Safety and Efficacy of Adipose-Derived Stem Cells to Treat Complex Perianal Fistulas Patients With Crohn's Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine safety and efficacy of eASCs (expanded adult stem cells) for treatment of complex perianal fistulas in patients with Crohn's disease.

Detailed Description
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Complex perianal fistulas are a source of great distress for suffers. In Crohn's disease, options are limited, and surgery is often associated with incontinence and recurrence. The biological properties of stem cells derived from adult tissues make them candidates for the treatment of pathologies requiring tissue regeneration or in diseases where the healing process is altered. A proof-of-concept study, a phase 1 study and a phase 2 study [Clinicaltrials.gov identifier: NCT00115466] have all suggested that this approach is promising, even in patients whose fistula is associated with Crohn's disease. The present multicenter, placebo-controlled, phase 3 study aims to confirm the efficacy and safety shown in the previous phase 1 and phase 2 studies in the treatment of complex perianal fistulas in patients with Crohn's disease after 24 weeks from initial administration. Fistula closure is defined as absence of suppuration through the external orifice with complete re-epithelization of the external orifice and absence of collections >2cm directly related to the fistula tract treated, as measured by MRI.

Official Title
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Randomized, Single-blind, Placebo Controlled Multicenter Phase III Study to Assess the Efficacy and Safety of Expanded Autologous Adipose-derived Stem Cells (ASCs) (CX-401), for Treatment of Complex Perianal Fistulas in Perianal Crohn's Disease

Conditions
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Complex Perianal Fistula, Crohn Disease

Intervention / Treatment
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* Drug: Expanded autologous adipose-derived adult stem cells (eASCs)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Patients with Crohn's disease diagnosed at least 12 months earlier in accordance with accepted clinical, endoscopic, anatomopathological and/or radiologic criteria Presence of complex perianal fistula with 3 or fewer fistulous tracts assessed by MRI Patients with persistent and active complex perianal fistula and non-active luminal Crohn's disease defined by a CDAI ≤ 200. (Complex perianal fistula is defined as a fistula that meets one or more of the following criteria: High fistulas [high inter-sphincteric, high trans-sphincteric, extra-sphincteric or supra-sphincteric], presence of 3 or fewer external openings [tracts] associated with a complex perianal fistula, or pain/fluctuation Good general state of health according to the findings of the clinical history and the physical examination Women of a childbearing age with negative serum or urine pregnancy test (sensitive to 25 IU hCG). Both men and women should use appropriate birth control methods defined by the investigator Exclusion Criteria: Presence of severe proctitis (prominent friability, spontaneous bleeding, multiple erosions, deep ulcers) or dominant active luminal disease requiring immediate therapy, assessed by rectosigmoidoscopy Patients with a CDAI ≥201 Patients with an abscess unless a complete toilet of the area with drainage of the collections and the absence of abscess and other collections is confirmed prior to treatment start The presence of setons unless removed prior to the study procedure Presence of >3 fistulous tracts and/or external openings Patients with rectal and/or anal stenosis evaluated by rectoscopy or EUA Patients who have received infliximab or any other anti-TNF agent in the 8 weeks before the cell treatment administration Patients who have received tacrolimus or cyclosporine in the 4 weeks before the cell treatment administration Patients with rectovaginal fistula, anal fistula(s), and/or non-perianal enterocutaneous fistula Patients with HIV, HBV, HCV or treponema infection, whether active or latent Patients with a history of abuse of alcohol or other addictive substances in the 6 months prior to inclusion Patients with malignant tumor, except for basal cell or cutaneous squamous cell carcinoma, or patients with a prior history of malignant tumors, unless the neoplastic disease has been in remission for the previous 5 years Patients with cardiopulmonary disease which, in the opinion of the investigator, is unstable or sufficiently serious to exclude the patient from the study. Patients with any type of medical or psychiatric disease which, in the opinion of the investigator, could be grounds for exclusion from the study Patients with congenital or acquired immunodeficiencies Patients with abnormal laboratory test findings that contraindicate their inclusion in the study Patients allergic to local anesthetics or gadolinium (MRI contrast) MRI is unfeasible, (e.g. due to the presence of pacemakers, hip replacements or severe claustrophobia) Liposuction with extraction of at least 100 cm3 of fat from the abdominal wall is technically unfeasible or the patient does not consent to the procedure Patients in need of surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study, or a need for such surgery is foreseen in this region in the 26 weeks after treatment administration. Patients who have suffered major surgery or severe trauma in the prior 6 months Pregnant or breastfeeding women Patients who do not wish to or cannot comply with study procedures Patients currently receiving, or having received within 1 month prior to enrolment into this clinical trial, any investigational drug Patients unlikely to comply with study procedures

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASCs<br>Intralesional dose of 20 million cells at baseline with a possible second administration of 40 million cells in case of incomplete fistula closure following week 12 assessment. | Drug: Expanded autologous adipose-derived adult stem cells (eASCs)<br>* Administration will be preceded by localization and closure of the internal opening. Cell treatment injection will be performed following Major Ambulatory Surgery standards. Patients will receive an intralesional dose of 20 million cells at baseline. 50% of the cell suspension will be placed into the fistula walls of the internal opening, with the remaining 50% being injected across the wall tracts of the target fistula. Patients without healing (complete fistula closure) at week 12 will receive a second dose of 40 million cells, using the same treatment approach.<br>* Other names: Ontaril®;|
| Sham Comparator: Placebo<br>Instillation of saline solution into the fistulous tract, following identical tract preparation process as for the investigational treatment group. | Drug: Placebo<br>* Administration will be preceded by localization and closure of the internal opening following Major Ambulatory Surgery standards. Subjects will be receiving one treatment cycle with placebo consisting of intralesional instillation of 5 ml saline solution. Patients without healing (complete fistula closure) following week 12 assessment will continue to receive standard of care until the primary assessment of fistula closure at week 24. Patients with incomplete fistula closure at week 24 will be offered the possibility of participating in a separate open-label, single arm study using the ASCs derived from the liposuction procedure.<br>* Other names: Normale saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects in whom the external openings of the treated perianal fistula have closed |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects in whom the external openings of the treated perianal fistula have closed |  | 12 weeks | 
| Changes over time in the Perianal Disease Activity Index |  | 4, 10, 12, 16, 22 and 24 weeks | 
| Changes over time in the Crohn's Disease Activity Index |  | 10 and 22 weeks | 
| Changes over time in the MRI Score of Severity (MSS) |  | 12 and 24 weeks | 
| Quality of life assessment using the SF-36 questionnaire |  | 12 and 24 weeks | 
| Percentage of subjects for whom surgery is avoided |  | 24 weeks | 
| Adverse events |  | 4, 10, 12, 16, 22 and 24 weeks | 
| Clinically relevant variations in vital signs |  | 4, 10, 12, 16, 22 and 24 weeks | 
| Clinically relevant variations in laboratory tests |  | 4, 10, 12, 16, 22 and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complex perianal fistula, Crohn disease, Adipose-derived stem cells, Liposuction