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Phase 3 Study of Cx601 in Participants With Complex Perianal Fistulising Crohn's Disease

Phase 3
Completed
Conditions
Complex Perianal Fistulas in Adult Participants With Crohn's Disease
Interventions
Biological: Darvadstrocel
Registration Number
NCT03706456
Lead Sponsor
Takeda
Brief Summary

The purpose of this study is to evaluate the efficacy of darvadstrocel for the treatment of complex perianal fistulas in adult participants with Crohn's disease over 24 weeks.

Detailed Description

The drug being tested in this study is called Darvadstrocel (Cx601). This study will assess the efficacy for 24 and 52 weeks, and safety for 156 weeks of darvadstrocel when administered with intralesional injection in adult participants with Crohn's disease whose complex perianal fistulas were previously treated and refractory.

The study enrolled 22 participants. All participants who will meet the criteria will be assigned to screening period for approximately 5 weeks and after that will be enrolled the treatment period which will be the day of study product administration. After the treatment period, this study will include the follow-up period for approximately 52 weeks after study product administration, and the long-term follow-up period from Week 52 to Week 156.

This multi-center trial will be conducted in Japan. The overall time to participate is totally approximately 156 weeks (3 years) from the start of treatment period plus follow-up and long-term follow-up period. Participants will make multiple visits to the clinic and a final visit 156 weeks after treatment of study product for a follow-up assessment.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
22
Inclusion Criteria

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

  2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

  3. The participant who was diagnosed with Crohn's disease at least 6 months prior to the screening period according to the Diagnostic Criteria for Crohn's Disease issued by Research Group for Intractable Inflammatory Bowel Disease Designated as Specified Disease by the Ministry of Health, Labour and Welfare (MHLW) of Japan (revised January 2017).

  4. The participant is either a male or female outpatient, aged 18 years or older at the time of signing the informed consent form.

  5. The participant who has non-active or mildly active Crohn's disease defined by the Crohn's disease activity index (CDAI) =<220 evaluated at any time between Visit 1 and Visit 2.

  6. The participant who has complex perianal fistulas with a maximum of 2 internal openings and a maximum of 3 external openings, confirmed by clinical assessment and MRI. All of the external openings must connect to internal openings. Fistula must have been draining for at least 6 weeks prior to the screening. Complex perianal fistula is defined as the one that meets 1 or more of the following criteria:

    • High (ie, above the dentate line) inter-sphincteric or trans-sphincteric fistula, extrasphincteric fistula, or supra-sphincteric fistula.
    • Presence of >=2 external openings (tracts).
    • Associated fluid collections.

  7. The participant whose perianal fistulas were previously treated and have shown an inadequate response (absence of closure of part or all fistula tract, or new fistula during induction treatment) or a loss of response (fistula relapse after complete closure of initial fistula, or fistula worsening after partial closure of initial fistula during maintenance treatment) while they were receiving either immunosuppressants or biologics, or having documented intolerance (occurrence, at any time, of an unacceptable level of treatment-related side effects that makes necessary treatment discontinuation) to any of these treatments administered at least approved or recommended doses during the minimum period mentioned;

    • Antibiotics (ciprofloxacin or metronidazole): 1 or more month treatment.
    • Immunosuppressants (azathioprine, 6-mercaptopurine or methotrexate): 3 or more months treatment.
    • Biologics (anti-tumor necrosis factors [TNFs], anti-integrin or anti-interleukin [IL]-12/23): 14 or more weeks (16 or more weeks for anti-IL-12/23) standard treatment for induction or maintenance.

  8. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent up to Week 52 of the study.

  9. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent up to Week 52 of the study.

