Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn's Disease (ADMIRE-CD)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Cellerix ( TiGenix S.A.U. )
ClinicalTrials.gov Identifier:
NCT01541579
First received: February 21, 2012
Last updated: November 25, 2015
Last verified: September 2015
  Purpose
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.

Condition Intervention Phase
Crohn's Disease
Other: Cx601
Other: Saline solution
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Cellerix:

Primary Outcome Measures:
  • Combine remission of perianal fistulising Crohn's [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Combined Remission of perianal fistulising Crohn's disease defined as the clinical assessment of closure of all treated external openings (EO) that were draining at baseline despite gentle finger compression at week 24, and absence of collections > 2 cm of the treated perianal fistulas confirmed by centrally blinded MRI assessment by week 24.


Secondary Outcome Measures:
  • Efficacy Assessment by week 24 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    • Clinical Remission (CR) defined as closure of all treated EO that were draining at baseline despite gentle finger compression, as clinically assessed
    • Response defined as closure of at least 50% of all treated EO that were draining at baseline, as clinically assessed
    • Time to Clinical Remission (time from treatment start to 1st visit with closure of all treated EO as described above)
    • Time to Response (time from treatment start to 1st visit with closure of at least 50% of all treated EO as described above)
    • Relapse defined, in patients with CR at previous visit, as reopening of any of the treated EO with active drainage, or the development of a perianal collection > 2 cm of the treated perianal fistulas confirmed by centrally blinded MRI
    • Time to Relapse in patients with CR (time from CR to 1st visit with reopening of any of the treated EO as described above)
    • Severity of the perianal CD, assessed with the PDAI
    • QoL assessed by IBDQ
    • CDAI score
    • Van Assche

  • Efficacy Assessment by week 52 [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    • Combined Remission of perianal fistulising Crohn's disease at week 52 (as defined for week 24)
    • Clinical Remission defined as the closure of all treated external openings that were draining at baseline despite gentle finger compression, as clinically assessed at week 52
    • Response defined as closure of at least 50% of all treated external openings that were draining at baseline, as clinically assessed at week 52
    • Time to Combined Remission by week 52 (as defined for week 24)
    • Time to Clinical Remission by week 52 (as defined for week 24)
    • Time to Response by week 52 (as defined for week 24)
    • Relapse by week 52 in patients with Combined Remission at week 24 (as defined for week 24)
    • Time to Relapse by week 52 in patients with Combined Remission at week 24 (as defined for week 24)
    • Severity of the perianal Crohn's disease up to week 52 assessed PDAI
    • QoL up to week 52 by the IBDQ
    • CDAI score up to week 52
    • Van Assche score up to week 52

  • Efficacy Assessment by week 104 [ Time Frame: 104 Weeks ] [ Designated as safety issue: No ]
    • Clinical Remission of perianal fistulising Crohn's disease defined as the clinical assessment of closure of all treated external openings that were draining at baseline despite gentle finger compression at week 104
    • Relapse by week 104 in patients with Combined Remission at week 52, defined as reopening of any of the treated external openings with active drainage as clinically assessed
    • Time to Relapse by week 104 in patients with Combined Remission at week 52 (defined as time from Combined Remission to first visit with reopening of any of the treated external openings with active drainage as clinically assessed)
    • Severity of the perianal Crohn's disease, assessed with the Perianal Disease Activity Index (PDAI) up to week 104
    • Quality of Life (QoL) assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ) up to week 104
    • CDAI score up to week 104

  • Safety analysis throughout the study: [ Time Frame: week 24, 52 and 104 ] [ Designated as safety issue: Yes ]
    • Adverse events including: Treatment emergent Adverse Events (TEAEs), TEAEs related to study treatment, Treatment emergent Serious Adverse Events (TESAEs), TESAEs related to study treatment, TEAEs leading to study withdrawal, adverse events related to surgical procedure(s) to provide study treatment, deaths Only SAEs will be reported during the 2nd follow-up period between week 52 and week 104.
    • Physical examination
    • Vital signs
    • Laboratory tests (biochemistry, haematology, urinalysis)


Estimated Enrollment: 278
Study Start Date: July 2012
Estimated Study Completion Date: May 2017
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Other: Cx601
120 million cells administered by intralesional injection.
Placebo Comparator: 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.
Other: Saline solution
24 mL saline solution by intralesional injection

