臨床研究等提出・公開システム

A Phase 3, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of Darvadstrocel in the Treatment of Complex Perianal Fistula in Pediatric Subjects with Crohn's Disease over a Period of 24 Weeks and an Extended Follow-up Period for a Total of up to 52 Weeks

A Study of Darvadstrocel for Treating of Complex Perianal Fistula in Children and Teenagers With Crohn's Disease

7

In the ITT analysis set, most subjects were male (5 subjects; 71.4%). The mean (SD) age was 15.7 (1.38) years; the youngest subject was aged 14 years. All 7 subjects (100.0%) were White. The mean (SD) BMI was 24.81 (6.991) kg/m^2. The mean (SD) time since CD diagnosis to screening was 4.2 (3.70) years. At baseline, 1 subject (14.3%) had a previous surgery/procedure related to CD (type of surgery/procedure: other incision and drainage of abscess) in the perianal region. Previous surgeries related to perianal disease had occurred in 4 subjects (57.1%) (1 subject reported 5 previous surgeries, and 3 subjects reported 1 previous surgery each), the most common type being drainage - seton placement. At the preparation visit, 3 subjects (42.9%) had 1 internal opening and 1 external opening. Two subjects (28.6%) had 2 internal openings and 2 external openings. One subject (14.3%) had 1 internal opening and 2 external openings, and 1 subject (14.3%) had 1 internal opening and 3 external openings.

Overall, 20 subjects were screened, and 13 subjects experienced screen failure. A total of 7 subjects were enrolled and were treated with darvadstrocel. All 7 subjects completed the study.

A total of 7 subjects were treated with darvadstrocel in this study. All subjects received a full dose of 24 mL of darvadstrocel. The summary of the safety data is the following: - Through Week 24, a total of 5 of 7 subjects (71.4%) experienced 11 treatment-emergent AEs (TEAEs). Through Week 52, a total of 6 of 7 subjects (85.7%) experienced 12 TEAEs. Through Week 52, the most common TEAE by PT was Crohn's disease (2 subjects; 28.6%); all other PTs were reported for 1 subject (14.3%) each. - All TEAEs were either mild or moderate in intensity; no subjects had a TEAE that was severe in intensity through Week 24 or Week 52. - No TEAEs were considered by the investigator to be related to darvadstrocel or the darvadstrocel administration procedure through Week 24 or Week 52. - A total of 2 of 7 subjects (28.6%) experienced a treatment-emergent SAE (TESAE) through Week 24, and no additional TESAEs were reported after Week 24 through Week 52. The TESAEs of proctalgia and anal abscess, reported for 1 subject (14.6%) each, were moderate in intensity and recovered/resolved during the study. Neither of the TESAEs were considered related to darvadstrocel or the darvadstrocel administration procedure. - No deaths were reported in the study through Week 52. - No subjects were withdrawn or discontinued from the study due to a TEAE or TESAE through Week 52. - No subjects had an AESI as reported by the investigator through Week 24 or Week 52. - There were no notable trends for any clinical laboratory evaluations, vital sign parameters, or physical examination findings during the study. - There were no pregnancies reported during the study. The results of this study demonstrated that darvadstrocel was well tolerated through Week 52. The safety profile remained consistent with previously reported accumulated data in adults, and no new safety signals were identified.