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Exclusion Criteria
  1. The participant whose CDAI is >220 at any time between Visit 1 and Visit 2, or who has active Crohn's disease requiring a new of escalating immediate therapy.
  2. The participant who has concomitant rectovaginal or rectovesical fistulas.
  3. The participant who has >2 internal openings of >3 external openings.
  4. The participant who is naïve to protocol required treatment for complex perianal fistulising Crohn's disease (ie, antibiotics, immunosuppressants or biologics).
  5. The participant who has an abscess or collections >2 cm.
  6. The participant who has rectal and/or anal stenosis and/or active proctitis, which would restrict the surgical procedure.
  7. The participant who underwent surgery other than drainage or seton placement for the to be treated fistula.
  8. The participant who has diverting stomas.
  9. The participant who was treated with systemic steroids in the 4 weeks prior to study product administration.
  10. The participant receiving cytapheresis therapy.
  11. The participant who requires new treatment with immunosuppressants/biologics/non-tapered systematic steroids during the screening period.
  12. The participant who has renal impairment defined by creatinine clearance below 60 mL/minute calculated using Cockcroft-Gault formula or by serum creatinine >=1.5 × upper limit of normal (ULN).
  13. The participant who has hepatic impairment defined by both total bilirubin >=1.5 × ULN, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >=2.5 × ULN.
  14. The participant who has history of abuse of alcohol or other addictive substances in the 6 months prior to the screening period.
  15. The participant who has malignant tumour or who has a history of malignant tumour, including any type of fistula carcinoma.
  16. The participant who has abnormal, severe, progressive, uncontrolled hepatic, hematological, gastrointestinal (except Crohn's disease), endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease, or the participant who developed any of the above diseases within 3 months prior to the screening period.
  17. The participant who has congenital or acquired immunodeficiency, including participants known to be Human Immunodeficiency Virus (HIV) carriers.
  18. The participant who has clinically significant chronically active hepatopathy of any origin, including hepatic cirrhosis, and participants who is persistent positive for hepatitis B virus (HBV) surface antigen (HBsAg) and quantitative HBV polymerase chain reaction (PCR), or positive serology for hepatitis C virus (HCV) and quantitative HCV-PCR within 6 months prior to the screening period.
  19. The participant who has known allergies or hypersensitivity to antibiotics (including but not limited to penicillin, streptomycin, gentamicin, aminoglycosides), Human Serum Albumin (HSA), bovine-derived materials, local anesthetics or gadolinium (MRI contrast agent).
  20. The participant for whom MRI scan is contraindicated (eg, due to the presence of a pacemaker, a history of hip replacements, or severe claustrophobia).
  21. The participant who has major surgery (eg, surgery under general anesthesia, laparotomy, thoracotomy, craniotomy) or severe trauma within 6 months prior to the screening period.
  22. The female participant who is pregnant, or is lactating.
  23. The participant who has received any investigational drug within 12 weeks (84 days) prior to the screening.
  24. The participant who has received expanded allogeneic adipose-derived stem cells (eASC) in a previous clinical study or as a therapeutic agent.
  25. The participant who needs perianal surgery other than fistulas preparation required by the protocol during the screening, or the participant who will receive a perianal surgery within 24 weeks after study product administration.
  26. The participant for whom anesthesia is contraindicated.
  27. The participant who received excluded medications or treatment.
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Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Darvadstrocel 24 mLDarvadstrocelDarvadstrocel (Cx601) 24 mL suspension of 120 million cells of expanded allogeneic adipose-derived stem cells (eASC) as an intralesional injection, once on Day 1.
Primary Outcome Measures
NameTimeMethod
Percentage of Participants With Combined Remission of Perianal Fistulising Crohn's Disease (CD) at Week 24Week 24

Combined remission of perianal fistulising CD is defined as the clinically confirmed closure of all treated external openings that were draining at Screening despite gentle finger compression, and absence of collections \>2 cm in the treated fistulas, confirmed by central magnetic resonance imaging (MRI) assessment at Week 24 visit. In case of missing values, last observation carried forward (LOCF) method was applied. Percentages are rounded off to the nearest decimal point.

Secondary Outcome Measures
NameTimeMethod
Percentage of Participants With Combined Remission of Perianal Fistulising CD at Week 52Week 52

Combined remission is defined as the clinically confirmed closure of all treated external openings that were draining at the screening despite gentle finger compression, and absence of collections \>2 cm in the treated fistulas which is confirmed by the central MRI assessment at Week 52 visit. In case of missing values, LOCF method was applied. Percentages are rounded off to the nearest decimal point.

Time to Relapse of Perianal Fistulising CD by Week 24 in Participants With Clinical Remission at a Previous VisitUp to Week 24

Time to Relapse is defined as the time from the first visit by which clinical remission is observed to the first visit by which relapse is observed. Relapse is defined as the clinically confirmed reopening of any of the treated external openings with active drainage, or the development of a collection \>2 cm in the treated fistulas confirmed by central MRI assessment.

Change From Baseline in Perianal Disease Activity Index (PDAI): Total Score at Week 24Baseline and Week 24

The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) Discharge; (b) Pain; (c) Restriction of sexual activity; (d) Type of perianal disease; and (e) Degree of induration. Each item is graded on a 5-point scale where 0 indicates no symptoms and 4 indicates severe symptoms and total range of score is from 0 to 20. Higher score indicates more severe disease. Negative change from Baseline indicates improvement.

Percentage of Participants With Clinical Remission of Perianal Fistulising CD at Week 24Week 24

Clinical remission of perianal fistulising CD is defined as the clinically confirmed closure of all treated external openings that were draining at Screening despite gentle finger compression at Week 24 Visit. In case of missing values, LOCF method was applied. Percentages are rounded off to the nearest decimal point.

