Repairing Peri-Anal Fistulas with regenerative cell therapeutics: study protocol for a double-blinded randomized controlled phase I-II trial from Denmark (REP-PAF).

[BACKGROUND] Surgical treatment of high anal fistulas is challenging and associated with a relatively high rate of complications and failure. Stem cell therapy has shown promising results for fistulas associated with Crohn's disease but remains less studied in cryptoglandular fistulas. This clinical trial is being performed to evaluate the outcome of treating complex cryptoglandular perianal fistulas (PAFs) using minimal surgical debridement combined with either non-cultured (autologous) or cultured (allogeneic) adipose-derived regenerative cells (ADRCs). The primary outcome is the clinical healing rate after 12 months. Secondary outcomes include functional outcomes regarding quality of life and anal continence (measured by the 36-Item Short Form Health Survey [SF-36] and the Wexner Fecal Incontinence Score), risk factors for fistula recurrence, radiological healing assessed by magnetic resonance imaging, and comparison of autologous versus allogeneic ADRCs with respect to cell characterization, immune responses, and efficacy.

[METHODS] This is a double-blinded, randomized interventional non-inferiority, phase I-II clinical trial using two approved investigational medicinal products. The study will be conducted at the surgical department, Odense University Hospital OUH, in Odense, Denmark. Inclusion criterion is an adult patient (≥ 18 years) with complex PAF (high transsphincteric or suprasphincteric), involving more than 30% of the anal sphincter. Key exclusion criteria are ongoing suppuration, simple anal fistula, ano- or rectovaginal fistula, inflammatory bowel disease, body mass index (BMI) of < 18.5 kg/m, known allergy to penicillin or streptomycin, pregnancy, and verified syphilis, human immunodeficiency virus (HIV), or hepatitis on screening test. The primary investigator (PI) is responsible for participants' recruitment. Eligible patients will undergo 1-day surgery, including debridement of the fistula tract and closure of the internal orifice, liposuction from the anterior abdominal wall, injection of 30-40 mL of autologous microfat around the fistula tract, and injection of 30 million stem cells (either autologous ADRCs or allogeneic ADRC001) according to randomization (1:1 allocation ratio). Patients who receive treatment will attend follow-up visits at 3, 6, and 12 months postoperatively. Serious adverse events will be reported including large abscess formation, wound dehiscence causing fecal incontinence, sepsis, major bleeding, and serious allergic reactions. The trial has been approved by the European Medicines Agency EMA and is monitored by the Good Clinical Practice (GCP) Unit at OUH. A total of 75 patients will be included. Recruitment began in October 2024, with a planned duration of 3 years.

[DISCUSSION] The trial intervention is designed as a minimally invasive treatment with the potential to shorten and ease recovery, enable a quicker return to daily activities and work, and avoid sphincter damage, thereby preserving function. The trial is expected to provide evidence on whether allogeneic ADRCs combined with microfat are a viable alternative to autologous ADRCs with microfat for the treatment of PAF.

[TRIAL REGISTRATION] Clinical Trials Information System (CTIS) EU CT 2022-502659-73-01. Registered on 18 November 2023.

[CLINICALTRIALS] org NCT0 6303752. Registered on 25 February 2024.