to rejection. These properties lead investigators to hypothesize that that these may be they may be beneficial in treating inflammatory bowel disease.

Detailed Description
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In this trial, investigators will infuse donor bone marrow mesenchymal stromal cells intravenously, as a treatment for pediatric Crohn's disease or ulcerative colitis that has not responded to conventional therapies. Mesenchymal stromal cells support the development of blood cells within the bone marrow. They have also been demonstrated to travel to areas of inflammation, to alter immune responses, to decrease pro-inflammatory cytokines, and to promote tissue repair. Infusion of these cells does not lead to rejection. These properties lead investigators to hypothesize that that these may be they may be beneficial in treating inflammatory bowel disease. Investigators will culture donated bone marrow mesenchymal stromal cells in a unique automated system, and infuse the cells in a fresh, replicating stage of growth. This study is to test the safety and tolerability of donor mesenchymal stromal cells in children with Inflammatory Bowel Disease.

Official Title
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Safety and Tolerability Of Allogeneic Mesenchymal Stromal Cells in Pediatric Inflammatory Bowel Disease

Conditions
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Inflammatory Bowel Diseases

Intervention / Treatment
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* Biological: Allogeneic bone marrow-derived mesenchymal stromal cells


Participation Criteria
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Eligibility Criteria
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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. Clinically significant abnormal biochemical and hematological parameters, including: Neutrophil count < 1000 cells/mm3 Hemoglobin < 8 g/dl Platelet count ≤ 130 cells/mm3 Creatinine ≥ 1.2 x the upper limit of normal Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥ 2x the upper limit of normal 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

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesenchymal Stromal Cells (MSCs)<br>A fixed dose of Mesenchymal Stromal Cells (MSCs) 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. | Biological: Allogeneic bone marrow-derived mesenchymal stromal cells<br>* 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). 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Experience Serious Adverse Events, Adverse Events, and/or Early Treatment Discontinuations. | 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. Weekly infusions for 8 weeks, post-treatment assessment 45 days after last infusion, three additional follow-up visits over 2 years. | 45 days after the last infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Clinical Response | Proportion of subjects that achieve a clinical response by 45 days after last infusion, as defined by a decrease in PCDAI from baseline by greater than or equal to 12.5 points (for CD) or a decrease in PUCAI of greater than or equal to 20 points (for UC). | 45 days after last infusion | 
| Number of Subjects Demonstrating an Improvement of Laboratory Tests Reflecting Systemic Inflammation. | Improvement in laboratory parameters (i.e. C-reactive protein, fecal calprotectin, anti-HLA antibodies, and viral specific T-cell activity) | 45 days after last infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn disease, ulcerative colitis, mesenchymal stromal cells, inflammatory bowel diseases