Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn's Disease

NCT ID: NCT01541579

Last Updated: 2019-11-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 278 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2016-11-30

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).

Conditions

Crohn's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Treatment Arm

Cx601 is a cell suspension in aseptic buffered solution containing human expanded adipose-derived stem cells (eASCs) of allogeneic origin in disposable vials with no preservative agents. The cells will be given at a dose of 120 million cells (5 million cells / mL) for intralesional injection.

Group Type: EXPERIMENTAL

Cx601

Intervention Type: OTHER

120 million cells administered by intralesional injection.

Placebo-control group

Placebo (saline solution) will be given also for intralesional injection at the same quantity (volume, 24 mL) and following the same schedule.

Group Type: PLACEBO_COMPARATOR

Saline solution

Intervention Type: OTHER

24 mL saline solution by intralesional injection

Interventions

Cx601

120 million cells administered by intralesional injection.

Intervention Type: OTHER

Saline solution

24 mL saline solution by intralesional injection

Intervention Type: OTHER

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.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tigenix S.A.U.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Julian Panes, MD

Role: STUDY_CHAIR

Hospital Clinic of Barcelona

Julian Panes, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Clinic of Barcelona

Lili Kazemi-Shirazi, Professor

Role: PRINCIPAL_INVESTIGATOR

Medical University of Vienna

Karl Mrak, MD

Role: PRINCIPAL_INVESTIGATOR

Krankenhaus, St. Veit/Glan

Marc Ferrante, MD

Role: PRINCIPAL_INVESTIGATOR

Universitaire Ziekenhuizen KU Leuven

Kurt Van der Speeten, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Oost-Limburg, Genk

Danny de Looze, Professor

Role: PRINCIPAL_INVESTIGATOR

Gent University Hospital

Filip Baert, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Hartziekenhuis, Roeselare

Daniel C Baumgart, Professor

Role: PRINCIPAL_INVESTIGATOR

Charite University, Berlin, Germany

Axel Dignass, Professor

Role: PRINCIPAL_INVESTIGATOR

Kilikum Frankfurt

Max Reinshagen, Professor

Role: PRINCIPAL_INVESTIGATOR

Kinikum Braunschweig

Silvio Danese, MD

Role: PRINCIPAL_INVESTIGATOR

Instituto Clinico Humanitas IRCCS, Milano

Vito Annese, MD

Role: PRINCIPAL_INVESTIGATOR

Azienda Ospedaliero-Universitaria Careggi

Anna Kohn, MD

Role: PRINCIPAL_INVESTIGATOR

Azienda Ospedaliera San Camillo-Forlanini, Rome

Alfredo Papa, MD

Role: PRINCIPAL_INVESTIGATOR

Università Cattolica del Sacro Cuore, Rome

Giacomo C Sturniolo, Professor

Role: PRINCIPAL_INVESTIGATOR

Azienda Ospedaliera di Padova

Andrea Belluzi, MD

Role: PRINCIPAL_INVESTIGATOR

Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola Malpighi

Gabriele Riegler, Professor

Role: PRINCIPAL_INVESTIGATOR

University of Campania Luigi Vanvitelli

Bas Oldenburg, MD

Role: PRINCIPAL_INVESTIGATOR

UMCU, Utrecht

Adriaan A van Bodegraven, MD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Gigs van den Brink, Professor

Role: PRINCIPAL_INVESTIGATOR

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

María D Martín Arranz, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario La Paz

Jose M Gallardo Valverde, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario Reina Sofía, Cordoba

Javier Pérez Gisbert, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital La Princesa, Madrid

Belén Beltrán Niclós, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario La Fe

Carlos Taxonera Samsó, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Clínico San Carlos, Madrid

Fernando de la Portilla de Juan, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Virgen del Rocío, Seville

Ricardo Rada Morgades, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Juan Ramón Jiménez, Huelva

Gonzalo Gómez Gómez, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario 12 de Octubre, Madrid

Daniel Carpio López, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Montecelo, Pontevedra

Xavier Cortés Rizo, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Sagunto, Valencia

Torsten Kucharzik, Professor

Role: PRINCIPAL_INVESTIGATOR

Klinikum Lüneburg

Andreas Sturm, Professor

Role: PRINCIPAL_INVESTIGATOR

Krakenhaus Walfriede, Berlin

Antonio López Sanromán, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Universitario Ramon y Cajal

Joaquín Hinojosa de Val, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Manises, Valencia

