Stem Cells for the Treatment of Pouchitis

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and feasibility of using allogeneic bone marrow derived mesenchymal stem cells (MSCs) to treat people with medically refractory Pouchitis.

Detailed Description
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Proctocolectomy with ileal pouch anal anastomosis (IPAA) remains the procedure of choice for patients with chronic ulcerative colitis (CUC). IPAA allows at-risk tissue to be removed with restoration of intestinal continuity while maintaining favorable long-term functional outcomes and quality of life. While less than 30% of patients experience short-term postoperative morbidity following IPAA, up to 15% of pouches will ultimately fail due to technical or inflammatory complications, the majority of which manifest as a fistula from the pouch to the perianal or vaginal locations. After anastomotic leak, the second leading cause of pouch fistulas is the development of Crohn's disease of the pouch. While the majority of pouches are constructed for CUC, up to 25% will end up having a change in diagnosis to CD which manifests as refractor pouchitis, strictures of the proximal small bowel, or most often as peripouch fistulas. Pouch failure due to refractory pouchitis are notoriously difficult to treat, and reconstructive pouch surgery or transanal repairs are often not offered due to suspicion of recurrent pouchitis following pouch reconstruction. The reality is that patients with refractory pouchitis will end up with a major reconstructive transabdominal operation in a select few for attempt at pouch salvage, or, most likely, a permanent end ileostomy after pouch excision. This can be a devastating outcome in some patients as it impacts body image and quality of life. Similar to refractory pouchitis, Crohn's related perianal and rectovaginal fistula are other phenotypes of inflammatory bowel disease that are also notoriously difficult to treat with conventional medical and surgical options. Despite an ever expanding repertoire of biologic therapy and surgical intervention, sustained healing rates are less than 30%. This has driven investigators to search for alternative approaches, and in 2003 investigators reported successful healing of a refractory Crohn's rectovaginal fistula following injection of mesenchymal stem cells (MSCs). Following this success, several phase I, II, and III trials designed to study the safety and efficacy of MSCs for perianal CD, all of which have reported encouraging results with superior efficacy compared to conventional medical and surgical therapies. Over 300 perianal CD patients have now been treated without increase in adverse events and no risk of incontinence. Given the high safety profile, and substantial success in treating perianal CD, the investigators are using a GMP grade allogeneic adipose derived MSCs to establish safety and secondarily monitor for healing in patients with medically refractory pouchitis. This trial will use allogeneic bone marrow derived mesenchymal stem cells (MSCs) to produce regenerative signals which alter the ileal pouch microbiome and local inflammatory mileau. Patients with CD of the pouch suffer chronic immunosuppression and surgical intervention and desperately need an improved therapeutic. The research aims to address the root cause of this inflammation, especially the interactions of the intestinal microbiome and host immune response through a novel therapeutic approach. The specific rationale for MSCs in medical refractory pouchitis is based opon 1) their anti-inflammatory properties; 2) published experience of MSC in this condition and perianal Crohn's fistula demonstrating efficacy and safety; 3) existence of cGMP methods for their isolation and growth. The study will enroll adult patients with medically refractory pouchitis, whose next option in the treatment plan would be major reconstructive abdominal surgery or pouch excision with a permanent end ileostomy.

Official Title
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A Phase I Study of Bone Marrow Derived Mesenchymal Stem Cells (MSCs) for the Treatment of Medically Refractory Pouchitis

Conditions
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Pouchitis, Crohn's Disease, Pouch, Ileal, Ulcerative Colitis Chronic, Inflammatory Bowel Diseases

Intervention / Treatment
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* Drug: Mesenchymal Stem Cells (MSCs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women 18-75 years of age Residents of the United States Medically refractory pouchitis defined as lack of response to antibiotics, immunomodulators, and/or biologics Concurrent therapies with corticosteroids, 5-ASA drugs, thiopurines, MTX, antibiotics, anti-TNF therapy, anti-integrin and anti-interleukin are permitted if have been on them for at least 2 months prior to study enrollment without change No malignant or premalignant intestinal condition, ruled out on colonoscopy within 90 days of MSC delivery Ability to comply with protocol Competent and able to provide written informed consent Must have failed or have a contraindication to standard medical therapy including anti-TNF, anti-interleukin, or anti-integrin agent Exclusion Criteria: Inability to give informed consent Clinically significant medical conditions within the six months before administration of MSCs: e.g. myocardial infarction, active angina, congestive heart failure or other conditions that would, in the opinion of the investigators, compromise the safety of the patient Specific exclusions: HIV Hepatitis B or C Abnormal CBC at screening Abnormal AST or ALT at screening History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment Investigational drug use within thirty (30) days of baseline Pregnant or breastfeeding Multifocal proximal small bowel involvement which resembles Crohn's of the small bowel Evidence of pelvic sepsis and pelvic penetrating fistulizing disease Patients with intestinal diversion above the level of the pouch Neoplasia of pouch Change in medical regimen for pouchitis in the two months prior to study enrollment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment Arm<br>Submucosal endoscopic injection of 60 million allogeneic bone marrow derived mesenchymal stem cells (MSCs) into ileal pouch at baseline and possibly again after 3 months if not completely healed. | Drug: Mesenchymal Stem Cells (MSCs)<br>* Endoscopic injection of allogeneic bone marrow derived mesenchymal stem cells (MSCs) to the ileal pouch.<br>* Other names: Allogeneic Bone Marrow Derived Mesenchymal Stem Cells (MSCs);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Number of adverse events that occur throughout the study. | Change from Baseline over 12 months after the MSC injection | 
| Healing | PDAI endoscopic activity less than or equal to 1, Clinical PDAI score less than or equal to 2, and total PDAI less than or equal to 4 | Change from Baseline over 12 months after the MSC Injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoscopic Remission | PDAI endoscopic activity less than or equal to 1 Mayo Endoscopic score less than or equal to 1, defined as the absence of friability or ulceration | Change from Baseline over 12 months after the MSC Injection | 
| Clinical Remission | Clinical PDAI score less than or equal to 2 MDPAI score less than or equal to 4 | Change from Baseline over 12 months after the MSC Injection | 
| Endoscopic Improvement | Reduction in the endoscopic PDAI score, but still greater than 1 Reduction in the Mayo endoscopic score, but still greater than 1 Reduction in endoscopic MPDAI score by 2 or more points | Change from Baseline over 12 months after the MSC Injection | 
| Clinical Improvement | Reduction in the clinical PDAI score of 2 or more points Reduction in the Clinical MPDAI score of 2 or more points Decrease in 24-hour stool frequency | Change from Baseline over 12 months after the MSC Injection | 
| Partial Clinical Healing measured with the Pouchitis Disease Activity Index No No response | No improvement in the PDAI overall, endoscopic, or clinical scores No decrease in Mayo endoscopic severity score No decrease in 24 hour stool frequency | Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection | 
| Partial Clinical Healing | Decrease in C-reactive protein serum levels by greater than 50% | Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection | 
| Partial Clinical Healing | Decreased mucosal ulceration on pouchoscopy | Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection | 
| Partial Clinical Healing | Improved healing on endoscopic biopsy or surgical pathology as compared to pre-MSC delivery endoscopic biopsies. | Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection | 
| Assess for alloimmune response | Measure HLA Class B Antibody Screening | Baseline, 1 month, 3 month, 12 month after MSC injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pouchitis, Mesenchymal Stem Cells, Crohn's Disease, Inflammatory Bowel Diseases, Ulcerative Colitis