Mesenchymal Stem Cells for the Treatment of Pouch Fistulas in Crohn's (IPAAF)

A Phase I 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

This clinical trial was entered in error. Please refer to the correct entry of this study using the following link: https://clinicaltrials.gov/ct2/show/NCT04519684

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 an ileal pouch anal anastomosis (IPAA) who develop a fistula in the setting of Crohn's disease of the pouch.

Proctocolectomy with ileal pouch anal anastomosis (IPAA) remains the procedure of choice for patients with ulcerative colitis (UC). 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. Pouch failure due to a fistula tract is notoriously difficult to treat. Despite immunosuppressive medications and attempts at local repair, most patients will end up with a pouch excision and permanent ostomy. This can be a devastating outcome in some patients as it impacts body image and quality of life. Pelvic sepsis following original IPAA has been reported in 5% to 25% of patients, and is the leading cause of pouch failure due to the development of pelvic fibrosis and decreased distensibility of the pouch, ultimately resulting in poor pouch function. One of the leading causes of pelvic sepsis and development of a pouch fistula is Crohn's Disease (CD) of the pouch. While the majority of pouches are constructed for UC, up to 25% of patients with an IPAA will end up having a change in diagnosis from UC to CD or development of de novo CD of the pouch. The first report of successful healing of a Crohn's fistula with mesenchymal stem cells (MSCs) was in 2003. Since them great enthusiasm has spurred several phase I phase II, and phase III trials designed to study the safety and efficacy of MSCs for perianal CD, all of which have reported encouraging results with regard to safety and efficacy. With over 300 patients now treated, there is a large body of evidence supporting the local delivery of MSCs to heal perianal Crohn's fistulas. Peri-pouch fistulas are similar to Crohn's perianal fistulas except that instead of the rectum containing the internal opening of the fistula, the internal opening is in the ileal pouch, constructed in place of the rectum. Given the high safety profile and relative success in treating perianal Crohn's disease with mesenchymal stem cells, the investigators are using a GMP grade allogeneic bone marrow derived MSC cell line to establish safety and secondarily monitor for healing in patients with ileal pouch fistulas in the setting of Crohn's disease of the pouch. This trial will use allogeneic bone marrow derived mesenchymal stem cells (MSCs) to produce regenerative signals. The specific rationale for MSCs in IPAA is based upon 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. This study will enroll adult men and women who have undergone IPAA at least six months prior and now have a peri-pouch fistula related to Crohn's disease of the pouch. Patients who are refractory to conventional medical therapy will be considered. Patients enrolled will be those that meet current indications.

Direct injection of 75 million allogeneic bone marrow derived mesenchymal stem cells (MSC) into ileal pouch fistula at baseline and possibly again after 3 months if not completely healed.

Allogeneic bone marrow derived mesenchymal stem cells (MSCs) direct injection to an ileal pouch fistula in the setting of Crohn's disease of the pouch

Evaluate the number of adverse event occurring during the trial (including clinically significant changes in physical examination, radiographic images, safety lab tests, vital signs).

Baseline, Drug administration Visit, Day 1, 1 week, 2 weeks, 1 month, 2 months, 3 month, 6 month, 12 month after each MSCs injection

Number of Participants with: Complete 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 Partial 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 Partial Response MRI with an absence of a fluid collection >2 cm in 2 of 3 dimensions, lack of worsening inflammation or new tracts formed Lack of Response Radiographic healing which does not meet the threshold for Partial Response Decreased symptoms Greater than 50% reduction in drainage as reported by the patient at study visits.

Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 month, 6 month, 12 month after each 100% cessation of drainage on both clinical exam with deep palpation and per patient MSCs injection

Number of Participants with: Complete Healing 100% cessation of drainage on both clinical exam with deep palpation and per patient report and epithelization of the external fistula opening Partial 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 Partial Response Less than 50% cessation of drainage on both clinical exam with deep palpation and per patient report and epithelization of the external fistula opening Lack of Response Clinical healing which does not meet the threshold for Partial Response Decreased symptoms Greater than 50% reduction in drainage as reported by the patient at study visits.

Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 month, 6 month, 12 month after each 100% cessation of drainage on both clinical exam with deep palpation and per patient MSCs injection

Measure HLA Class I & II SAB Antibody Screening - measures the presence (positive) or absence (negative) of antibodies

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 (>3 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 3 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 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) 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, Patients 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 Patients with a non-abscessed chronic cavity will not be included in enrollment Known allergy to DMSO solution

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