Mesenchymal Stem Cells for the Treatment of Rectovaginal Fistulas in Participants With Crohn's Disease

Study Overview
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Brief Summary
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Approximately 10% of all female Crohn's patients have a rectovaginal fistula. Rectovaginal fistulas cause air, stool, and/or drainage per vagina and may be associated with pain, recurrent urinary tract infections and diminished quality of life. Conventional therapy includes immunosuppressive medications used to treat Crohn's disease and various surgical interventions. However, all have limited ability to heal these fistulas. The purpose of this study is to determine the safety and efficacy of using allogeneic bone marrow derived mesenchymal stem cells (MSCs) to treat people with rectovaginal fistulas in the setting of Crohn's disease.

Detailed Description
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This study is designed to determine the safety and efficacy of direct injection of adult allogeneic bone marrow derived mesenchymal stem cells for the treatment of rectovaginal fistulas in the setting of Crohn's disease. 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 patients 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 six month visit to receive an injection of MSCs, and will be followed for one year after treatment for a total duration of 18 months.

Official Title
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A Phase IB/IIA Study of Adult Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Rectovaginal Fistulas in the Setting of Crohn's Disease.

Conditions
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Rectovaginal Fistula, Crohn Disease, Crohn Disease of Vulva, Rectolabial; Fistula

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: Females 18-75 years of age with a diagnosis of Crohn's disease for at least six months duration. Single-tract, rectovaginal fistula in the setting of Crohn's disease. 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, and ability to comply with protocol 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 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 30 days 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 Inability to wean corticosteroids Unwilling to agree to use acceptable contraception methods during participation in study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

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 adult allogeneic bone marrow derived mesenchymal stem cells at a dose of 75 million cells into rectovaginal fistula at baseline with a possible repeat injection at 3 months if not completely healed from the first injection. | Drug: Mesenchymal Stem Cells<br>* Adult allogeneic bone marrow derived mesenchymal stem cells for the treatment of rectovaginal fistulas in the setting of Crohn's disease.<br>|
| Placebo Comparator: Placebo<br>Direct injection of normal saline with a possible repeat injection at 3 months if not completely healed from the first injection. 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 rectovaginal fistula. | 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 rectovaginal fistula in the setting of Crohn's disease as assessed by protocol CCF-Stem Cells IBD-003 | 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 rectovaginal fistula 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 complete closure of the fistula tract upon assessment with an examination under anesthesia | 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 rectovaginal fistula 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 partial closure of the fistula tract upon assessment with an examination under anesthesia | 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 rectovaginal fistula 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 post-injection of 75 million allogeneic bone marrow derived MSC's for the treatment of rectovaginal fistula 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, rectovaginal fistula, mesenchymal stem cells, mesenchymal stem cell