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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

Trial duration

16 Mar 2021 → 7 May 2025

Decision date (initial)

2023-07-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas Inc.

External identifiers

EU CT number

2023-503973-39-00

EudraCT number

2020-003193-48

ClinicalTrials.gov

NCT04701411

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of darvadstrocel in combined remission at Week 24 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.

Secondary objectives 6

1. To evaluate the efficacy of darvadstrocel in clinical remission at Week 24 and Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
2. To evaluate the efficacy of darvadstrocel in clinical response at Week 24 and Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years
3. To evaluate the efficacy of darvadstrocel in time to clinical remission up to Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
4. To evaluate the efficacy of darvadstrocel in time to clinical response up to Week 52 for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years.
5. To evaluate the efficacy of darvadstrocel on relapse by Week 52 in pediatric subjects with combined remission at Week 24.
6. To evaluate the safety of darvadstrocel for the treatment of complex perianal fistula in pediatric subjects with CD aged 4 to <18 years over 52 weeks.

Conditions and MedDRA coding

Complex Perianal Fistulas in Crohn's Disease

Study design 1 period

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001561-PIP01-13

Plan to share IPD

Yes

IPD plan description

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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
2. 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.
3. The subject is male or female aged 4 to <18 years at the time of study treatment administration.
4. The subject has a CD diagnosis based on accepted clinical, endoscopic, histological and/or radiologic criteria at least 6 months before the screening visit.
5. 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).
6. 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.
7. The subject has inactive or mildly active luminal CD
8. 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.
9. 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.

Exclusion criteria 32

1. The subject has received any investigational compound within 12 weeks/84 days before screening.
2. The subject has received darvadstrocel/eASC in a previous clinical study or as a therapeutic agent.
3. 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.
4. The subject weighs <10 kg at screening.
5. The subject has, in the judgment of the investigator, clinically significant abnormal hematological parameters of hemoglobin, hematocrit, or erythrocytes at screening.
6. The subject has a history of hypersensitivity or allergies to darvadstrocel or any of its excipients.
7. The subject takes or is required to take excluded medications listed in the protocol.
8. The subject has concomitant perianal fistula(s) with only internal or external opening(s).
9. The subject has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or ileo-colonic fistula(s).
10. The subject has an abscess >2 cm, unless resolved in the preparation procedure.
11. The subject has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical procedure.
12. The subject underwent surgery for the fistula other than drainage or seton placement.
13. The subject has diverting stomas.
14. The subject has ongoing systemic corticosteroid treatment or has been treated with systemic corticosteroids within 4 weeks before screening.
15. The subject requires new treatment with immunosuppressants/anti- TNF agents during the screening period.
16. 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.
17. 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.
18. The subject has a serum creatinine ≥2 × upper limit of normal (ULN).
19. 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.
20. The subject has known history of abuse of alcohol or other addictive substances in the 6 months before screening.
21. The subject has malignant tumor or a prior history of any malignant tumor, including any type of fistula carcinoma.
22. 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.
23. 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.
24. 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.
25. 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.
26. The subject has previously received a bone marrow transplant.
27. The subject has a contraindication to MRI scan or other planned study procedures.
28. The subject has a contraindication to the anesthetic procedure.
29. The subject had major surgery or severe trauma within 6 months before the screening visit.
30. 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.
31. If male, the subject intends to donate sperm during the course of this study.
32. The subject does not wish to or cannot comply with study procedures.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of subjects who achieve combined remission at Week 24, where combined remission is defined as: a) The closure of all treated external openings that were draining at baseline despite gentle finger compression AND b)Absence of abscess(es) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by central (MRI) assessment.

Secondary endpoints 8

1. Efficacy at Week 24: Proportion of subjects who achieve clinical remission at Week 24, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
2. Efficacy at week 24: Proportion of subjects with clinical response at Week 24, where clinical response is defined as closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
3. Efficacy at Week 52: Proportion of subjects who achieve clinical remission at Week 52, where clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.
4. Efficacy at Week 52: Time to clinical remission (weeks) assessed at each clinic visit up to Week 52. This is defined as the time from treatment start to first visit at which clinical remission is observed before Week 52; where clinical remission is said to occur if a clinical assessment shows closure of all treated external openings that were draining at baseline despite gentle finger compression.
5. Efficacy at Week 52: Proportion of subjects with clinical response at Week 52, where clinical response is defined as closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
6. Efficacy at Week 52: Time to clinical response (weeks) assessed at each clinic visit up to Week 52. This is defined as the time from treatment start to first visit at which clinical response is observed before Week 52; where clinical response is said to occur if a clinical assessment shows closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression.
7. Efficacy at Week 52: Proportion of subjects with relapse by Week 52, in subjects with combined remission at Week 24, where relapse is defined as reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed in subjects who were in combined remission at Week 24.
8. Safety Endpoints 1. Incidence of AEs. 2. Incidence of SAEs. 3. Incidence of adverse events of special interest (AESIs). 4. Vital signs. 5. Laboratory parameters (biochemistry, hematology, and urinalysis).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

95 Hayden Avenue

City

Lexington

Postcode

02421-7942

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Kabir Ahmed

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Raghavan Vasudevan

Third parties 3

Locations

3 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 3 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications