Clinical trial NCT01541579: Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn's Disease
Official title: A Phase III, Randomized, Double Blind, Parallel Group, Placebo Controlled, Multicentre Study to Assess Efficacy and Safety of Expanded Allogeneic Adipose-derived Stem Cells (eASCs) for the Treatment of Perianal Fistulising Crohn's Disease Over a Period of 24 Weeks and an Extended Follow-up Period up to 104 Weeks.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Crohn's Disease
Keywords: Perianal fistulising Crohn's disease.
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-03-01
Enrollment: 278
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The current multicentre phase III study is proposed to confirm in an add-on therapy design compared to a placebo-control group, the efficacy of adipose-derived stem cells (eASCs) from healthy donors for the treatment of complex anal fistulas in patients with Crohn's disease over a 24-week period and an extended follow-up period up to 104 weeks.

Detailed description: The current multicentre phase III study is proposed to confirm in an add-on therapy design compared to a placebo-control group, the efficacy of adipose-derived stem cells (eASCs) from healthy donors for the treatment of complex anal fistulas in patients with Crohn's disease over a 24-week period and an extended follow-up period up to 104 weeks. Subject with perianal fistulising Crohn's disease will be treated with Cx601, suspension of eASCs, at a dose of 120 million cells administered by intralesional injection. The treatment of complex perianal fistulas by local application of eASCs intends to improve significantly the local conditions with very few inconveniences (ambulatory procedure) and minimal risk of possible complications (anal incontinence). Therefore, this is a new therapeutic resource that is expected to be safe and efficacious as well as is expected to improve the quality of life of the patients in this highly debilitating and chronic condition. This treatment would prevent one of the main causes of anal incontinence, would diminish recurrence of the fistula disease and would reduce drastically the significant disorders provoked by the standard fistula surgery in the patients. Indeed, patients can be discharged according to the "One Day Surgical" procedures (major ambulatory surgery).

Eligibility criteria: Inclusion Criteria:

The reference population will consist of patients with perianal fistulising Crohn´s disease refractory to at least one of the following treatments: antibiotics, immunosuppressants or anti-tumor necrosis factor (TNF). Naïve patients are excluded, and those patients refractory to antibiotics will represent less than 25% of the total recruited patients.

All of them must comply with the following inclusion criteria:

1. Signed informed consent.
2. Patients with Crohn's Disease (CD) diagnosed at least 6 months earlier in accordance with accepted clinical, endoscopic, histological and/or radiologic criteria.
3. Presence of complex perianal fistulas with a maximum of 2 fistulas (internal openings) and a maximum of 3 external openings, assessed by clinical assessment and MRI. Fistula must have been draining for at least 6 weeks prior to the inclusion. A complex perianal fistula is defined as a fistula that met one or more of the following criteria during its evolution:

   * High inter-sphincteric, trans-sphincteric, extra-sphincteric or supra-sphincteric.
   * Presence of ≥ 2 external openings (tracts).
   * Associated collections
4. Non-active or mildly active luminal CD defined by a CDAI ≤ 220.
5. Patients of either sex aged 18 years or older
6. Good general state of health according to clinical history and a physical examination.
7. For women of a childbearing age, they must have negative serum or urine pregnancy test (sensitive to 25 IU human chorionic gonadotropin (hCG)). Both men and women should use appropriate birth control methods defined by the investigator.

Exclusion Criteria:

1. Presence of dominant luminal active Crohn's disease requiring immediate therapy.
2. CDAI \>220.
3. Concomitant rectovaginal fistulas
4. Patient naïve to specific treatment for perianal fistulising Crohn's disease including antibiotics
5. Presence of an abscess or collections \> 2 cm, unless resolved in the preparation procedure (week -3 to day 0).
6. Presence of \> 2 fistular lesions.
7. Presence of \> 3 external openings.
8. Rectal and/or anal stenosis and / or active proctitis, if this means a limitation for any surgical procedure.
9. Patient who underwent surgery for the fistula other than drainage or seton placement.
10. Patient with diverting stomas
11. Patient with ongoing steroid treatment or treated with steroids in the last 4 weeks
12. Renal impairment defined by creatinine clearance below 60 ml/min calculated using Cockcroft-Gault formula or by serum creatinine ≥ 1.5 x upper limit of normality (ULN)
13. Hepatic impairment defined by both of the following laboratory ranges:

