A Study of Darvadstrocel for Treating Complex Perianal Fistulas in Children and Teenagers With Crohn's Disease

A Phase 3, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of Darvadstrocel in the Treatment of Complex Perianal Fistula in Pediatric Subjects With Crohn's Disease Over a Period of 24 Weeks and an Extended Follow-up Period for a Total of up to 52 Weeks

A perianal fistula is an abnormal passageway that develops between the rectum and the skin near the anus. The fistula is considered complex if it branches into several openings or an abscess is also present.

The main aim of this study is to learn if complex perianal fistulas in children and teenagers close after treatment with darvadstrocel.

2 to 3 weeks before treatment with darvadstrocel, each participant will have surgery to clean the fistula and to drain any abscesses. On the day of treatment, each participant will have the fistula cleaned and will receive an injection of darvadstrocel near the fistula, under anesthetic.

For up to 1 year after treatment, participants will regularly visit the clinic for follow-up. The fistula will be examined and any side effects from the treatment will be recorded. Participants will have an MRI at one clinic visit (about 24 weeks after treatment).

The drug being tested in this study is called darvadstrocel (Cx601, cell suspension containing 120 million cells of allogeneic expanded adipose-derived mesenchymal stem cells [eASCs]). Darvadstrocel is being tested to treat complex perianal fistula in pediatric participants who have Crohn's disease (CD). This study will look at the safety and efficacy of darvadstrocel in the treatment of complex perianal fistula in CD.

The study will enroll at least 20 patients who will receive a single dose of darvadstrocel.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 52 weeks.

Participants will make multiple visits to the clinic. In unavoidable circumstances, such as the coronavirus disease 2019 pandemic, exceptions may be granted for alternative methods for conducting participant visits with approval by the medical monitor and/or sponsor.

Inclusion Criteria:

1. Has a CD diagnosis based on accepted clinical, endoscopic, histological and/or radiologic criteria at least 6 months before the screening visit.

2. Has complex perianal fistula refractory to at least one of the following treatments: immunosuppressants or biologics (anti-TNFs, anti-integrin, anti-interleukin [IL] 12/23). Fistula(s) refractory to therapy is defined in this study as follows: Immunosuppressants: Inadequate response after 3 months, based on clinical assessment, or more treatment with azathioprine, 6-mercaptopurine or methotrexate. Biologics: Inadequate response after 14 weeks (16 weeks for anti-IL 12/23), based on clinical assessment, or more standard treatment for induction and maintenance.

3. A complex perianal fistula(s) that meets one or more of the following criteria, modified from the American Gastroenterological Association (AGA) technical review: High intersphincteric, transsphincteric, extrasphincteric, or suprasphincteric as assessed by MRI. Presence of 2 or 3 external openings (tracts) as assessed by clinical examination. Associated fluid (abscess) collections as determined by MRI.

   This study requires that the participant has complex perianal fistulas with a maximum of 2 internal openings and a maximum of 3 external openings, based on clinical assessment. Darvadstrocel treatment is targeted for fistulas that connect between internal and external openings. A central reading of a locally performed pelvic MRI will be performed to confirm the location of the fistula and potential associated perianal abscess(es). Fistulas must have been draining for at least 6 weeks before the screening visit. Participants with actively draining simple subcutaneous fistulas, at the time of the screening visit, are not allowed in this study.

4. Has inactive or mildly active luminal CD defined by meeting all of the following criteria:

   1. Colonoscopy, flexible sigmoidoscopy or rectoscopy performed either at screening or within the 6 months before screening, demonstrating no rectal ulcers larger than 0.5 cm. A participant who has documented rectal ulcers larger than 0.5 cm within the 6 months before screening but has undergone subsequent treatment may be eligible if there are no rectal ulcers larger than 0.5 cm on a sigmoidoscopy or rectoscopy performed after treatment or at the time of screening.
   2. The improvement of, or no worsening in stool frequency, sustained for 1 week or more, in the interval between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 4(a) and the screening visit.
   3. No initiation or intensification of treatment with corticosteroids, immunosuppressants, or monoclonal antibody dose regimen between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 4(a) and the screening visit.

Exclusion Criteria:

1. Has received any investigational compound within 12 weeks/84 days before screening.
2. Has received darvadstrocel/eASC in a previous clinical study or as a therapeutic agent.
3. The participant weighs <10 kg at screening.
4. Has concomitant perianal fistula(s) with only internal or external opening(s).
5. Has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or ileo-colonic fistula(s).
6. Has an abscess >2 cm, unless resolved in the preparation procedure.
7. Has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical procedure.
8. The participant underwent surgery for the fistula other than drainage or seton placement.
9. Has diverting stomas.
10. Has ongoing systemic corticosteroid treatment or has been treated with systemic corticosteroids within 4 weeks before screening.
11. The participant requires new treatment with immunosuppressants/anti-TNF agents during the screening period.
12. The participant has known or suspected COVID-19 by the investigator within the past 2 months (additional testing may be performed at the discretion of the investigator). Positive antibody testing for COVID without other evidence of current or recent active infection does not exclude participation. Participants who were in screening at the time that COVID-19-related factors resulted in discontinuation may also be rescreened with approval of the sponsor or designee.
13. The participant requires surgery in the perianal region for reasons other than fistulas at the time of screening or foreseen either during the study and/or during the 24 weeks after treatment administration.
14. Has malignant tumor or a prior history of any malignant tumor, including any type of fistula carcinoma.
15. Has current or recent (within 3 months before the screening) history of abnormal, severe, progressive, uncontrolled hepatic, hematologic, gastrointestinal (except CD), endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease.
16. Has either congenital or acquired immunodeficiencies, including participants known to be HIV carriers or participants with, in the judgment of the investigator, are suspected to have monogenic inflammatory bowel disease.
17. Has previously received a bone marrow transplant.
18. Has a contraindication to MRI scan or other planned study procedures.
19. Has a contraindication to the anesthetic procedure.
20. Had major surgery or severe trauma within 6 months before the screening visit.