A Long-term Safety Study of a Second Treatment with Darvadstrocel for Treating Complex Perianal Fistulas in Adults with Crohn's Disease

Prior treatment

• The subject has lack of clinical response to prior treatment with darvadstrocel, where clinical response is defined as closure of at least 50% of all treated external fistula openings that were draining at baseline despite gentle finger compression or in the case of a unique fistula, a partial closure of the fistula.
• The subject has severe rectal and/or anal stenosis that would make it impossible to follow the surgery procedure.
• The subject has severe proctitis (rectal ulcers >0.5 cm) that would make it impossible to follow the surgery procedure.
• The subject has had major surgery of the gastrointestinal tract within 6 months before baseline or any minor surgery of the gastrointestinal tract 3 months before baseline.
• The subject has had local major perianal surgery and/or treatment with darvadstrocel within 6 months before baseline. The abscess drainage, cleaning surgery, or seton placement are not considered as “local major surgery” in this protocol.
• The subject has an increased risk for a surgical procedure.
  • The subjects has a known 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 (PCR) or positive serology for hepatitis C virus (HCV) and quantitative HCV PCR within 6 months before the baseline visit.

Other illness

• The subject has a contraindication to MRI scan (eg, due to the presence of pacemaker, hip replacement, severe claustrophobia, or renal insufficiency as defined by local clinical guidelines).
• The subject has any prior invasive malignancy diagnosed within the last 3 years before baseline visit. Subjects with basal cell carcinoma of the skin completely resected outside the perineal region can be included.
• The subject has a current or recent (within 6 months before the baseline visit) history of severe, progressive, and/or uncontrolled hepatic, hematologic, gastrointestinal (other than CD), renal, endocrine, pulmonary, cardiac, neurologic, or psychiatric disease that may result in subject’s increased risk from study participation and/or lack of compliance with study procedures.
• The subject has a history of hypersensitivity or allergies to darvadstrocel or related compounds.

Lab values

• The subject has a history of hypersensitivity or allergies to penicillin or to aminoglycosides; Dulbecco modified eagle medium; bovine serum; local anesthetics or gadolinium.
• The subject is currently participating in a double-blind clinical study with darvadstrocel. Subjects participating in the ongoing INSPIRE (Alofisel-5003) registry study would need to withdraw from that study in order to enroll in this study.
  • The subject is currently receiving or has received any other IMP within the last 3 months or at least 5 times the respective elimination half-life time, whichever is longer, before signing the ICF.
  • 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 major alterations in any of the following laboratory tests: a) Serum creatinine levels >1.5 times the upper limit of normal (ULN). b) Total bilirubin >1.5 × ULN. c) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3.0 × ULN. d) Hemoglobin <10.0 g/dL. e) Platelets <75.0 × 109/L. f) Albumin <3.0 g/dL.

Other

• If female, the subject is pregnant or breastfeeding, or intending to become pregnant before participating in this study, during the study, or intending to donate ova during such time period.
• If male, the subject intends to donate sperm during this study.
• The subject has a contraindication to the anesthetic procedure.
• The subject does not wish to or cannot comply with study procedures.

• In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
• The subject signs and dates a written, informed consent form (ICF) and any required privacy authorization before the initiation of any study procedures.
• The subject is male or female and aged 18 years or older.
• The subject has complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on clinical assessment and a reading of a locally performed contrast enhanced (gadolinium) pelvic MRI. Fistula(s) must have been draining for at least 6 weeks prior to baseline visit. A complex perianal fistula is defined as a fistula that meets 1 or more of the following criteria: a) High inter-sphincteric, high trans-sphincteric, extrasphincteric or suprasphincteric. b) Presence of ≥2 external openings. c) Associated perianal abscess(es). Note: Abscesses that are larger than 2 cm in at least 2 dimensions on MRI must be confirmed to have been drained
• The subject has already received treatment with darvadstrocel for a complex perianal fistula at least 6 months prior to baseline visit for retreatment, and their physician has planned a repeat treatment administration for the original tract (full remission not obtained or relapse of fistula draining) or for a new complex perianal fistula tract.
• The subject has controlled or mildly active CD (defined as patient reported outcomes measure derived from Crohn’s Disease Activity Index [CDAI] patient reported outcome score-2 [PRO-2] score <14).
• 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 signing of informed consent and until 1 year after repeat administration.
• A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to use a highly effective/effective method of contraception from signing of informed consent and until 1 year after repeat administration.