Efficacy and Safety Evaluation of Darvadstrocel for Complex Perianal Fistulas in Pediatric Crohn's Disease: A Phase 3, Open-Label, Multicenter Study

Trial ID: 2023-503973-39-00
Protocol: Darvadstrocel-3004
Sponsor: Takeda Development Center Americas Inc.

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Diseases & Conditions

Anal fistula Crohn's disease

Objectives

The primary objective of this study is to evaluate the **efficacy** of darvadstrocel in achieving combined remission at Week 24 for the treatment of complex perianal fistula in pediatric subjects with Crohn's Disease (CD) aged 4 to <18 years. This is clinically relevant as achieving remission can significantly improve the quality of life and reduce complications associated with complex perianal fistulas in this patient population.

Secondary objectives include:

Evaluating the efficacy of darvadstrocel in clinical remission at Week 24 and Week 52.
Assessing the efficacy in clinical response at Week 24 and Week 52.
Determining the time to clinical remission up to Week 52.
Evaluating the time to clinical response up to Week 52.
Assessing the efficacy on relapse by Week 52 in subjects with combined remission at Week 24.
Evaluating the safety of darvadstrocel over 52 weeks.

Participants

The clinical trial involves a total of **5 participants** diagnosed with **Complex Perianal Fistulas in Crohn's Disease**. The study population comprises both male and female pediatric subjects aged 4 to less than 18 years. Participants were selected based on their diagnosis of Crohn's Disease, confirmed through clinical, endoscopic, histological, and/or radiologic criteria at least six months prior to the screening visit. The trial includes individuals with complex perianal fistulas that are refractory to treatments such as immunosuppressants or biologics. Participants are required to have inactive or mildly active luminal Crohn's Disease. The study population is considered vulnerable, and all participants or their legally acceptable representatives provided informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial does not specify any particular lifestyle modifications or restrictions for participants beyond the use of contraception for sexually active subjects of childbearing potential.

Plans and Procedures

The clinical trial is a **Phase 3, open-label, multicenter study** designed to evaluate the efficacy and safety of Darvadstrocel in the treatment of complex perianal fistulas in pediatric subjects with **Crohn's Disease**. The trial aims to assess the combined remission at Week 24 and includes an extended follow-up period for a total duration of up to 52 weeks. The study involves pediatric subjects aged 4 to less than 18 years who have a confirmed diagnosis of Crohn's Disease and complex perianal fistulas refractory to previous treatments such as immunosuppressants or biologics. The trial is not categorized as low intervention and involves the administration of Darvadstrocel via **intralesional use**.

The trial design includes several key elements of research methodology. Participants will undergo a screening visit to confirm eligibility based on inclusion criteria, such as the ability to understand and comply with protocol requirements, and the presence of complex perianal fistulas as assessed by MRI and clinical examination. The primary endpoint is the proportion of subjects achieving combined remission at Week 24, defined as the closure of all treated external openings and the absence of abscesses greater than 2 cm, confirmed by MRI. Secondary endpoints include clinical remission and response rates at Weeks 24 and 52, as well as safety assessments including adverse events and laboratory parameters.

Study visits are structured to monitor the progress and safety of participants. Following the initial screening visit, participants will attend regular follow-up visits to assess clinical outcomes and any adverse events. The end-of-study visit will occur at Week 52, marking the conclusion of the participant's involvement in the trial. The expected length of participant involvement is up to 52 weeks, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that warrant discontinuation as determined by the investigator.

Treatment

The clinical trial involves the administration of **Alofisel**, a suspension for injection containing **allogeneic adipose tissue-derived mesenchymal stem cells expanded**. This experimental medication is utilized for the treatment of complex perianal fistula in pediatric subjects with Crohn's Disease. The pharmaceutical form of Alofisel is a suspension for injection, and it is administered via **intralesional use**. The dosage is specified as 5 million cells per milliliter, with a maximum total dose amounting to 120 million cells. The treatment period is limited to a maximum of one day, and the medication is classified under the ATC code L04, indicating its role as an immunosuppressive agent. Alofisel is not formulated specifically for pediatric use, and it is designated as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The administration of Alofisel is monitored to ensure participant compliance, although specific compliance monitoring strategies are not detailed in the provided data. The trial aims to evaluate the efficacy and safety of Alofisel over a 24-week period, with an extended follow-up for a total of up to 52 weeks. The study is conducted in an open-label, multicenter format, focusing on pediatric subjects aged 4 to less than 18 years.

Efficacy

The efficacy of Darvadstrocel in the treatment of complex perianal fistula in pediatric subjects with Crohn's Disease will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of subjects achieving combined remission at Week 24. Combined remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression, along with the absence of abscesses greater than 2 cm in at least two dimensions, confirmed by central MRI assessment.

Secondary endpoints include several measures of efficacy at both Week 24 and Week 52. At Week 24, the proportion of subjects achieving clinical remission, defined as the closure of all treated external openings that were draining at baseline, will be evaluated. Additionally, the clinical response, defined as the closure of at least 50% of all treated external openings, will be assessed. At Week 52, similar assessments will be conducted, including the time to clinical remission and response, as well as the proportion of subjects experiencing relapse, defined as the reopening of any treated fistula external openings with active drainage in subjects who were in combined remission at Week 24.

These efficacy parameters will be measured and collected at specified timepoints, including Week 24 and Week 52, using clinical assessments and MRI evaluations. The analysis will focus on the proportion of subjects meeting the defined criteria for remission and response, providing a comprehensive evaluation of the treatment's efficacy over the study period.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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.

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Exclusion Criteria

The subject has received any investigational compound within 12 weeks/84 days before screening.
The subject has received darvadstrocel/eASC in a previous clinical study or as a therapeutic agent.
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.
The subject weighs <10 kg at screening.
The subject has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at screening.
The subject has a history of hypersensitivity or allergies to darvadstrocel or any of its excipients.
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).
The subject has an abscess >2 cm, unless resolved in the preparation procedure.
The subject has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical procedure.
The subject underwent surgery for the fistula other than drainage or seton placement.
The subject has diverting stomas.
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 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 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 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 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 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 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 previously received a bone marrow transplant.
The subject has a contraindication to MRI scan or other planned study procedures.
The subject has a contraindication to the anesthetic procedure.
The subject had major surgery or severe trauma within 6 months before the screening visit.
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.