Study of Mesenchymal Stem Cells for the Treatment of Ileal Pouch Fistula's in Participants With Crohn's Disease

Study Overview
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Brief Summary
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Restorative proctocolectomy with ileal pouch anal anastomosis (IPAA) is the procedure of choice for patients with ulcerative colitis, familial adenomatous polyposis, and select patients with Crohn's disease due to overall low patient morbidity and good quality of life. However, some patients can develop Crohn's disease of the pouch, a clinical diagnosis of Crohn's disease following IPAA. One of the manifestations of Crohn's disease of the pouch includes a fistula from the pouch that travels to the vagina or perianal area. These fistulas can be quite difficult to manage with medications and local surgical intervention, and, on occasion result in a reconstruction pouch but more often require a pouch excision with permanent end ileostomy. The purpose of this study is to evaluate the safety and efficacy of using allogeneic bone marrow derived mesenchymal stem cells to treat people who have a peri-pouch fistula related to a clinical diagnosis of Crohn's disease of the pouch.

Detailed Description
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This aim of this study is to determine the safety and efficacy of adult allogeneic bone marrow derived mesenchymal stem cells (MSCs), for the treatment of medically refractory peri-pouch fistulizing disease in the setting of Crohn's disease of the pouch. The study will randomize 20 participants. Enrolled participants will be randomized to treatment group with MSCs, versus placebo in a 3:1 fashion. Participants in the treatment group will have a direct injection of MSCs at a dose of 75 million cells. This will be given as a direct injection in and around the fistula tract. Participants will be evaluated for complete healing at three months. If complete healing has been achieved participants will continue to be followed for one year. If complete healing has not been achieved at three months, participants will be eligible for a second injection of MSCs at the same dose of 75 million cells. Control participants without complete healing from placebo will cross over at the 6 month visit to receive an injection of MSCs and will be followed for one year after treatment to a total duration of 18 months. The primary efficacy analysis will be conducted at the month 6 time point.

Official Title
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A Phase IB/IIA Study of Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Ileal Anal Anastomosis and Ileal Pouch Fistulas in the Setting of Crohn's Disease of the Pouch

Conditions
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Ileal Pouch, Crohn Disease

Intervention / Treatment
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* Drug: Mesenchymal stem cells
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Men and women 18-75 years of age who have undergone an ileal pouch anal anastomosis at least 6 months prior who have developed a clinical diagnosis of Crohn's disease of the pouch as determined by a combination of clinical symptoms, pouchoscopy with biopsy, enterography. Single and multi-tract (up to 2 internal and 3 external openings) fistula tract arising from the ileal pouch, ileal anal anastomosis, or anal canal distal to anastomosis that travels to the perianal skin, perineal body, or vagina. Patients with fistulas that arise from the pouch, anastomosis, or anal canal distal to the anastomosis will both be included in enrollment. Acceptable internal openings and tract locations for the fistula to arise from include the ileal pouch body, the pouch anal anastomosis, and the anal canal distal to the anastomosis. Acceptable external openings and tract locations for the fistula to arise from include the perianal skin, perineal body, and/or the vaginal wall. Concurrent Crohn's related therapies with stable doses (>2 months) corticosteroids, 5-ASA drugs, immunomodulators, anti-TNF therapy, anti-integrin and anti-interleukin are permitted. Have failed conventional medical therapies described above, defined as a lack of response to systemic immune suppression (e.g. azathioprine, methotrexate, 6-mercaptopurine) or biologic (e.g. anti-TNF, anti-integrin, anti-interleukin) therapies to treat fistulizing CD for at least 2 months Have no contraindications to MR evaluations: e.g. pacemaker or magnetically active metal fragments, claustrophobia Competent and able to provide written informed consent Ability to comply with protocol. Exclusion Criteria Inability to give informed consent. Severe antibiotic refractory pouchitis Severe cuffitis refractory to antibiotics Change in medical management for CD in the previous 2 months or changes anticipated in the next 2 months 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 subject. Specific exclusions; HIV Hepatitis B or C Abnormal CBC at screening i. Platelets <50 kg/uL or greater than 1.5 million kg/uL ii. WBC <50 x kg/uL iii. Hbg <7.0 g/dL d. Abnormal AST or ALT at screening(defined as >/= 2x ULN) History of cancer including melanoma (with the exception of localized skin cancers) within one year of screening History of colorectal cancer within 5 years Investigational drug within thirty (30) days of baseline Pregnant or breast feeding or trying to become pregnant Branching fistula tract that has > 2 internal openings or 3 external openings, Subjects with greater than 3 blind/branching tracts are excluded Fistula tracts on the left and/or right side are allowed Allergic to local anesthetics Unwilling to agree to use acceptable contraception methods during participation in study Subjects with a non-abscessed chronic cavity will not be included in 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mesenchymal stem cells<br>Direct injection of allogeneic bone marrow derived mesenchymal stem cells at a dose of 75 million cells into the ileal pouch fistula(s) at baseline with a possible repeat injection at 3 months if not completely healed from the first injection. | Drug: Mesenchymal stem cells<br>* Allogeneic bone marrow derived mesenchymal stem cells<br>|
| Placebo Comparator: Placebo<br>Direct injection of normal saline. If not completely healed after 6 months, participants will then cross over to the treatment group to receive a direct injection of allogeneic bone marrow derived mesenchymal stem cells at a dose of 75 million cells into ileal pouch fistula(s). | Other: Placebo<br>* Normal Saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related adverse events | Number of participants with treatment related adverse events post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of medically refractory pouch fistulizing disease as assessed by protocol CCF-Stem Cells IBD-002 | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete clinical healing | Number of participants with complete clinical healing post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of medically refractory pouch fistulizing disease in the setting of Crohn's disease of the pouch. Complete Healing is defined as: Radiographic Healing: MRI with an absence of a fluid collection >2 cm in 3 of 3 dimensions, lack of edema, inflammation or sign of active inflammatory response. A remnant scar of a fistula tract may remain Clinical Healing: 100% cessation of drainage on both clinical exam with deep palpation and per patient report and epithelization of the external fistula opening | Month 6, Month 12 | 
| Partial healing | Number of participants with partial clinical healing,post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of medically refractory pouch fistulizing disease in the setting of Crohn's disease Partial Healing is defined as: Radiographic Healing: MRI with an absence of a fluid collection >2 cm in 2 of 3 dimensions, lack of edema, inflammation or sign of active inflammatory response. A remnant scar of a fistula tract may remain Clinical healing: Greater than or equal to 50 % cessation of drainage on both clinical exam with deep palpation and per patient report and epithelization of the external fistula opening | Month 6, Month 12 | 
| Lack of response | Number of participants with lack of response post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of medically refractory pouch fistulizing disease in the setting of Crohn's disease Lack of Response is defined as: Radiographic and Clinical healing which does not meet the threshold for Partial Healing | Month 6, Month 12 | 
| Worsening disease | Number of participants with worsening disease-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of medically refractory pouch fistulizing disease in the setting of Crohn's disease Worsening Disease is defined as: Radiographic: MRI with a fluid collection >2 cm in 2 of 3 dimensions, edema, inflammation or sign of active inflammatory response. An increased number of tracts may be seen, or increased branching from the primary tract, Clinical: Increased drainage per patient report and on clinical exam | Month 6, Month 12 |