Treatment of Complex Anal Fistulas Using Centrifuged Adipose Tissue Containing Progenitor Cells

Study Overview
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Brief Summary
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In the treatment of complex anal fistulas transplant of freshly collected autologous adipose tissue mechanically fragmented or centrifuged adipose tissue (CAT) might be an alternative to in vitro expanded autologous or allogeneic adipose-derived stem cells, showing remarkable efficacy in diverse therapeutic indications. The aim of our study is to evaluate randomly the efficacy and safety of the use of CAT in the healing process of complex anal fistulas, except for Crohn's disease (CD) related fistulas.

Detailed Description
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This monocentric randomized controlled study was designed to test the efficacy and safety of injection of CAT for treatment of complex fistula-in ano, not associated with CD . The study was conducted at the Second Surgical Unit of the University Hospital of Ferrara, located in the North East of Italy. All consecutive patients referred to our clinic with complex anal fistula were screened. Patients were enrolled from May 2016 through May 2019. Eligible patients were randomly assigned, according to a 1:1 scheme, to receive treatment with or without CAT (120 patients totally). The primary endpoint was defined as the proportion of patients whose fistula was completely healed within 4 weeks after surgery. Fistula healing was defined as the absence of any anal symptom, with no discharge from the fistula and a closed external opening confirmed on clinical evaluation. Fistula healing was eventually confirmed by a pelvic MRI at 3 months after surgery.Moreover, we analyzed postoperative pain measured by Visual Analogue Scale for 2 weeks after surgery to evaluate whether CAT injection could modulate pain, and recurrence at 6 months to evaluate the long-term efficacy of CAT injection. Faecal continence was assessed before surgery and at 6-months follow-up visit using the Cleveland Clinical Florida Fecal Incontinence (CCF-FI) questionnaire. Adipose tissue from periombelical or lateral abdomen was harvested from these patients by liposuction to prepare CAT using Coleman's technique.Complex anal fistulas were treated by conventional surgery. Once the seton (present in the most of patients) was removed, after identification of internal opening, necrotic and inflamed tissues were excised using a cone-like fistulectomy or debrided with a wire brush to remove granulation tissue by the help of fistuloscope (VAAFT modified, without destroying the fistulous track with monopolar electrode). Before CAT injection, the internal opening was treated in two ways: by simply closing it using 2-0 Vicryl stitches on the muscular and mucosal layers or by performing a mucosal advancement rectal flap. CAT was injected into the submucosal layer surrounding the internal opening, and around the fistula tract wall (in case of VAAFT modified) or inside the perianal wound after fistulectomy, using a 1-mL syringe equipped with a 22-gauge and 30-mm length needle, dividing injections at all quadrants of fistula wall, or distributing the CAT inside the perianal wound, at different levels by using multiple passes from the internal to the external openings until there was firm swelling surrounded the fistula tract. The external opening was approximated loosely with a suture to allow drainage of the fistula, but not extrusion of the centrifuged adipose tissue. The amount of product injected may vary depending on the total amount harvested but it should be not less than 10 ml. Patients were assessed for fistula healing, pain (VAS) and AEs at 1 week, 2 weeks, 4 weeks, 8 weeks, three months, and 6 months after treatment. Assessment consisted of clinical examination and AEs and VAS registration. Pelvic MRI was performed at 3 months after surgery. The Cleveland Clinical Florida Fecal Incontinence (CCF-FI) questionnaire was administered before surgery and at 6-months follow-up visit. At the final visit patients were also asked about their overall satisfaction with the procedure, with ratings from very satisfied to very dissatisfied.

Official Title
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Efficacy and Safety of Treatment of Complex Anal Fistulas Not Associated With Crohn's Disease Using Centrifuged Adipose Tissue Containing Progenitor Cells: a Randomized Controlled Clinical Trial

Conditions
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Anal Fistula

Intervention / Treatment
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* Procedure: Autologous centrifuged adipose tissue (CAT) injection after anal fistulectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 years or older with complex perianal fistulas Exclusion Criteria: Inflammatory bowel diseases, Crohn's Disease (CD) or Ulcerative Colitis (UC) Hepatitis B or C virus Infection with Human immunodeficiency virus Surgery for a malignant tumor during the previous 5 years (excluding in situ carcinoma) Previous pelvic radiotherapy Autoimmune disease Active tuberculosis Symptoms of septicemia Breastfeeding or pregnant women Women unwilling to use contraception during the study Psychiatric disorders Alcoholism Drug dependency Allergy to local anesthetics

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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Accepts Healthy Volunteers

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
Interventional Model Description: This monocentric randomized controlled study was designed to test the efficacy and safety of injection of CAT for treatment of complex fistula-in ano, not associated with CD . Eligible patients were randomly assigned, according to a 1:1 scheme, to receive treatment with or without CAT. In the experimental arm, anal fistulas were treated by conventional surgery, and CAT injection. No experimental treatment (CAT) was administered to the control arm.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAT injection group<br>After fistulectomy for complex anal fistula, CAT (harvested from abdominal subcutaneous adipose tissue by Coleman's procedure) was injected into the tissue surrounding the internal opening, and inside the perianal wound obtained after fistulectomy. | Procedure: Autologous centrifuged adipose tissue (CAT) injection after anal fistulectomy<br>* Collection and injection of autologous adipose tissue in complex anal fistulas in one surgical step under locoregional or general anesthesia.<br>|
| No Intervention: No CAT injection group<br>Patients of this group were treated with anal fistulectomy without CAT injection. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fistula healing rate within 6 months after surgery | Fistula healing was defined as the absence of any anal symptom, with no discharge from the fistula and a closed external opening confirmed on clinical evaluation. Fistula healing was eventually confirmed by a pelvic MRI at 3 months after surgery | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of autologous adipose tissue injection | Safety was evaluated by the overall incidence and severity of Adverse Events (AEs) up to 4 weeks following surgery. | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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complex fistula-in ano, adipose tissue, stem cell therapy