E-CEL UVEC Cell Injection Treatment of Perianal Fistulas

A Multi-center, Randomized, No Treatment, Concurrent Controlled Study of E-CEL UVEC CELLS for the Treatment of Perianal Fistula

The purpose of this study is to determine if experimental therapy (E-CEL UVEC Cells), a very minimally invasive procedure, can treat patients with perianal fistulas.

Inclusion Criteria:

1. Age 18 or older

2. Willing and able to provide informed consent and medically eligible

3. Diagnosed with perianal fistula per the following criteria:

   1. Diagnosis documented by physical/clinical examination and imaging specifically performed to assess the number and course of the perianal fistula tract---i.e., magnetic resonance imaging (MRI) and/or ultrasound
   2. Single tract without residual abscess cavity
   3. Low transsphincteric and intersphincteric fistulas that cross less than 30% of the external sphincter

   i. Fistula internal opening width ≤ 3 mm. d. Maximum tract length of 10 cm e. Consistent with cryptoglandular origin f. Fistula-related pain of NRS < 3 (NRS 0-10) g. Absence of history of Crohn's disease, ulcerative colitis or other inflammatory bowel diseases

4. For female patients of childbearing potential:

   1. A negative serum or urine pregnancy test at screening is required prior to enrollment
   2. Patient must be willing to use a highly effective method of contraception from the start of the screening period until at least 3 months after completion of last treatment

5. For male patients who can father a child and are having intercourse with females of childbearing potential who are not using adequate contraception:

   1. Patient must be willing to use a recommended method of contraception and refrain from sperm donation from the start of screening period until for at least 3 months after completion of the last treatment

Exclusion Criteria:

1. Concomitant rectovaginal fistulas

2. Patients with an active abscess or suspicion of an active, untreated microabscess

3. Presence of signs and symptoms suggestive or suspicious of an acute active infection or flare-up.

4. Fistula-related pain measured as NRS ≥ 3 (NRS Scale 0-10) in the last 7 days.

   • If the subject is eligible except for this exclusion criteria of fistula-related pain, then it is recommended that a loose seton be placed to reduce the fistula pain. In this particular situation, once the fistula-related pain is ≤ 2 on NRS (preferably 0 or 1), then the subject may be enrolled and the loose seton removed just prior to the 1st treatment with the investigational product.

5. Presence of rectal and/or anal stenosis

6. Presence of setons unless removed prior to the treatment

7. Patients with known bleeding disorders.

8. Patients with known risk factors for thrombus formation.

9. Patients with overlying wound and skin infections.

10. Patients with ongoing systemic steroid treatment or treated with steroids within the last 4 weeks prior to treatment

11. Renal impairment defined by creatinine clearance below 90 mL/min calculated using Cockcroft-Gault formula or by serum creatinine ≥ 1.5 x upper limit of normality (ULN)

12. Hepatic impairment defined by both of the following laboratory ranges:

    • Total bilirubin ≥ 1.5 x ULN unless benign congenital hyperbilirubinemia.
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 x ULN

13. Known history of untreated alcohol or other addictive substance abuse in the 6 months prior to enrollment

14. Active malignant tumor (tumors must be in complete remission for ≥ 6 months with completion of maintenance chemotherapy and/or radiation cycles), at least 6 months prior to first treatment

15. Current recent history of abnormal, severe, progressive, uncontrolled hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral diseases

16. Congenital immunodeficiencies

17. Major surgery or severe trauma within the previous 3 months

18. Patients who are candidates for solid organ transplantation or who may have a high likelihood of needing a solid organ transplant (e.g., progressive heart failure)

19. Female patients who are pregnant or breastfeeding or planning to become pregnant or breastfeed during the treatment regimen with investigational product (Arm A: 0-12 weeks; Arm B (with crossover): 0-24 weeks).

20. Patients who have known hypersensitivity or documented allergy to dimethyl sulfoxide (DMSO)

21. Patients who do not wish to or cannot comply with study procedures, including completion of all scheduled study visits and treatments

22. Patients currently receiving, or having received any investigational drug within 6 months prior to E-CEL UVEC cell therapy