Percentage of Participants With Response of Perianal Fistulising CD at Week 24Week 24

Response of perianal fistulising CD is defined as the clinically confirmed closure of at least 50 percent of all treated external openings that were draining at Screening despite gentle finger compression at Week 24 visit. In case of missing values, LOCF method was applied. Percentages are rounded off to the nearest decimal point.

Time to Response of Perianal Fistulising CD by Week 24Up to Week 24

Time to response is defined as the time from the study product administration to the first visit by which response is observed. Response is defined as the clinically confirmed closure of at least 50 percent of all treated external openings that were draining at Screening despite gentle finger compression.

Percentage of Participants With Relapse of Perianal Fistulising CD at Week 24 in Participants With Clinical Remission at a Previous VisitWeek 24

Relapse is defined as the clinically confirmed reopening of any of the treated external openings with active drainage, or the development of a collection \>2 cm in the treated fistulas confirmed by central MRI assessment in participants who achieved clinical remission before Week 24. LOCF method was applied. Percentages are rounded off to the nearest decimal point.

Percentage of Participants With Response of Perianal Fistulising CD at Week 52Week 52

Response is defined as the clinically confirmed closure of at least 50 percent of all treated external openings that were draining at the screening despite gentle finger compression at Week 52 visit. In case of missing values, LOCF method was applied. Percentages are rounded off to the nearest decimal point.

Time to Clinical Remission of Perianal Fistulising CD by Week 52Up to Week 52

Time to clinical remission is defined as the time from the study product administration to the first visit by which clinical remission is observed. Clinical remission is defined as the clinically confirmed closure of all treated external openings that were draining at Screening despite gentle finger compression.

Time to Clinical Remission of Perianal Fistulising CD by Week 24Up to Week 24

Time to clinical remission is defined as the time from the study product administration to the first visit by which clinical remission is observed. Clinical remission is defined as the clinically confirmed closure of all treated external openings that were draining at Screening despite gentle finger compression.

Change From Baseline in PDAI: Pain Sub-Score at Week 52Baseline and Week 52

The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) Discharge; (b) Pain; (c) Restriction of sexual activity; (d) Type of perianal disease; and (e) Degree of induration. The pain item is graded on a 5-point scale ranging from no symptoms (score of 0) to severe symptoms (score of 4) and total range of score is from 0 to 20. Higher score indicates more severe disease. Negative change from Baseline indicates improvement.

Change From Baseline in PDAI: Discharge Sub-Score at Week 24Baseline and Week 24

The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) Discharge; (b) Pain; (c) Restriction of sexual activity; (d) Type of perianal disease; and (e) Degree of induration. The discharge item is graded on a 5-point scale where 0 indicates no symptoms and 4 indicates severe symptoms and total range of score is from 0 to 4. Higher score indicates more severe disease. Negative change from Baseline indicates improvement.

Change From Baseline in PDAI: Pain Sub-Score at Week 24Baseline and Week 24

The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) Discharge; (b) Pain; (c) Restriction of sexual activity; (d) Type of perianal disease; and (e) Degree of induration. The pain item is graded on a 5-point scale where 0 indicates no symptoms and 4 indicates severe symptoms and total range of score is from 0 to 4. Higher score indicates more severe disease. Negative change from Baseline indicates improvement.

Change From Baseline in Crohn's Disease Activity Index (CDAI): Total Score at Week 24Baseline and Week 24

CDAI score is calculated from the following 8 items: (a) Number of liquid or very soft stools; (b) Abdominal pain; (c) General wellbeing; (d) Extraintestinal complications; (e) Antidiarrhoeal drugs; (f) Abdominal mass; (g) Hematocrit; and (h) Body weight. Scores of some items in CDAI are calculated based on patient diary. Total score ranges from 0 to 600. Higher score means more severe disease and especially severe disease was defined as a value of greater than 450. Negative change from Baseline indicates improvement.

Change From Baseline in Van Assche Score at Week 24Baseline and Week 24

The Van Assche score represents the magnetic resonance imaging (MRI)- based severity of perianal lesion associated with Crohn's disease. Based on MRI data, the number, location and extension of fistula tracts, hyperintensity on T2-weighted images, presence or absence of collections (cavities \>3 mm in diameter), and rectal wall involvement will be evaluated. The score range was from 0 to 22. Higher score means more severe disease. Negative change from Baseline indicates improvement.

Percentage of Participants With Clinical Remission of Perianal Fistulising CD at Week 52Week 52

Clinical remission is defined as the clinically confirmed closure of all treated external openings that were draining at screening despite gentle finger compression at Week 52 visit. In case of missing values, LOCF method was applied. Percentages are rounded off to the nearest decimal point.

