Safety and Efficacy of Adipose-Derived Stem Cells to Treat Complex Perianal Fistulas Patients With Crohn's Disease (FATT)

Randomized, Single-blind, Placebo Controlled Multicenter Phase III Study to Assess the Efficacy and Safety of Expanded Autologous Adipose-derived Stem Cells (ASCs) (CX-401), for Treatment of Complex Perianal Fistulas in Perianal Crohn's Disease

The purpose of this study is to determine safety and efficacy of eASCs (expanded adult stem cells) for treatment of complex perianal fistulas in patients with Crohn's disease.

Study Overview

• Status: Terminated
• Conditions: Crohn Disease; Complex Perianal Fistula
• Intervention / Treatment: Drug: Expanded autologous adipose-derived adult stem cells (eASCs); Drug: Placebo

Detailed Description

Complex perianal fistulas are a source of great distress for suffers. In Crohn's disease, options are limited, and surgery is often associated with incontinence and recurrence.

The biological properties of stem cells derived from adult tissues make them candidates for the treatment of pathologies requiring tissue regeneration or in diseases where the healing process is altered.

A proof-of-concept study, a phase 1 study and a phase 2 study [Clinicaltrials.gov identifier: NCT00115466] have all suggested that this approach is promising, even in patients whose fistula is associated with Crohn's disease.

The present multicenter, placebo-controlled, phase 3 study aims to confirm the efficacy and safety shown in the previous phase 1 and phase 2 studies in the treatment of complex perianal fistulas in patients with Crohn's disease after 24 weeks from initial administration. Fistula closure is defined as absence of suppuration through the external orifice with complete re-epithelization of the external orifice and absence of collections >2cm directly related to the fistula tract treated, as measured by MRI.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • University of Vienna
• Netherlands
  • Amsterdam, Netherlands
    • Academic Medical Center
• Spain
  • Córdoba, Spain, 14004
    • Hospital Reina Sofia
  • Léon, Spain, 24071
    • Complejo Hospitalario de León
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28006
    • Hospital Universitario de la Princesa
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Madrid, Spain, 28007
    • Hospital Gregorio Marañón
  • Madrid, Spain, 28035
    • Hospital Puerta de Hierro
  • Pontevedra, Spain, 36001
    • Complejo Hospitalario de Pontevedra
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Germans Trias i Pujol
  • Valencia
    • Sagunto, Valencia, Spain, 46520
      • Hospital de Sagunto

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent
• Patients with Crohn's disease diagnosed at least 12 months earlier in accordance with accepted clinical, endoscopic, anatomopathological and/or radiologic criteria
• Presence of complex perianal fistula with 3 or fewer fistulous tracts assessed by MRI
• Patients with persistent and active complex perianal fistula and non-active luminal Crohn's disease defined by a CDAI ≤ 200. (Complex perianal fistula is defined as a fistula that meets one or more of the following criteria: High fistulas [high inter-sphincteric, high trans-sphincteric, extra-sphincteric or supra-sphincteric], presence of 3 or fewer external openings [tracts] associated with a complex perianal fistula, or pain/fluctuation
• Good general state of health according to the findings of the clinical history and the physical examination
• Women of a childbearing age with negative serum or urine pregnancy test (sensitive to 25 IU hCG). Both men and women should use appropriate birth control methods defined by the investigator

Exclusion Criteria:

