A Phase 3 Study to Evaluate the Efficacy and Safety of Darvadstrocel in the Treatment of Complex Perianal Fistula in Pediatric Subjects with Crohn's Disease.

Prior treatment

• The subject has received any investigational compound within 12 weeks/84 days before screening.
• The subject has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical procedure.
• The subject has ongoing systemic corticosteroid treatment or has been treated with systemic corticosteroids within 4 weeks before screening.
• The subject requires new treatment with immunosuppressants/anti- TNF agents during the screening period.
• The subject 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.
• The subject has received darvadstrocel/eASC in a previous clinical study or as a therapeutic agent.
• The subject has known history of abuse of alcohol or other addictive substances in the 6 months before screening.
• The subject has malignant tumor or a prior history of any malignant tumor, including any type of fistula carcinoma.
• The subject 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.
• The subject has previously received a bone marrow transplant.
• The subject had major surgery or severe trauma within 6 months before the screening visit.
• The subject takes or is required to take excluded medications listed in the protocol.
• The subject has concomitant perianal fistula(s) with only internal or external opening(s).
• The subject has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or ileo-colonic fistula(s).

Other illness

• The subject underwent surgery for the fistula other than drainage or seton placement.
• The subject 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. Subjects 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.
• The subject has either congenital or acquired immunodeficiencies, including subjects known to be HIV carriers or subjects with, in the judgment of the investigator, are suspected to have monogenic inflammatory bowel disease.
• The subject has a known clinically significant chronically active hepatopathy of any origin, including cirrhosis and subjects with persistent positive hepatitis B surface antigen and quantitative hepatitis B virus polymerase chain reaction, or positive serology for hepatitis C virus (IgG) and quantitative hepatitis C virus polymerase chain reaction at the screening visit.
• The subject has a history of hypersensitivity or allergies to darvadstrocel or any of its excipients.

Lab values

• The subject has a serum creatinine ≥2 × upper limit of normal (ULN).
• The subject has hepatic impairment defined by both of the following laboratory ranges: a) Total bilirubin ≥1.5 × ULN. b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2 × ULN.
• The subject has known allergies or hypersensitivity to antibiotics (including benzylpenicillin/streptomycin, gentamicin [used in the darvadstrocel manufacturing process]) human serum albumin; Dulbecco Modified Eagle's Medium, material of bovine origin, or local anesthetics.
• The subject has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at screening.

Other

• The subject has an abscess >2 cm, unless resolved in the preparation procedure.
• The subject has diverting stomas.
• The subject has a contraindication to MRI scan or other planned study procedures.
• The subject has a contraindication to the anesthetic procedure.
• The subject is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling), or may consent under duress.
• A female subject who is pregnant or is lactating or intending to become pregnant before participating in this study or during the study; or intending to donate ova during such time period.
• If male, the subject intends to donate sperm during the course of this study.
• The subject does not wish to or cannot comply with study procedures.
• The subject weighs <10 kg at screening.

• In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
• The subject, or when applicable, the subject's legally acceptable representative, signs and dates a written, informed consent/pediatric assent form and any required privacy authorization before the initiation of any study procedures.
• The subject is male or female aged 4 to <18 years at the time of study treatment administration.
• The subject has a CD diagnosis based on accepted clinical, endoscopic, histological and/or radiologic criteria at least 6 months before the screening visit.
• The subject 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).
• 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 2or 3 external openings (tracts) as assessed by clinical examination. -Associated fluid (abscess) collections as determined by MRI.
• The subject has inactive or mildly active luminal CD
• A male subject who is *nonsterilized and sexually active with a female partner of childbearing potential agrees to use barrier method of contraception (eg, condom with or without spermicide)* from the time of signing of informed consent/pediatric assent throughout the duration of the study. The female partner of a male subject should also be advised to use a highly effective method of contraception.
• A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to use a highly effective method of contraception from the time of signing of informed consent/pediatric assent throughout the duration of the study.