Autologous adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistula: A randomized clinical trial with long-term follow-up.

Mariano Garcia-Arranz,Damián Garcia-Olmo,Jorge Baixauli,Fernando Portilla,María Dolores Herreros,José Gracia-Solana,Jacinto Garcia-Garcia,Héctor Guadalajara,The Fispac Collaborative Group ,José Manuel Ramirez,Felipe Prosper,Fermín Sanchez-Guijo

doi:10.1002/sctm.19-0271

Abstract

The aim of this clinical trial (ID Number NCT01803347) was to determine the safety and efficacy of autologous adipose‐derived stem cells (ASCs) for treatment of cryptoglandular fistula. This research was conducted following an analysis of the mistakes of a same previous phase III clinical trial. We designed a multicenter, randomized, single‐blind clinical trial, recruiting 57 patients. Forty‐four patients were categorized as belonging to the intent‐to‐treat group. Of these, 23 patients received 100 million ASCs plus intralesional fibrin glue (group A) and 21 received intralesional fibrin glue (group B), both after a deeper curettage of tracks and closure of internal openings. Fistula healing was defined as complete re‐epithelialization of external openings. Those patients in whom the fistula had not healed after 16 weeks were eligible for retreatment. Patients were evaluated at 1, 4, 16, 36, and 52 weeks and 2 years after treatment. Results were assessed by an evaluator blinded to the type of treatment. After 16 weeks, the healing rate was 30.4% in group A and 42.8% in group B, rising to 55.0% and 63.1%, respectively, at 52 weeks. At the end of the study (2 years after treatment), the healing rate remained at 50.0% in group A and had reduced to 26.3% in group B. The safety of the cellular treatment was confirmed and no impact on fecal continence was detected. The main conclusion was that autologous ASCs for the treatment of cryptoglandular perianal fistula is safe and can favor long‐term and sustained fistula healing.

Highlights

Perianal fistula has an incidence of 1.1 to 2.2 per 10 000 persons per year
Our group began to explore the use of adiposederived mesenchymal stromal cells (ASCs) as a treatment option for patients with complex perianal fistula,[6] hypothesizing that the immunomodulatory and anti-inflammatory capabilities of adipose-derived stem cells (ASCs) could contribute to the healing process, improving outcomes as defined by fistula closure; healing was defined as the absence of drainage through the external openings and complete re-epithelization of these openings.[7,8,9]
A phase III clinical trial conducted to study cryptoglandular fistula using autologous ASCs failed to find an advantage of the intervention over the control group, possibly owing to issues related to the use of the cell product and trial design

Summary

Introduction

Perianal fistula has an incidence of 1.1 to 2.2 per 10 000 persons per year. The vast majority of cases are due to cryptoglandular disease.[1,2] In most patients, this condition may be successfully cured by surgery, but surgical treatment of complex fistulas remains a challenge, with a high rate of recurrence and frequent side effects such as fecal incontinence.[3,4,5]Seventeen years ago, our group began to explore the use of adiposederived mesenchymal stromal cells (ASCs) as a treatment option for patients with complex perianal fistula,[6] hypothesizing that the immunomodulatory and anti-inflammatory capabilities of ASCs could contribute to the healing process, improving outcomes as defined by fistula closure; healing was defined as the absence of drainage through the external openings and complete re-epithelization of these openings.[7,8,9] In phase I and II studies, the use of autologous ASCs was proved to be safe for the treatment of fistulas having both a cryptoglandular and Crohn origin.[10,11,12] A phase III clinical trial conducted to study cryptoglandular fistula using autologous ASCs failed to find an advantage of the intervention over the control group, possibly owing to issues related to the use of the cell product and trial design. Control of the cell implant was not exhaustive, causing high injection speed and not always in the appropriate areas.[13] Later, a phase III clinical trial in Crohn perianal fistula using allogeneic ASCs showed a clear advantage when using these cells over the control group,[14] in long-term evaluation.[15]

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