Mesenchymal Stem Cells for the Treatment of Perianal Fistulizing Crohn's Disease (PFCD)

A Phase IB/IIA Study of Adult Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Perianal Fistulizing Crohn's Disease

The purpose of this study is to determine the safety and efficacy of using adult allogeneic bone marrow derived mesenchymal stem cells (MSCs), to treat people for medically refractory perianal fistulizing Crohn's disease.

Crohn's disease (CD), a chronic transmural inflammatory disease of the gastrointestinal tract, continues to increase in incidence for unknown reasons. According to population based studies, at least 26% of patients with CD will develop perianal fistulas in the first two decades following diagnosis, particularly those with colonic and rectal involvement. These patients experience significant morbidity due to pain, persistent drainage, recurrent perianal sepsis, and ongoing need to access medical care resulting in increased costs and impaired quality of life. Unfortunately, perianal fistulizing Crohn's disease is notoriously difficult to cure with 37% of patients experiencing refractory disease. As a result, patients cycle through numerous immunosuppressive medications that can have significant side effects, and >90% undergo multiple surgical interventions putting them at risk of incontinence. The specific rationale for MSCs in perianal Crohn's fistulas is based upon 1) their anti-inflammatory and immunomodulatory properties; 2) several studies reporting the safety and efficacy of MSCs for the treatment of perianal Crohn's fistula; 3) existence of safe manufacturing methods for isolation and expansion of MSCs. This study will enroll 20 participants that have Crohn's disease with medically and surgically refractory perianal fistulizing disease. Participants enrolled will be those that meet particular criteria for participation in the clinical trial. Enrolled participants will be randomized to treatment group with adult allogeneic bone marrow derived mesenchymal stem cells, 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 again three months after this as above, and will be followed for one year after treatment to a total duration of 18 months.

Direct injection of adult allogeneic bone marrow derived mesenchymal stem cells, at a dose of 75 million cells into perianal fistula(s) at baseline with a possible repeat injection at 3 months if not completely healed from the first injection.

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 adult allogeneic bone marrow derived mesenchymal stem cells, at a dose of 75 million cells into perianal fistula(s)

Direct injection of adult allogeneic bone marrow derived mesenchymal stem cell product, at a dose of 75 million cells into perianal fistula(s)

Number of participants with treatment related adverse events post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of perianal fistula(s) in the setting of Crohn's disease as assessed by protocol CCF-Stem Cells IBD-001

Number of participants with complete clinical healing post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of perianal fistula(s) in the setting of Crohn's disease. 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

Number of participants with partial clinical healing post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of perianal fistula(s) in the setting of Crohn's disease Partial clinical 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

Number of participants with lack of response post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of perianal fistula(s) 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

Number of participants with worsening of disease post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of perianal fistula(s) 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

Inclusion Criteria Men and Women 18-75 years of age with a diagnosis of Crohn's disease for at least six months duration. Single and Multi-tract Perianal fistula, with or without previous failed surgical repair. Have no contraindications to MR evaluations: e.g. pacemaker or magnetically active metal fragments, claustrophobia Ability to comply with protocol Competent and able to provide written informed consent Concurrent Crohn's-related therapies with stable doses (>2 months) corticosteroids, 5- ASA drugs, immunomodulators, anti-TNF therapy, anti-integrin and anti-interleukin therapies are permitted 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 subject. Specific exclusions: Hepatitis B or C HIV 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 one month of treatment Pregnant or breast feeding or trying to become pregnant. Presence of a rectovaginal or perineal body fistula Change in Crohn's immunosuppressive regimen within the 2 months prior to enrollment Uncontrolled intestinal Crohn's disease which will require escalation for medical therapy or surgery within 2 months of enrollment Severe anal canal disease that is stenotic and requires dilation Female participant unwilling to agree to use acceptable contraception methods during participation in study

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