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) (ADMIRE-CD-II)

• ClinicalTrials.gov Identifier: NCT03279081
• Recruitment Status: Completed
• First Posted: September 12, 2017
• Last Update Posted: January 12, 2024
• Sponsor: Tigenix S.A.U.
• Information provided by (Responsible Party): Takeda ( Tigenix S.A.U. )

Tracking Information

• First Submitted Date: July 21, 2017
• First Posted Date: September 12, 2017
• Last Update Posted Date: January 12, 2024
• Actual Study Start Date: September 15, 2017
• Actual Primary Completion Date: January 23, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 15, 2020)

Percentage of Participants with Combined Remission at Week 24 [ Time Frame: 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.

Original Primary Outcome Measures (submitted: September 8, 2017)

Combined Remission of complex perianal fistula(s) [ Time Frame: By week 24 ]

Combined Remission of complex perianal fistula(s) at week 24

Current Secondary Outcome Measures (submitted: January 17, 2020)

• Percentage of Participants with Clinical Remission at Week 24 [ Time Frame: Week 24 ]
  Clinical remission is defined as closure of all treated external openings that were draining at baseline despite gentle finger compression.
• Time to Clinical Remission up to Week 24 [ Time Frame: 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) ]
  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.
• Percentage of Participants with Clinical Response at Week 24 [ Time Frame: 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.
• Time to Clinical Response up to Week 24 [ Time Frame: 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) ]
  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.
• Percentage of Participants with Combined Remission at Week 52 [ Time Frame: 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.
• Percentage of Participants with Clinical Remission at Week 52 [ Time Frame: Week 52 ]
  Clinical remission is defined as closure of all treated external openings that were draining at baseline despite gentle finger compression.
• Percentage of Participants with Clinical Response at Week 52 [ Time Frame: 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.
• Time to Clinical Remission up to Week 52 [ Time Frame: 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 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.
• Time to Clinical Response up to Week 52 [ Time Frame: 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) ]
  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.
• Percentage of Participants with Relapse from Week 24 Combined Remission [ Time Frame: Week 24 ]
  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.
• Percentage of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs) [ Time Frame: Week 24 and Week 52 ]
• Number of Participants With TEAEs Related to Vital Sign Parameters [ Time Frame: Week 24 and Week 52 ]
• Number of Participants With TEAEs Related to Clinical Laboratory Parameters [ Time Frame: Week 24 and Week 52 ]

Original Secondary Outcome Measures (submitted: September 8, 2017)

• Efficacy of Cx601 [ Time Frame: By week 24 ]
  Clinical remission at week 24
• Efficacy of Cx601 [ Time Frame: By week 52 ]
  Clinical remission at week 52
• Efficacy of Cx601 [ Time Frame: By week 24 ]
  Clinical response at week 24
• Efficacy of Cx601 [ Time Frame: By week 52 ]
  Clinical response at week 52
• Percentage of Adverse Events, Serious Adverse Events, and their severity summarised according to MedDRA dictionnary by week 24. [ Time Frame: By week 24 ]
  Percentage of Adverse Events, Serious Adverse Events, and their severity summarised according to MedDRA dictionnary by week 24.
• Percentage of Adverse Events, Serious Adverse Events, and their severity summarised according to MedDRA dictionnary by week 52. [ Time Frame: By week 52 ]
  Percentage of Adverse Events, Serious Adverse Events, and their severity summarised according to MedDRA dictionnary by week 52.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Crohn's Disease

Intervention

• Drug: Cx601
  Cx601 eASCs intralesional injection.
• Other: Placebo
  Cx601 placebo-matching eASCs intralesional injection.

Study Arms

• Experimental: Cx601
  Cx601 eASCs 120 million cells (5 million cells per milliliter [mL]) will be administered once by intralesional injection.
  Intervention: Drug: Cx601
• Placebo Comparator: Placebo
  CX601 placebo-matching eASCs cells will be administered once by intralesional administration.
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 17, 2023): 569
• Original Estimated Enrollment (submitted: September 8, 2017): 326
• Actual Study Completion Date: July 26, 2023
• Actual Primary Completion Date: January 23, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Signed informed consent.
2. Participants of either gender greater than or equal to (>=) 18 years and less than or equal to (<=) 75 years of age.
3. Participants with CD diagnosed at least 6 months prior to Screening visit in accordance with accepted clinical, endoscopic, histological and/or radiological criteria.

4. 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.

5. 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.

6. 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.
7. 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:

1. Concomitant rectovaginal or rectovesical fistula(s).
2. Participant naïve to prior specific medical treatment for complex perianal fistula(s) including immunosuppressant (IS) or anti-TNFs.
3. 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).
4. 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.
5. Participant with diverting stomas.
6. Active, uncontrolled infection requiring parenteral antibiotics.
7. Participant with ongoing systemic or rectal steroids for CD in the last 2 weeks prior to the Preparation visit.

8. 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
9. Suspected or documented infectious enterocolitis within two weeks prior to Screening visit.
10. 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.
11. 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.
12. Participants with primary sclerosing cholangitis.
13. 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.
14. Congenital or acquired immunodeficiencies, including participants known to be HIV carriers
15. Known allergies or hypersensitivity to penicillin or aminoglycosides; Dulbecco Modified Eagle's Medium (DMEM); bovine serum; local anaesthetics or gadolinium (MRI contrast).
16. Contraindication to MRI scan (example, due to the presence of pacemakers, hip replacements or severe claustrophobia).
17. Severe trauma within 6 months prior to Screening visit.
18. Pregnant or breastfeeding women.
19. Participants who do not wish to or cannot comply with study procedures.
20. Participants currently receiving, or having received any investigational drug within 3 months prior to Screening visit.
21. Participants previously treated with Cx601 or other allogeneic stem-cell therapy cannot be enrolled into this clinical study.
22. 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.
23. 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.
24. Contraindication to the anaesthetic procedure.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Poland, Puerto Rico, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT03279081
• Other Study ID Numbers: Cx601-0303; 2017-000725-12 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda ( Tigenix S.A.U. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Tigenix S.A.U.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Takeda

• PRS Account: Takeda
• Verification Date: January 2024