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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 3, Multicenter, Open-Label, Uncontrolled Study to Evaluate the Efficacy and Safety of Cx601 in the Treatment of Complex Perianal Fistulas in Adult Patients With Crohn's Disease

Conditions
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Complex Perianal Fistulas in Adult Participants With Crohn's Disease

Intervention / Treatment
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* Biological: Darvadstrocel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In the opinion of the investigator, the participant is capable of understanding and complying with the protocol requirements. 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. 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). The participant is either a male or female outpatient, aged 18 years or older at the time of signing the informed consent form. 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. 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. 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. 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. 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. Exclusion Criteria: 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. The participant who has concomitant rectovaginal or rectovesical fistulas. The participant who has >2 internal openings of >3 external openings. The participant who is naïve to protocol required treatment for complex perianal fistulising Crohn's disease (ie, antibiotics, immunosuppressants or biologics). The participant who has an abscess or collections >2 cm. The participant who has rectal and/or anal stenosis and/or active proctitis, which would restrict the surgical procedure. The participant who underwent surgery other than drainage or seton placement for the to be treated fistula. The participant who has diverting stomas. The participant who was treated with systemic steroids in the 4 weeks prior to study product administration. The participant receiving cytapheresis therapy. The participant who requires new treatment with immunosuppressants/biologics/non-tapered systematic steroids during the screening period. 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). 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. The participant who has history of abuse of alcohol or other addictive substances in the 6 months prior to the screening period. The participant who has malignant tumour or who has a history of malignant tumour, including any type of fistula carcinoma. 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. The participant who has congenital or acquired immunodeficiency, including participants known to be Human Immunodeficiency Virus (HIV) carriers. 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. 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). The participant for whom MRI scan is contraindicated (eg, due to the presence of a pacemaker, a history of hip replacements, or severe claustrophobia). 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. The female participant who is pregnant, or is lactating. The participant who has received any investigational drug within 12 weeks (84 days) prior to the screening. The participant who has received expanded allogeneic adipose-derived stem cells (eASC) in a previous clinical study or as a therapeutic agent. 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. The participant for whom anesthesia is contraindicated. The participant who received excluded medications or treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Darvadstrocel 24 mL<br>Darvadstrocel (Cx601) 24 mL suspension of 120 million cells of expanded allogeneic adipose-derived stem cells (eASC) as an intralesional injection, once on Day 1. | Biological: Darvadstrocel<br>* Darvadstrocel cell suspension for intralesional injection.<br>* Other names: Cx601;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Combined Remission of Perianal Fistulising Crohn's Disease (CD) at Week 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Remission of Perianal Fistulising CD at Week 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. | Week 24 | 
| Percentage of Participants With Response of Perianal Fistulising CD at Week 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. | Week 24 | 
| Time to Clinical Remission by 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. | Up to Week 24 | 
| Time to Response by 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. | Up to Week 24 | 
| Percentage of Participants With Relapse at Week 24 in Participants With Clinical Remission at a Previous Visit | 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. | Week 24 | 
| Time to Relapse by Week 24 in Participants With Clinical Remission at a Previous Visit | 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. | Up to Week 24 | 
| Change From Baseline in Perianal Disease Activity Index (PDAI): Total Score at 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 20. Higher score indicates more severe disease. Negative change from Baseline indicates improvement. | Baseline and Week 24 | 
| Change From Baseline in PDAI: Discharge Sub-Score at 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. | Baseline and Week 24 | 
| Change From Baseline in PDAI: Pain Sub-Score at 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. | Baseline and Week 24 | 
| Change From Baseline in Crohn's Disease Activity Index (CDAI): Total Score at 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. | Baseline and Week 24 | 
| Change From Baseline in Van Assche Score at Week 24 | 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 score range was from 0 to 22. Higher score means more severe disease. Negative change from Baseline indicates improvement. | Baseline and Week 24 | 
| Percentage of Participants With Combined Remission at Week 52 | Reported data will be percentage of participants who will meet combined remission criteria at Week 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. In case of missing values, LOCF method will be applied. | Week 52 | 
| Percentage of Participants With Clinical Remission at Week 52 | Reported data will be percentage of participants who will meet clinical remission criteria at Week 52. In case of missing values, LOCF method will be applied. | Week 52 | 
| Percentage of Participants With Response at Week 52 | Reported data will be percentage of participants who will meet response criteria at Week 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. In case of missing values, LOCF method will be applied. | Week 52 | 
| Time to Combined Remission by Week 52 | Reported data will be time to combined remission from baseline by Week 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. | Week 52 | 
| Time to Clinical Remission by Week 52 | Reported data will be time to clinical remission from baseline by Week 52. | Week 52 | 
| Time to Response by Week 52 | Reported data will be time to response from baseline by Week 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. | Week 52 | 
| Percentage of Participants With Relapse at Week 52 in Participants With Clinical Remission at Week 24 | Reported data will be percentage of participants who will meet relapse criteria at Week 52 in participants with clinical remission at Week 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. | Week 52 | 
| Time to Relapse by Week 52 in Participants With Clinical Remission at Week 24 | Reported data will be time to relapse from baseline by Week 52 in participants with clinical remission at Week 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. | Up to Week 52 | 
| PDAI: Total Score at 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 means more severe disease. | Week 52 | 
| PDAI: Discharge Sub-Score at 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 means more severe disease. | Week 52 | 
| PDAI: Pain Sub-Score at 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 means more severe disease. | Week 52 | 
| CDAI: Total Score at 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 range of score is more than 0. Higher score means more severe disease and especially severe disease was defined as a value of greater than 450. | Week 52 | 
| Van Assche Score at 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. Higher score means more severe disease. | Week 52 |