    * Total bilirubin ≥ 1.5 x ULN
    * Aspartate aminotransferase (AST) and alanine aminotransferase(ALT) ≥ 2.5 x ULN
14. Known history of abuse of alcohol or other addictive substances in the 6 months prior to inclusion.
15. Malignant tumour or patients with a prior history of any malignant tumour, including any type of fistula carcinoma.
16. Current or recent history of abnormal, severe, progressive, uncontrolled hepatic, haematological, gastrointestinal (except CD), endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease.
17. Congenital or acquired immunodeficiencies.
18. Known allergies or hypersensitivity to antibiotics including but not limited to penicillin, streptomycin, gentamicin, aminoglycosides; Human Serum Albumin (HSA); Dulbecco Modified Eagle's Medium (DMEM); materials of bovine origin; local anaesthetics or gadolinium (MRI contrast).
19. Contraindication to MRI scan, (e.g., due to the presence of pacemakers, hip replacements or severe claustrophobia).
20. Major surgery or severe trauma within the previous 6 months.
21. Pregnant or breastfeeding women.
22. Patients who do not wish to or cannot comply with study procedures.
23. Patients currently receiving, or having received within 3 months prior to enrolment into this clinical study, any investigational drug.
24. Patients previously treated with eASCs can not be enrol into this clinical study.
25. Subjects who need surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study, or for whom such surgery is foreseen in this region in the 24 weeks after treatment administration.
26. Contraindication to the anaesthetic procedure.