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01541579

  Show 52 Study Locations
Sponsors and Collaborators
TiGenix S.A.U.
Investigators
Study Chair: Julian Panes, MD Hospital Clinic of Barcelona
Principal Investigator: Julian Panes, MD Hospital Clinic of Barcelona
Principal Investigator: Lili Kazemi-Shirazi, Professor Medizinische Universität Wien
Principal Investigator: Karl Mrak, MD Krankenhaus, St. Veit/Glan
Principal Investigator: Marc Ferrante, MD Leuven University Hospital
Principal Investigator: Kurt Van der Speeten, MD Hospital Oost-Limburg, Genk
Principal Investigator: Danny de Looze, Professor Gent University Hospital
Principal Investigator: Filip Baert, MD Hospital Hartziekenhuis, Roeselare
Principal Investigator: Daniel C Baumgart, Professor Charite University, Berlin, Germany
Principal Investigator: Axel Dignass, Professor Kilikum Frankfurt
Principal Investigator: Max Reinshagen, Professor Kinikum Braunschweig
Principal Investigator: Silvio Danese, MD Instituto Clinico Humanitas IRCCS, Milano
Principal Investigator: Vito Annese, MD Azienda Ospedaliero-Universitaria Careggi, Firenze
Principal Investigator: Anna Kohn, MD Azienda Ospedaliera San Camillo-Forlanini, Rome
Principal Investigator: Alfredo Papa, MD Università Cattolica del Sacro Cuore, Rome
Principal Investigator: Giacomo C Sturniolo, Professor Azienda Ospedaliera di Padova
Principal Investigator: Andrea Belluzi, MD Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola Malpighi
Principal Investigator: Gabriele Riegler, Professor Second University of Naples
Principal Investigator: Bas Oldenburg, MD UMCU, Utrecht
Principal Investigator: Adriaan A van Bodegraven, MD VUmc Amsterdam
Principal Investigator: Gigs van den Brink, Professor AMC Amsterdam
Principal Investigator: María D Martín Arranz, MD Hospital Universitario La Paz, Madrid
Principal Investigator: Jose M Gallardo Valverde, MD Hospital Universitario Reina Sofía, Cordoba
Principal Investigator: Javier Pérez Gisbert, MD Hospital La Princesa, Madrid
Principal Investigator: Belén Beltrán Niclós, MD Hospital Universitario La Fe
Principal Investigator: Carlos Taxonera Samsó, MD Hospital Clínico San Carlos, Madrid
Principal Investigator: Fernando de la Portilla de Juan, MD Hospital Virgen del Rocío, Seville
Principal Investigator: Ricardo Rada Morgades, MD Hospital Juan Ramón Jiménez, Huelva
Principal Investigator: Gonzalo Gómez Gómez, MD Hospital Universitario 12 de Octubre, Madrid
Principal Investigator: Daniel Carpio López, MD Hospital de Montecelo, Pontevedra
Principal Investigator: Xavier Cortés Rizo, MD Hospital de Sagunto, Valencia
Principal Investigator: Torsten Kucharzik, Professor Klinikum Lüneburg
Principal Investigator: Andreas Sturm, Professor Krakenhaus Walfriede, Berlin
Principal Investigator: Antonio López Sanromán, MD Hospital Universitario Ramon y Cajal
Principal Investigator: Joaquín Hinojosa de Val, MD Hospital de Manises, Valencia
Principal Investigator: Xavier González Argenté, MD Son Espases, Palma de Mallorca
Principal Investigator: Maria Nachury, MD CHRU de Lille
Principal Investigator: Frank Zerbib, MD CHU Bordeaux
Principal Investigator: Stéphanie Viennot, MD University Hospital, Caen
Principal Investigator: Jean-Louis Dupas, MD Centre Hospitalier Universitaire, Amiens
Principal Investigator: Jean-Charles Grimaud, MD CHU de Marseille
Principal Investigator: Xavier Hebuterne, Professor CHU de Nice
Principal Investigator: Matthieu Allez, Professor Hôpital Saint Louis Paris
Principal Investigator: Yoram Bouhnik, MD Hôpital Beaujon, Clichy
Principal Investigator: Matti Waterman, MD Rambam MC, Haifa
Principal Investigator: Shomron Ben-Horin, MD Sheba MC, Tel Hashomer
Principal Investigator: Sigal Fishman, MD Tel Aviv Sourasky MC, Tel Aviv
Principal Investigator: Eran Goldin, Professor Sharee Zedek MC, Jerusalem
Principal Investigator: Irit Avni-Biron, MD Rabin MC, Petah Tikva
Principal Investigator: Herbert Tilg, Professor Univ.-Klinik Innsbruck
Principal Investigator: Lennard Gilissen, MD Catharina Ziekenhuis Eindhoven
Principal Investigator: Carlos Pastor, MD Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
Principal Investigator: Wolfgang Kruis, Professor Evangelisches Krankenhaus Kalk, Köln
  More Information

No publications provided

Responsible Party: Cellerix ( TiGenix S.A.U. )
ClinicalTrials.gov Identifier: NCT01541579     History of Changes
Other Study ID Numbers: Cx601-0302 
Study First Received: February 21, 2012
Last Updated: November 25, 2015
Health Authority: Austria: Agency for Health and Food Safety
Austria: Ethikkommission
Belgium: Ethics Committee
Belgium: Federal Agency for Medicinal Products and Health Products
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Committee for the Protection of Personnes
Germany: Ethics Commission
Germany: Paul-Ehrlich-Institut
Israel: Ethics Commission
Israel: Ministry of Health
Italy: Ethics Committee
Italy: The Italian Medicines Agency
Netherlands: Ministry of Health, Welfare and Sport
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Spain: Ethics Committee

Keywords provided by Cellerix:
Perianal fistulising Crohn's disease.

Additional relevant MeSH terms:
Crohn Disease
Digestive System Diseases
Gastroenteritis
Gastrointestinal Diseases
Inflammatory Bowel Diseases
Intestinal Diseases
Pharmaceutical Solutions
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on February 07, 2016