Xavier González Argenté, MD

Role: PRINCIPAL_INVESTIGATOR

Son Espases, Palma de Mallorca

Maria Nachury, MD

Role: PRINCIPAL_INVESTIGATOR

CHRU de Lille

Frank Zerbib, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux

Stéphanie Viennot, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Caen

Jean-Louis Dupas, MD

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Universitaire, Amiens

Jean-Charles Grimaud, MD

Role: PRINCIPAL_INVESTIGATOR

CHU de Marseille

Xavier Hebuterne, Professor

Role: PRINCIPAL_INVESTIGATOR

Centre Hospitalier Universitaire de Nice

Matthieu Allez, Professor

Role: PRINCIPAL_INVESTIGATOR

Hôpital Saint Louis Paris

Yoram Bouhnik, MD

Role: PRINCIPAL_INVESTIGATOR

Hôpital Beaujon, Clichy

Matti Waterman, MD

Role: PRINCIPAL_INVESTIGATOR

Rambam MC, Haifa

Shomron Ben-Horin, MD

Role: PRINCIPAL_INVESTIGATOR

Sheba MC, Tel Hashomer

Sigal Fishman, MD

Role: PRINCIPAL_INVESTIGATOR

Tel Aviv Sourasky MC, Tel Aviv

Eran Goldin, Professor

Role: PRINCIPAL_INVESTIGATOR

Sharee Zedek MC, Jerusalem

Irit Avni-Biron, MD

Role: PRINCIPAL_INVESTIGATOR

Rabin MC, Petah Tikva

Herbert Tilg, Professor

Role: PRINCIPAL_INVESTIGATOR

Univ.-Klinik Innsbruck

Lennard Gilissen, MD

Role: PRINCIPAL_INVESTIGATOR

Catharina Ziekenhuis Eindhoven

Carlos Pastor, MD

Role: PRINCIPAL_INVESTIGATOR

Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz

Wolfgang Kruis, Professor

Role: PRINCIPAL_INVESTIGATOR

Evangelisches Krankenhaus Kalk, Köln

Locations

Univ.-Klinik Innsbruck

Innsbruck, , Austria

Krankenhaus

Saint Veit/Glan, , Austria

Medizinische Universität

Vienna, , Austria

Hospital Oost-Limburg

Genk, , Belgium

Gent University Hospital

Ghent, , Belgium

Leuven University Hospital

Leuven, , Belgium

Hospital Hartziekenhuis

Roeselare, , Belgium

CHU d'Amiens

Amiens, , France

CHU de Bordeaux

Bordeaux, , France

CHU de Caen

Caen, , France

Hôpital Beaujon

Clichy, , France

CHRU de Lille

Lille, , France

CHU de Marseille

Marseille, , France

CHU de Nice

Nice, , France

Hôpital Saint-Louis

Paris, , France

Charite

Berlin, , Germany

Krakenhaus Walfriede

Berlin, , Germany

Klinikum Braunscheweig

Braunschweig, , Germany

Evangelisches Krankenhaus Kalk

Cologne, , Germany

Klinikum Frankfurt

Frankfurt am Main, , Germany

Klinikum Lüneburg

Lüneburg, , Germany

Rambam MC

Haifa, , Israel

Sharee Zedek MC

Jerusalem, , Israel

Rabin MC

Petah Tikva, , Israel

Tel Aviv Sourasky MC

Tel Aviv, , Israel

Sheba MC

Tel Litwinsky, , Israel

Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola Malpighi

Bologna, , Italy

Azienda Ospedaliero-Universitaria Careggi

Florence, , Italy

Instituto Clinico Humanitas IRCCS

Milan, , Italy

Seconda Università degli Studi di Napoli

Napoli, , Italy

Azienda Ospedaliera di Padova

Padua, , Italy

Azienda Ospedaliera San Camillo-Forlanini

Rome, , Italy

Università Cattolica del Sacro Cuore

Rome, , Italy

AMC

Amsterdam, , Netherlands

VUMC

Amsterdam, , Netherlands

Catharina Ziekenhuis

Eindhoven, , Netherlands

UMCU

Utrecht, , Netherlands

Hospital de Manises

Manises, Valencia, Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital Universitario Reina Sofia

Córdoba, , Spain

Hospital Juan Ramon Jimenez

Huelva, , Spain

Hospital Ramón y Cajal

Madrid, , Spain

Fundacion Jimenez Diaz

Madrid, , Spain

Hospital 12 de Octubre

Madrid, , Spain

Hospital Clinico San Carlos

Madrid, , Spain

Hospital La Princesa

Madrid, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Son Espases

Palma de Mallorca, , Spain

Hospital de Montecelo

Pontevedra, , Spain

Hospital Virgen del Rocio

Seville, , Spain

Hospital de Sagunto

Valencia, , Spain

Hospital Universitario La Fe

Valencia, , Spain

Countries

Austria; Belgium; France; Germany; Israel; Italy; Netherlands; Spain

References

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.

Reference Type: DERIVED

PMID: 34890373 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29277560 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27477896 (View on PubMed)

Other Identifiers

Cx601-0302

Identifier Type: -

Identifier Source: org_study_id