Study to Assess Efficacy and Safety of Cx601, Adult Allogeneic Expanded Adipose-derived Stem Cells (eASC) for the Treatment of Complex Perianal Fistula(s) in Participants With Crohn's Disease (CD)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the combined remission of complex perianal fistulas, defined as the clinical assessment at Week 24 of closure of all treated external openings that were draining at baseline despite gentle finger compression, and absence of collections greater than (>) 2 centimeter (cm) (in at least 2 dimensions) confirmed by blinded central magnetic resonance imaging (MRI) assessment at Week 24.

Detailed Description
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This study is to assess the efficacy and safety of Cx601, eASC, for the treatment of complex perianal fistulas in participants with Crohn's disease. The study will randomize approximately 554 participants. Cx601 eASCs intralesional injection Placebo - Cx601 placebo-matching eASCs intralesional injection Study treatments will be allocated, on a 1:1 ratio, by central randomization through interactive web response system (IWRS). The study will follow an add-on design, participants receiving any ongoing concomitant medical treatment, at stable doses at the time of screening, for the CD will be allowed to continue it throughout the study. The primary efficacy analysis, will be conducted at Week 24 timepoint. The double blind design will be maintained up to Week 52 (both participant and investigator) by a specific blinding for study treatment administration and for evaluating its efficacy. This multicenter trial will be conducted globally across 150 centers. The overall time to participate in this study is approximately 5 years.

Official Title
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A Phase-III, Randomized, Double-blind, Parallel-group, Placebo-controlled, International, Multicentre Study to Assess Efficacy and Safety of Cx601, Adult Allogeneic Expanded Adipose-derived Stem Cells (eASC) for the Treatment of Complex Perianal Fistula(s) in Patients With Crohn's Disease Over a Period of 24 Weeks and a Follow-up Period up to 52 Weeks

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Cx601
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent. Participants of either gender greater than or equal to (>=) 18 years and less than or equal to (<=) 75 years of age. Participants with CD diagnosed at least 6 months prior to Screening visit in accordance with accepted clinical, endoscopic, histological and/or radiological criteria. Presence of complex perianal fistula(s) with a maximum of 2 internal openings and a maximum of 3 external openings based on clinical assessment; a central reading of a locally performed contrast enhanced (gadolinium) pelvic MRI will be performed to confirm location of the fistula and potential associated perianal abscess(es). Fistula(s) must have been draining for at least 6 weeks prior to Screening visit. Actively draining simple subcutaneous fistula(s), at the time of Screening visit, are not allowed in this study. A complex perianal fistula is defined as a fistula that meets one or more of the following criteria : High inter-sphincteric, high trans-sphincteric, extra-sphincteric or suprasphincteric. Presence of >=2 external openings. Associated perianal abscess(es). Note: Abscesses that are larger than 2 cm at least 2 dimensions on MRI must be confirmed to have been drained adequately by the surgeon during the preparation curettage in order to be eligible. Clinically controlled, nonactive or mildly active CD, during the last six months prior to Screening visit with: A patient reported outcomes (PRO-2) score <14 at Screening, AND A colonoscopy documenting the absence of ulcers larger than 0.5 cm in the colonic mucosa: - If colonoscopy data are not available within 6 months prior to Screening: A simple endoscopic score for Crohn's Disease (SES-CD) <=6 with absence of rectal ulcers larger than 0.5 cm must be documented in a colonoscopy performed at Screening before randomization. - If colonoscopy data are available within 6 months prior to Screening, the following must be documented, otherwise a new colonoscopy (as above) will be mandatory: The absence of ulcers larger than 0.5 cm in the colonic mucosa AND the improvement or no worsening in abdominal pain and/or in the diarrhea, sustained for one week or more, since the last colonoscopy was performed in the clinical records until Screening visit. AND o No hemoglobin decrease >=2.0 gram per deciliter (g/dL) or an unexplained rising C-reactive protein (CRP), > 5.0 milligram per liter (mg/L) to a concentration above the referenced upper limit of normal (ULN) (unless the rise is due to a known process other than luminal Crohn's Disease), since the last colonoscopy was performed as compared to results during the Screening visit. AND o no initiation or intensification