Sponsor decision

The main aim is to check the long term side effects of a repeat treatment of darvadstrocel and to see if that treatment improves symptoms of Crohn's disease and complex perianal fistula. Participants will attend 8 clinic visits and will receive 1 treatment of darvadstrocel at the third visit. A magnetic resonance imaging (MRI) will be performed several times during the study.

The biological being tested in this study is called darvadstrocel (Alofisel). This study is examining the long-term safety and efficacy of a repeat dose of darvadstrocel in people who have Crohn's disease and complex perianal fistula.

The study will enroll approximately 50 patients. Participants will be assigned to one treatment group to receive:

• Darvadstrocel 120 million cells

All participants would be allowed to receive one repeat dose of darvadstrocel in the whole study. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 3 years. Participants will make multiple visits to the clinic.

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant signs and dates a written, ICF and any required privacy authorization before the initiation of any study procedures.

3. The participant is male or female and aged 18 years or older.

4. The participant 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:

   1. High inter-sphincteric, high trans-sphincteric, extra-sphincteric or suprasphincteric.
   2. Presence of ≥2 external openings.
   3. 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 adequately by the surgeon during the preparation curettage in order to be eligible.

5. The participant 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.

6. The participant has controlled or mildly active Crohn's disease (CD) (defined as patient reported outcomes measure derived from CDAI patient reported outcome score-2 [PRO-2] score <14).

7. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use barrier method of contraception (e.g. condom with or without spermicide) from signing of informed consent and until 1 year after repeat administration.

8. A female participant 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.

Exclusion Criteria:

1. The participant 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.

2. The participant has a history of hypersensitivity or allergies to darvadstrocel or related compounds.

3. The participant has a history of hypersensitivity or allergies to penicillin or to aminoglycosides; Dulbecco modified eagle medium; bovine serum; local anesthetics or gadolinium.

4. The participant is currently participating in a double-blind clinical study with darvadstrocel. Participants participating in the ongoing INSPIRE registry (Alofisel-5003) study would need to withdraw from that study in order to enroll in this study.

5. The participant is currently receiving or has received any other investigational medicinal product (IMP) within the last 3 months or at least 5 times the respective elimination half-life time, whichever is longer, before signing the ICF.

6. 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.

   a) 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.

7. The participant has major alterations in any of the following laboratory tests:

   1. Serum creatinine levels >1.5 times the upper limit of normal (ULN).
   2. Total bilirubin >1.5 × ULN.
   3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3.0 × ULN.
   4. Hemoglobin <10.0 grams per deciliter (g/dL).
   5. Platelets <75.0 × 10^9 per liter (/L).
   6. Albumin <3.0 g/dL.

8. The participant has an increased risk for a surgical procedure.

9. The participant has a known chronically active hepatopathy of any origin, including cirrhosis and participants 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.

10. If female, the participant 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.

11. If male, the participant intends to donate sperm during this study.

12. The participant has a contraindication to MRI scan (e.g., due to the presence of pacemaker, hip replacement, severe claustrophobia, or renal insufficiency as defined by local clinical guidelines).

13. The participant has a contraindication to the anesthetic procedure.

14. The participant has severe rectal and/or anal stenosis that would make it impossible to follow the surgery procedure.

15. The participant has severe proctitis (rectal ulcers >0.5 cm) that would make it impossible to follow the surgery procedure.

16. The participant has any prior invasive malignancy diagnosed within the last 3 years before baseline visit. Participants with basal cell carcinoma of the skin completely resected outside the perineal region can be included.

17. The participant 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 participant's increased risk from study participation and/or lack of compliance with study procedures.

18. The participant 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.

19. The participant 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.

20. The participant does not wish to or cannot comply with study procedures.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.