Primary outcomes:
measure: Combine remission of perianal fistulising Crohn's
timeFrame: 24 weeks
Secondary outcomes:
measure: Efficacy Assessment by week 24
timeFrame: 24 weeks
measure: Efficacy Assessment by week 52
timeFrame: 52 weeks
measure: Efficacy Assessment by week 104
timeFrame: 104 Weeks
measure: Safety analysis throughout the study:
timeFrame: week 24, 52 and 104
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Univ.-Klinik Innsbruck
city: St. Veit/Glan
country: Austria
facility: Krankenhaus
city: Wien
country: Austria
facility: Medizinische Universität
city: Genk
country: Belgium
facility: Hospital Oost-Limburg
city: Gent
country: Belgium
facility: Gent University Hospital
city: Leuven
country: Belgium
facility: Leuven University Hospital
city: Roeselare
country: Belgium
facility: Hospital Hartziekenhuis
city: Amiens
country: France
facility: CHU d'Amiens
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Caen
country: France
facility: CHU de Caen
city: Clichy
country: France
facility: Hôpital Beaujon
city: Lille
country: France
facility: CHRU de Lille
city: Marseille
country: France
facility: CHU de Marseille
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Berlin
country: Germany
facility: Charite
city: Berlin
country: Germany
facility: Krakenhaus Walfriede
city: Braunschweig
country: Germany
facility: Klinikum Braunscheweig
city: Frankfurt/Main
country: Germany
facility: Klinikum Frankfurt
city: Köln
country: Germany
facility: Evangelisches Krankenhaus Kalk
city: Lüneburg
country: Germany
facility: Klinikum Lüneburg
city: Haifa
country: Israel
facility: Rambam MC
city: Jerusalem
country: Israel
facility: Sharee Zedek MC
city: Petah Tikva
country: Israel
facility: Rabin MC
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky MC
city: Tel Hashomer
country: Israel
facility: Sheba MC
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Milano
country: Italy
facility: Instituto Clinico Humanitas IRCCS
city: Napoli
country: Italy
facility: Seconda Università degli Studi di Napoli
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Rome
country: Italy
facility: Azienda Ospedaliera San Camillo-Forlanini
city: Rome
country: Italy
facility: Università Cattolica del Sacro Cuore
city: Amsterdam
country: Netherlands
facility: AMC
city: Amsterdam
country: Netherlands
facility: VUMC
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Utrecht
country: Netherlands
facility: UMCU
city: Manises
country: Spain
facility: Hospital de Manises
state: Valencia
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Cordoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Huelva
country: Spain
facility: Hospital Juan Ramon Jimenez
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Palma de Mallorca
country: Spain
facility: Son Espases
city: Pontevedra
country: Spain
facility: Hospital de Montecelo
city: Seville
country: Spain
facility: Hospital Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital de Sagunto
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
Study officials:
affiliation: Hospital Clinic of Barcelona
name: Julian Panes, MD
role: STUDY_CHAIR
affiliation: Hospital Clinic of Barcelona
name: Julian Panes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Vienna
name: Lili Kazemi-Shirazi, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Krankenhaus, St. Veit/Glan
name: Karl Mrak, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Marc Ferrante, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Oost-Limburg, Genk
name: Kurt Van der Speeten, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Gent University Hospital
name: Danny de Looze, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Hartziekenhuis, Roeselare
name: Filip Baert, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Charite University, Berlin, Germany
name: Daniel C Baumgart, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Kilikum Frankfurt
name: Axel Dignass, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Kinikum Braunschweig
name: Max Reinshagen, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Clinico Humanitas IRCCS, Milano
name: Silvio Danese, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliero-Universitaria Careggi
name: Vito Annese, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliera San Camillo-Forlanini, Rome
name: Anna Kohn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Università Cattolica del Sacro Cuore, Rome
name: Alfredo Papa, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliera di Padova
name: Giacomo C Sturniolo, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola Malpighi
name: Andrea Belluzi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Campania Luigi Vanvitelli
name: Gabriele Riegler, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: UMCU, Utrecht
name: Bas Oldenburg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam UMC, location VUmc
name: Adriaan A van Bodegraven, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Gigs van den Brink, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Paz
name: María D Martín Arranz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Reina Sofía, Cordoba
name: Jose M Gallardo Valverde, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital La Princesa, Madrid
name: Javier Pérez Gisbert, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario La Fe
name: Belén Beltrán Niclós, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Clínico San Carlos, Madrid
name: Carlos Taxonera Samsó, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Virgen del Rocío, Seville
name: Fernando de la Portilla de Juan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Juan Ramón Jiménez, Huelva
name: Ricardo Rada Morgades, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario 12 de Octubre, Madrid
name: Gonzalo Gómez Gómez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Montecelo, Pontevedra
name: Daniel Carpio López, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Sagunto, Valencia
name: Xavier Cortés Rizo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Klinikum Lüneburg
name: Torsten Kucharzik, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Krakenhaus Walfriede, Berlin
name: Andreas Sturm, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital Universitario Ramon y Cajal
name: Antonio López Sanromán, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Manises, Valencia
name: Joaquín Hinojosa de Val, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Son Espases, Palma de Mallorca
name: Xavier González Argenté, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU de Lille
name: Maria Nachury, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Bordeaux
name: Frank Zerbib, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Caen
name: Stéphanie Viennot, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Universitaire, Amiens
name: Jean-Louis Dupas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Marseille
name: Jean-Charles Grimaud, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Universitaire de Nice
name: Xavier Hebuterne, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Saint Louis Paris
name: Matthieu Allez, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Beaujon, Clichy
name: Yoram Bouhnik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rambam MC, Haifa
name: Matti Waterman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sheba MC, Tel Hashomer
name: Shomron Ben-Horin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tel Aviv Sourasky MC, Tel Aviv
name: Sigal Fishman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sharee Zedek MC, Jerusalem
name: Eran Goldin, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Rabin MC, Petah Tikva
name: Irit Avni-Biron, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Univ.-Klinik Innsbruck
name: Herbert Tilg, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Catharina Ziekenhuis Eindhoven
name: Lennard Gilissen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
name: Carlos Pastor, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Evangelisches Krankenhaus Kalk, Köln
name: Wolfgang Kruis, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Garcia-Olmo D, Gilaberte I, Binek M, D Hoore AJL, Lindner D, Selvaggi F, Spinelli A, Panes J. Follow-up Study to Evaluate the Long-term Safety and Efficacy of Darvadstrocel (Mesenchymal Stem Cell Treatment) in Patients With Perianal Fistulizing Crohn's Disease: ADMIRE-CD Phase 3 Randomized Controlled Trial. Dis Colon Rectum. 2022 May 1;65(5):713-720. doi: 10.1097/DCR.0000000000002325.
citation: Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Diez MC, Tagarro I, Leselbaum A, Danese S; ADMIRE CD Study Group Collaborators. Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn's Disease. Gastroenterology. 2018 Apr;154(5):1334-1342.e4. doi: 10.1053/j.gastro.2017.12.020. Epub 2017 Dec 24.
citation: Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Leselbaum A, Danese S; ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016 Sep 24;388(10051):1281-90. doi: 10.1016/S0140-6736(16)31203-X. Epub 2016 Jul 29.