of treatment with corticosteroids, immunosuppressants or monoclonal antibodies (mAbs) dose regimen since the last endoscopy up to Screening visit. Participants whose perianal fistulas were previously treated and have shown an inadequate response or a loss of response while they were receiving either an immunosuppressive agent or tumour necrosis factor (TNF)-alpha antagonist or vedolizumab or ustekinumab, or having documented intolerance to any of these treatments administered at least at approved or recommended doses during the minimum period mentioned: Immunosuppressive agents: at least 3 months treatment with azathioprine (2-3 milligram per kilogram per day [mg/kg/day]), 6-mercaptopurine (1-1.5 mg/kg/day), or subcutaneous/intramuscular methotrexate (25 mg/week) prior to Screening for the study. TNFalpha antagonists: Infliximab: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1 intravenous dose of 5 milligram per kilogram (mg/kg) followed by the same dose 2 and 6 weeks after. For maintenance: 5-10 mg/kg intravenously every 8 weeks, or more frequently. Adalimumab: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn's disease prior to screening for the study. For induction: 1 subcutaneous dose of 160 milligram (mg), followed by 80 mg 2 weeks after. For maintenance: 40 mg subcutaneously every other week, or weekly. Certolizumab l: at least 14 weeks treatment at the approved doses for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: 1 subcutaneous dose of 400 mg, followed by the same dose 2 and 4 weeks after. For maintenance: 400 mg subcutaneously every 2 to 4 weeks. Anti-integrin: at least 14 weeks treatment of the approved dose for induction and/or maintenance in Crohn´s disease prior to screening for the study. For induction: Vedolizumab 300 mg. For maintenance: Vedolizumab 300 mg every 4 to 8 weeks. Anti-interleukin (IL)-12/23: at least 16 weeks treatment of the approved dose in Crohn´s disease prior to screening for the study. For induction: Ustekinumab, approximately 6mg/kg intravenously initially then followed by 90 mg subcutaneously every 8 weeks. Women of childbearing potential (WCBP) must have negative serum pregnancy test at screening (sensitive to 25 international units [IU] human chorionic gonadotropin [hCG]). Both WCBP or male participants participating in this study, with a WCBP as partner, must agree to use an adequate method of contraception during the entire duration of the study. An adequate method of contraception is defined as complete, non-periodic sexual abstinence (refraining from heterosexual intercourse), single-barrier method, vasectomy, adequate hormonal contraception (to have started at least 7 days prior to Screening visit), or an intra-uterine device (to have been in place for at least 2 months prior to Screening visit). Exclusion Criteria: Concomitant rectovaginal or rectovesical fistula(s). Participant naïve to prior specific medical treatment for complex perianal fistula(s) including immunosuppressant (IS) or anti-TNFs. Presence of a perianal collection >2 cm in at least two dimensions on the central reading MRI at Screening visit that was not adequately drained as confirmed by the surgeon during the preparation procedure (week -3 to day 0). Severe rectal and/or anal stenosis and/or severe proctitis (defined as the presence of large >0.5 cm ulcers in the rectum) that make impossible to follow the surgery procedure manual. Participant with diverting stomas. Active, uncontrolled infection requiring parenteral antibiotics. Participant with ongoing systemic or rectal steroids for CD in the last 2 weeks prior to the Preparation visit. Participants with major alteration on any of the following laboratory tests or increased risk for the surgical procedure: Serum creatinine levels >1.5 times the ULN Total bilirubin >1.5 ULN Aspartate Transaminase (AST)/ Alanine Transaminase (ALT) >3 times ULN Hemoglobin <10.0 g/dL Platelets <75.0*10^9/L Albuminemia <3.0 g/dL Suspected or documented infectious enterocolitis within two weeks prior to Screening visit. Any prior invasive malignancy diagnosed within the last 5 years prior to Screening visit. Participants with basal-cell carcinoma of the skin completely resected outside the perineal region can be included. Current or recent (within 6 months prior to the Screening visit) history of severe, progressive, and/or uncontrolled hepatic, haematological, gastrointestinal (GI) (other than CD), renal, endocrine, pulmonary, cardiac, neurological or psychiatric disease that may result in participants increased risk from study participation and/or lack of compliance with study procedures. Participants with primary sclerosing cholangitis. Participants with known chronically active hepatopathy of any origin, including cirrhosis and participants with persistent positive 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 Screening. Congenital or acquired immunodeficiencies, including