Percentage of Participants With Relapse of Perianal Fistulising CD at Week 52 in Participants With Combined Remission at Week 24Week 52

Relapse is defined as the clinically confirmed reopening of any of the treated external openings with active drainage, or the development of a collection \>2 cm in the treated fistulas confirmed by central MRI assessment in participants who achieved combined remission at Week 24. Combined remission is defined as the clinically confirmed closure of all treated external openings that were draining at Screening despite gentle finger compression, and absence of collections \>2 cm in the treated fistulas, confirmed by the central MRI assessment. LOCF method was applied. Percentages are rounded off to the nearest decimal point.

Change From Baseline in Van Assche Total Score at Week 52Baseline and Week 52

The Van Assche score represents the MRI-based severity of perianal lesion associated with Crohn's disease. Based on MRI data, the number, location and extension of fistula tracts, hyperintensity on T2-weighted images, presence or absence of collections (cavities \>3 mm in diameter), and rectal wall involvement will be evaluated. The total score ranges from 0 to 22. Higher score indicates more severe disease. Negative change from Baseline indicates improvement.

Time to Combined Remission of Perianal Fistulising CD by Week 52Up to Week 52

Time to combined remission is defined as the time from the study product administration to the first visit by which combined remission is observed. Combined remission is defined as the clinically confirmed closure of all treated external openings that were draining at the screening despite gentle finger compression, and absence of collections \>2 cm in the treated fistulas which is confirmed by the central MRI assessment.

Time to Relapse of Perianal Fistulising CD by Week 52 in Participants With Combined Remission at Week 24Up to Week 52

Time to relapse by Week 52 in participants who achieved combined remission at Week 24 is defined as the time from the combined remission at Week 24 to the first visit by which relapse is observed. Relapse is defined as the clinically confirmed reopening of any of the treated external openings with active drainage, or the development of a collection \>2 cm in the treated fistulas confirmed by central MRI assessment in participants who achieved combined remission at Week 24. Combined remission is defined as the clinically confirmed closure of all treated external openings that were draining at Screening despite gentle finger compression, and absence of collections \>2 cm in the treated fistulas, confirmed by the central MRI assessment.

Change From Baseline in PDAI: Discharge Sub-Score at Week 52Baseline and Week 52

The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) Discharge; (b) Pain; (c) Restriction of sexual activity; (d) Type of perianal disease; and (e) Degree of induration. The discharge item is graded on a 5-point scale ranging from no symptoms (score of 0) to severe symptoms (score of 4) and total range of score is from 0 to 20. Higher score indicates more severe disease. Negative change from Baseline indicates improvement.

Change From Baseline in CDAI: Total Score at Week 52Baseline and Week 52

CDAI score is calculated from the following 8 items: (a) Number of liquid or very soft stools; (b) Abdominal pain; (c) General wellbeing; (d) Extraintestinal complications; (e) Antidiarrhoeal drugs; (f) Abdominal mass; (g) Hematocrit; and (h) Body weight. Scores of some items in CDAI are calculated based on patient diary. Total score ranges from 0 to 600. Higher score indicates more severe disease and especially severe disease was defined as a value of greater than 450. Negative change from Baseline indicates improvement.

Time to Response of Perianal Fistulising CD by Week 52Up to Week 52

Time to response is defined as the time from the study product administration to the first visit by which response is observed. Response is defined as the clinically confirmed closure of at least 50 percent of all treated external openings that were draining at the Screening despite gentle finger compression.

Change From Baseline in PDAI: Total Score at Week 52Baseline and Week 52

The PDAI is a scoring system to evaluate the severity of perianal lesion associated with Crohn's disease. It includes the following 5 items: (a) Discharge; (b) Pain; (c) Restriction of sexual activity; (d) Type of perianal disease; and (e) Degree of induration. Each item is graded on a 5-point scale ranging from no symptoms (score of 0) to severe symptoms (score of 4) and total range of score is from 0 to 20. Higher score indicates more severe disease. Negative change from Baseline indicates improvement.

Trial Locations

Locations (11)

Sapporo Higashi Tokushukai Hospital

🇯🇵

Sapporo, Hokkaido, Japan

Mie University Hospital

🇯🇵

Tsu, Mie, Japan

Tohoku Rosai Hospital

🇯🇵

Sendai, Miyagi, Japan

Tohoku University Hospital

🇯🇵

Sendai, Miyagi, Japan

Hyogo College of Medicine

🇯🇵

Nishinomiya, Hyogo, Japan

Coloproctology Center Takano Hospital

🇯🇵

Kumamoto, Japan

Ieda Hospital

🇯🇵

Toyota, Aichi, Japan

Fukuoka University Chikushi Hospital

🇯🇵

Chikushino, Fukuoka, Japan

Yokohama Municipal Citizen's Hospital

🇯🇵

Yokohama, Kanagawa, Japan

Osaka University Hospital

🇯🇵

Suita, Osaka, Japan

JCHO Tokyo Yamate Medical Center

🇯🇵

Shinjuku, Tokyo, Japan

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