Primary efficacy endpoint: At Week 24, 3 of 7 subjects (42.9%) in the ITT analysis set achieved combined remission (95% CI: 9.9%-81.6%). Of the 4 subjects in the ITT analysis set who did not achieve combined remission at Week 24, 2 subjects (50.0%) were considered nonremitters based on clinical assessment or central MRI, and 2 subjects (50.0%) met the criteria for achieving combined remission on the basis of the clinical assessment and central MRI, but were considered nonremitters due to the use of rescue medications or procedures. Secondary efficacy endpoints: Efficacy at Week 24: For clinical remission at Week 24, 3 of 7 subjects (42.9%) in the ITT analysis set achieved clinical remission (95% CI: 9.9%-81.6%). For clinical response at Week 24, 5 of 7 subjects (71.4%) in the ITT analysis set achieved clinical response (95% CI: 29.0%-96.3%). Efficacy at Week 52: At Week 52, 2 of 7 subjects (28.6%) in the ITT analysis set achieved clinical remission (95% CI: 3.7%-71.0%). Two subjects (28.6%) achieved clinical remission at Week 24 and at Week 52, and 1 subject (14.3%) who had achieved clinical remission at Week 24 did not achieve clinical remission at Week 52. At Week 52, 2 of 7 subjects (28.6%) in the ITT analysis set achieved clinical response (95% CI: 3.7%-71.0%). Two subjects (28.6%) achieved clinical response at Week 24 and at Week 52, and 3 subjects (42.9%) who had achieved clinical response at Week 24 did not achieve clinical response at Week 52. Because of the small number of subjects in this study, the K-M estimate of the median time to clinical remission by Week 52 in the ITT analysis set was not evaluable. For the 3 subjects who achieved clinical remission at any visit by Week 52, the actual times to clinical remission were 6.1, 6.7, and 11.9 weeks. Because of the small number of subjects in this study, the K-M estimate of the median time to clinical response by Week 52 in the ITT analysis set was not evaluable. For the 6 subjects who achieved clinical response at any visit by Week 52, the actual times to clinical response were 6.1, 6.3, 6.6, 6.7, 7.3, and 11.9 weeks. Of the 3 subjects in the ITT analysis set who achieved combined remission at Week 24, 2 subjects (66.7%) did not experience relapse by Week 52, and 1 subject (33.3%) was missing relapse status at Week 52 (this subject did not have FCA at Week 52). CONCLUSION (Contiued): - This open-label study evaluated clinical efficacy and safety data of darvadstrocel in pediatric subjects aged 4 to <18 years with complex perianal fistulas due to CD that were refractory to biologics or immunosuppressants. The 7 enrolled subjects were aged 14 to >=17 years at the time of the study treatment administration. - Although the sample size of this study was small, a subset of pediatric subjects with complex perianal fistulas refractory to biologics or immunosuppressants achieved combined remission at Week 24 (3 of 7 subjects) after a single dose of darvadstrocel (120 million cells). Results of the secondary endpoints of clinical remission and clinical response at Week 24 were consistent with the primary efficacy endpoint. - Although the sample size of this study was small, a subset of subjects achieved clinical remission (2 of 7 subjects) and clinical response (2 of 7 subjects) at Week 52. Time to clinical remission and time to clinical response at Week 52 ranged from 6.1 to 11.9 weeks for the small number of subjects who achieved clinical remission or clinical response.

The results of this study demonstrated that darvadstrocel was generally safe and well tolerated in pediatric subjects with complex perianal fistula(s) due to CD. No new safety findings were identified. The overall safety profile observed in this study was consistent with the known safety profile of darvadstrocel in adults.

No

De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be reidentified (due to the limited number of study participants/study sites).

https://jrct.mhlw.go.jp/latest-detail/jRCT2033200314

Shikamura Mitsuhiro

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

smb.Japanclinicalstudydisclosure@takeda.com

Contact for Clinical Trial Information

Takeda Pharmaceutical Company Limited

1-1, Doshomachi 4-chome, Chuo-ku, Osaka

+81-662042111

smb.Japanclinicalstudydisclosure@takeda.com

Complete

June. 30, 2021

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Has a CD diagnosis based on accepted clinical, endoscopic, histological and/or radiologic criteria at least 6 months before the screening visit.
2. Has complex perianal fistula refractory to at least one of the following treatments: immunosuppressants or biologics (anti-tumor necrosis factor[TNF]s, anti-integrin, anti-interleukin [IL] 12/23). Fistula(s) refractory to therapy are defined in this study as follows: Immunosuppressants: Inadequate response after 3 months, based on clinical assessment, or more treatment with azathioprine, 6-mercaptopurine or methotrexate. Biologics: Inadequate response after 14 weeks (16 weeks for anti-IL 12/23), based on clinical assessment, or more standard treatment for induction and maintenance.
3. 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 magnetic resonance imaging (MRI). Presence of 2-3 external openings (tracts) as assessed by clinical examination. Associated fluid collections as determined by MRI.
This study requires that the participant has complex perianal fistulas with a maximum of 2 internal openings and a maximum of 3 external openings, based on clinical assessment. Darvadstrocel treatment is targeted for fistulas that connect between internal and external openings. A central reading of a locally performed pelvic MRI will be performed to confirm the location of the fistula and potential associated perianal abscess(es). Fistulas must have been draining for at least 6 weeks before the screening visit. Participants with actively draining simple subcutaneous fistulas, at the time of the screening visit, are not allowed in this study.
4. Has inactive or mildly active luminal CD defined by meeting all of the following criteria:
a. Colonoscopy, flexible sigmoidoscopy or rectoscopy performed either at screening or within the 6 months before screening, demonstrating no rectal ulcers larger than 0.5 cm. A participant who has documented rectal ulcers larger than 0.5 cm within the 6 months before screening but has undergone subsequent treatment may be eligible if there are no rectal ulcers larger than 0.5 cm on a sigmoidoscopy or rectoscopy performed after treatment or at the time of screening.
b. The improvement of, or no worsening in stool frequency, sustained for 1 week or more, in the interval between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 4(a) and the screening visit.
c. No initiation or intensification of treatment with corticosteroids, immunosuppressants, or monoclonal antibody dose regimen between the colonoscopy, flexible sigmoidoscopy or rectoscopy in inclusion criteria 4(a) and the screening visit.