participants known to be HIV carriers Known allergies or hypersensitivity to penicillin or aminoglycosides; Dulbecco Modified Eagle's Medium (DMEM); bovine serum; local anaesthetics or gadolinium (MRI contrast). Contraindication to MRI scan (example, due to the presence of pacemakers, hip replacements or severe claustrophobia). Severe trauma within 6 months prior to Screening visit. Pregnant or breastfeeding women. Participants who do not wish to or cannot comply with study procedures. Participants currently receiving, or having received any investigational drug within 3 months prior to Screening visit. Participants previously treated with Cx601 or other allogeneic stem-cell therapy cannot be enrolled into this clinical study. Any major surgery of the GI tract (including one or more segments of the colon or terminal ileum) within 6 months prior the screening or any minor surgery of the GI tract within 3 months prior to screening. Participants who had local perianal surgery other than drainage for the fistula within 6 months prior to the Screening visit, or those who may need surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study. Contraindication to the anaesthetic procedure.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cx601<br>Cx601 eASCs 120 million cells (5 million cells per milliliter [mL]) will be administered once by intralesional injection. | Drug: Cx601<br>* Cx601 eASCs intralesional injection.<br>|
| Placebo Comparator: Placebo<br>CX601 placebo-matching eASCs cells will be administered once by intralesional administration. | Other: Placebo<br>* Cx601 placebo-matching eASCs intralesional injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with 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 and absence of collection(s) >2 cm (in at least 2 dimensions) of the treated perianal fistula(s) confirmed by blinded central MRI assessment. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Clinical Remission at Week 24 | Clinical remission is defined as closure of all treated external openings that were draining at baseline despite gentle finger compression. | Week 24 | 
| Time to Clinical Remission up to Week 24 | Time to clinical remission is defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. | From the treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed (up to Week 24) | 
| Percentage of Participants with Clinical Response at Week 24 | Clinical response is defined as closure of at least 50 percent (%) of all treated external openings that were draining at baseline despite gentle finger compression. | Week 24 | 
| Time to Clinical Response up to Week 24 | Time to clinical response is defined as the time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline, despite gentle finger compression, as clinically assessed. | From treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline, despite gentle finger compression, as clinically assessed (up to Week 24) | 
| Percentage of Participants with Combined Remission at Week 52 | Combined Remission is defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression, and absence of collections >2 cm (in at least 2 dimensions) confirmed by blinded central MRI assessment. | Week 52 | 
| Percentage of Participants with Clinical Remission at Week 52 | Clinical remission is defined as closure of all treated external openings that were draining at baseline despite gentle finger compression. | Week 52 | 
| Percentage of Participants with Clinical Response at Week 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. | Week 52 | 
| Time to Clinical Remission up to Week 52 | Time to clinical remission is defined as the time from treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. | From treatment start to first visit with closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed (up to Week 52) | 
| Time to Clinical Response up to Week 52 | Time to clinical response is defined as time from treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed. | From treatment start to first visit with closure of at least 50% of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed (up to Week 52) | 
| Percentage of Participants with Relapse from Week 24 Combined Remission | Relapse is defined as reopening of any of the treated fistulas external openings with active drainage as clinically assessed, or the development of a perianal fluid collection >2 cm of the treated perianal fistula confirmed by centrally read MRI assessment in participants who were in combined remission at week 24. | Week 24 | 
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs) |  | Week 24 and Week 52 | 
| Number of Participants With TEAEs Related to Vital Sign Parameters |  | Week 24 and Week 52 | 
| Number of Participants With TEAEs Related to Clinical Laboratory Parameters |  | Week 24 and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, complex perianal fistula(s)