Evaluation of Autologous Adipose Tissue-Derived Stromal Vascular Fraction and Microfat for Refractory Perianal Crohn's Fistulas

The primary objective of this study is to assess the **efficacy** of local injection of autologous adipose-derived stromal vascular fraction (ADSVF) and microfat versus placebo for the treatment of complex refractory perianal Crohn's fistulas at week 24. This is clinically relevant as it aims to provide an effective treatment option for patients with this challenging condition, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Assessing the superiority of the autologous cellular treatment versus placebo on complete and partial response, defined by cessation and reduction of suppuration, respectively, at weeks 4, 12, 24, and 52.
• Evaluating the superiority of the treatment on complete healing, defined as closure of all external openings, at the same time points.
• Assessing the treatment's impact on the severity of perianal Crohn's disease, quality of life, Crohn's Disease Activity Index, and anal incontinence severity.
• Conducting a safety assessment.
• Analyzing changes in blood immune-inflammatory profile and their association with clinical response.
• Exploring the relationship between biological characteristics of ADSVF and clinical response.
• Identifying MRI characteristics of fistulas that predict treatment response.

The clinical trial focuses on individuals diagnosed with **Crohn's disease**, specifically targeting those with complex refractory perianal fistulas. The study population includes both male and female participants aged 18 years and older, all of whom are in a good general state of health as determined by clinical history and physical examination. Participants must have been diagnosed with Crohn's disease at least six months prior to the trial, with non-active or mildly active luminal disease, defined by a Crohn's Disease Activity Index (CDAI) of 220 or less. The trial does not involve a vulnerable population. Participants are required to have signed informed consent and must be affiliated with a social security scheme. Women of childbearing age are required to have a negative pregnancy test and, along with male participants, must use appropriate birth control methods as defined by the investigator. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed as a **randomized, double-blind, controlled** study to evaluate the efficacy of local injection of **autologous adipose tissue-derived stromal vascular fraction cells** and microfat versus placebo for the treatment of complex refractory perianal **Crohn's disease** fistulas. The trial is set to run from February 17, 2020, to March 17, 2027, with an estimated duration of seven years. Participants will be randomly assigned to receive either the investigational product, SVF 2 inj prep, or the placebo, Placebo SVF inj prep, both administered as a **suspension for injection** via local injection.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Crohn's disease at least six months prior, presence of refractory perianal fistulas, and a Crohn's Disease Activity Index (CDAI) of 220 or less. Participants must also be in good general health and, if of childbearing potential, must have a negative pregnancy test and agree to use birth control. Follow-up visits will occur at regular intervals to monitor the primary endpoint, which includes clinical assessment of fistula closure and MRI confirmation of absence of collections greater than 2 cm at week 24. Secondary endpoints will assess factors such as cessation of suppuration, reduction of discharge, and improvement in quality of life and disease activity indices.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The end-of-study visit will conclude the trial for each participant, ensuring all data is collected and any necessary follow-up care is arranged. The trial's methodology and design aim to provide robust data on the treatment's efficacy and safety, contributing valuable insights into managing refractory perianal Crohn's fistulas.

The clinical trial involves the administration of two primary treatments. The first treatment is the **SVF 2 inj prep**, which is an advanced therapy medicinal product. This experimental medication is a **suspension for injection** containing **autologous adipose tissue-derived stromal vascular fraction cells**. These cells are derived from the patient's own adipose tissue and are classified as a structurally diverse substance used in cell therapy. The medication is administered via **local injection**. The dosage is measured in million organisms, with a maximum daily and total dose of 30 million organisms. The treatment period is limited to one day.

The second treatment used in the trial is the **Placebo SVF inj prep**, which serves as the comparator treatment. This placebo is also a **suspension for injection** and contains **sodium chloride** and **human serum albumin 5%**. The placebo is administered through the same **local injection** route as the experimental treatment. The dosage and treatment period for the placebo are identical to those of the SVF 2 inj prep, with a maximum daily and total dose of 30 million organisms over a one-day treatment period. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol.

The efficacy of the clinical trial titled "Evaluation of Local Co-administration of Autologous ADIpose Derived Stromal Vascular Fraction With Microfat for Refractory Perianal **Crohn's** Fistulas: ADICROHN II" will be assessed through a series of primary and secondary endpoints. The primary endpoints include the clinical assessment of closure of all external openings that were drained at baseline, despite gentle finger compression, and MRI confirmation of the absence of collections greater than 2 cm in the treated perianal fistulas at week 24.

Secondary endpoints will evaluate several parameters, including the assessment of complete cessation of suppuration, significant reduction of discharge, and clinical assessment of closure of all external openings. Additional measures include the severity of perianal Crohn's disease using the Perianal Disease Activity Index (PDAI), improvement in Quality of Life as measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and the Crohn's Disease Activity Index (CDAI). The reduction of anal incontinence severity will be assessed using the Wexner score. Furthermore, the trial will assess adverse events, their severity, and causal relationship to the study product, as well as the quantification of regulatory lymphocyte subsets and soluble inflammatory molecules. Cellular composition, secretory activity, transcriptional profile, and MRI characteristics of the fistula will also be evaluated.