• Presence of severe proctitis (prominent friability, spontaneous bleeding, multiple erosions, deep ulcers) or dominant active luminal disease requiring immediate therapy, assessed by rectosigmoidoscopy
• Patients with a CDAI ≥201
• Patients with an abscess unless a complete toilet of the area with drainage of the collections and the absence of abscess and other collections is confirmed prior to treatment start
• The presence of setons unless removed prior to the study procedure
• Presence of >3 fistulous tracts and/or external openings
• Patients with rectal and/or anal stenosis evaluated by rectoscopy or EUA
• Patients who have received infliximab or any other anti-TNF agent in the 8 weeks before the cell treatment administration
• Patients who have received tacrolimus or cyclosporine in the 4 weeks before the cell treatment administration
• Patients with rectovaginal fistula, anal fistula(s), and/or non-perianal enterocutaneous fistula
• Patients with HIV, HBV, HCV or treponema infection, whether active or latent
• Patients with a history of abuse of alcohol or other addictive substances in the 6 months prior to inclusion
• Patients with malignant tumor, except for basal cell or cutaneous squamous cell carcinoma, or patients with a prior history of malignant tumors, unless the neoplastic disease has been in remission for the previous 5 years
• Patients with cardiopulmonary disease which, in the opinion of the investigator, is unstable or sufficiently serious to exclude the patient from the study.
• Patients with any type of medical or psychiatric disease which, in the opinion of the investigator, could be grounds for exclusion from the study
• Patients with congenital or acquired immunodeficiencies
• Patients with abnormal laboratory test findings that contraindicate their inclusion in the study
• Patients allergic to local anesthetics or gadolinium (MRI contrast)
• MRI is unfeasible, (e.g. due to the presence of pacemakers, hip replacements or severe claustrophobia)
• Liposuction with extraction of at least 100 cm3 of fat from the abdominal wall is technically unfeasible or the patient does not consent to the procedure
• Patients in need of surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study, or a need for such surgery is foreseen in this region in the 26 weeks after treatment administration.
• Patients who have suffered major surgery or severe trauma in the prior 6 months
• Pregnant or breastfeeding women
• Patients who do not wish to or cannot comply with study procedures
• Patients currently receiving, or having received within 1 month prior to enrolment into this clinical trial, any investigational drug
• Patients unlikely to comply with study procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ASCs; Intralesional dose of 20 million cells at baseline with a possible second administration of 40 million cells in case of incomplete fistula closure following week 12 assessment.	Drug: Expanded autologous adipose-derived adult stem cells (eASCs); Administration will be preceded by localization and closure of the internal opening. Cell treatment injection will be performed following Major Ambulatory Surgery standards. Patients will receive an intralesional dose of 20 million cells at baseline. 50% of the cell suspension will be placed into the fistula walls of the internal opening, with the remaining 50% being injected across the wall tracts of the target fistula. Patients without healing (complete fistula closure) at week 12 will receive a second dose of 40 million cells, using the same treatment approach.; Other Names: Cx401 (company code); Ontaril®
SHAM_COMPARATOR: Placebo; Instillation of saline solution into the fistulous tract, following identical tract preparation process as for the investigational treatment group.	Drug: Placebo; Administration will be preceded by localization and closure of the internal opening following Major Ambulatory Surgery standards. Subjects will be receiving one treatment cycle with placebo consisting of intralesional instillation of 5 ml saline solution. Patients without healing (complete fistula closure) following week 12 assessment will continue to receive standard of care until the primary assessment of fistula closure at week 24. Patients with incomplete fistula closure at week 24 will be offered the possibility of participating in a separate open-label, single arm study using the ASCs derived from the liposuction procedure.; Other Names: Normale saline solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of subjects in whom the external openings of the treated perianal fistula have closed	24 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of subjects in whom the external openings of the treated perianal fistula have closed	12 weeks
Changes over time in the Perianal Disease Activity Index	4, 10, 12, 16, 22 and 24 weeks
Changes over time in the Crohn's Disease Activity Index	10 and 22 weeks
Changes over time in the MRI Score of Severity (MSS)	12 and 24 weeks
Quality of life assessment using the SF-36 questionnaire	12 and 24 weeks
Percentage of subjects for whom surgery is avoided	24 weeks
Adverse events	4, 10, 12, 16, 22 and 24 weeks
Clinically relevant variations in vital signs	4, 10, 12, 16, 22 and 24 weeks
Clinically relevant variations in laboratory tests	4, 10, 12, 16, 22 and 24 weeks

Collaborators and Investigators

• Sponsor: Tigenix S.A.U.
• Investigators: Principal Investigator: Damián García-Olmo, MD, General Surgery Department, Hospital Universitario La Paz

Publications and helpful links

General Publications

• Garcia-Olmo D, Garcia-Arranz M, Garcia LG, Cuellar ES, Blanco IF, Prianes LA, Montes JA, Pinto FL, Marcos DH, Garcia-Sancho L. Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn's disease: a new cell-based therapy. Int J Colorectal Dis. 2003 Sep;18(5):451-4. doi: 10.1007/s00384-003-0490-3. Epub 2003 May 20.
• Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005 Jul;48(7):1416-23. doi: 10.1007/s10350-005-0052-6.
• Garcia-Olmo D, Herreros D, Pascual M, Pascual I, De-La-Quintana P, Trebol J, Garcia-Arranz M. Treatment of enterocutaneous fistula in Crohn's Disease with adipose-derived stem cells: a comparison of protocols with and without cell expansion. Int J Colorectal Dis. 2009 Jan;24(1):27-30. doi: 10.1007/s00384-008-0559-0. Epub 2008 Aug 12.
• Garcia-Olmo D, Garcia-Arranz M, Herreros D. Expanded adipose-derived stem cells for the treatment of complex perianal fistula including Crohn's disease. Expert Opin Biol Ther. 2008 Sep;8(9):1417-23. doi: 10.1517/14712598.8.9.1417.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (ACTUAL): February 1, 2010
• Study Completion (ACTUAL): February 1, 2010

Study Registration Dates

• First Submitted: June 21, 2011
• First Submitted That Met QC Criteria: June 21, 2011
• First Posted (ESTIMATE): June 22, 2011

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2019
• Last Update Submitted That Met QC Criteria: April 10, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Crohn disease; Adipose-derived stem cells; Liposuction; Complex perianal fistula
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Pathological Conditions, Anatomical; Rectal Diseases; Inflammatory Bowel Diseases; Intestinal Fistula; Digestive System Fistula; Fistula; Crohn Disease; Rectal Fistula
• Other Study ID Numbers: CX-401/FATT2; EudraCT: 2008-004286-25