1. Has received any investigational compound within 12 weeks/84 days before screening.
2. Has received darvadstrocel/expanded adipose-derived mesenchymal stem cells(eASC) in a previous clinical study or as a therapeutic agent.
3. The participant weighs <10 kg at screening.
4. Has concomitant perianal fistula(s) with only internal or external opening(s).
5. Has concomitant internal fistula(s) such as ileo-vesical, rectovaginal or ileo-colonic fistula(s).
6. Has an abscess>2 cm, unless resolved in the preparation procedure.
7. Has rectal and/or anal stenosis, and/or active proctitis, which would restrict the surgical procedure.
8. The participant underwent surgery for the fistula other than drainage or seton placement.
9. Has diverting stomas.
10. Has ongoing systemic corticosteroid treatment or has been treated with systemic corticosteroids within 4 weeks before screening.
11. The participant requires new treatment with immunosuppressants/anti-TNF agents during the screening period.
12. 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. 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.
13. The participant 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.
14. Has malignant tumor or a prior history of any malignant tumor, including any type of fistula carcinoma.
15. 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.
16. Has either congenital or acquired immunodeficiencies, including participants known to be HIV carriers or participants with, in the judgment of the investigator, are suspected to have monogenic inflammatory bowel disease.
17. Has previously received a bone marrow transplant.
18. Has a contraindication to MRI scan, or other planned study procedures.
19. Has a contraindication to the anesthetic procedure.
20. Had major surgery or severe trauma within 6 months before the screening visit.

Both

Crohn's Disease, Complex Perianal Fistula

Darvadstrocel (Cx601), 24 mL suspension of 120 million cells as a perilesional injection, once on Day 0.

1. Percentage of Participants who Achieve Combined Remission
Time Frame: Baseline and Week 24
Combined remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression, and absence of abscess (es) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by central magnetic resonance imaging (MRI) assessment.

1. Percentage of Participants who Achieve Clinical Remission
Time Frame: Baseline and Weeks 24 and 52
Clinical remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression.

2. Percentage of Participants who Achieve Clinical Response
Time Frame: Baseline and Weeks 24 and 52
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. Time to Clinical Remission
Time Frame: Baseline up to Week 52
Time to Clinical Remission is defined as the time in weeks 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.

4. Time to Clinical Response
Time Frame: Baseline up to Week 52
Time to clinical response defined as the time in weeks 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.

5. Percentage of Participants with Relapse in Participants with Combined Remission at Week 24
Time Frame: Baseline, Weeks 24 and 52
Relapse is defined as reopening of any of the treated fistula(s) external openings with active drainage as clinically assessed in participants who were in combined remission at Week 24.

6. Percentage of Participants with At Least One Adverse Event (AE)
Time Frame: From date of signing of informed consent form (ICF) up to Week 52
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.

7. Percentage of Participants with At Least One Serious Adverse Event (SAE)
Time Frame: From date of signing of ICF up to Week 52
An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

8. Percentage of Participants with At Least One Adverse Event of Special Interest (AESI)
Time Frame: From date of signing of ICF up to Week 52
An AESI include immunogenicity/alloimmune reactions, hypersensitivity, ectopic tissue formation, medication errors, tumorigenicity, transmission of infectious agents.

9. Percentage of Participants with Potentially Clinically Significant Vital Sign Values
Time Frame: Baseline up to Week 52
Vital signs will include body temperature (oral measurement), blood pressure (systolic and diastolic, resting more than 5 minutes), and heart rate (beats per minute).

10. Percentage of Participants with Potentially Clinically Significant Laboratory Values
Time Frame: Baseline up to Week 52
Laboratory parameters will include hematology, biochemistry, and urinalysis.

+81-3-5802-1584

Feb. 19, 2021

Italy/Netherlands/ Poland/Spain/Israel