Treatment of Fistulous Crohn's Disease by Implant of Autologous Mesenchymal Stem Cells Derived From Adipose Tissue

Crohn Disease Clinical Trial

Official title:

Treatment of Fistulous Crohn's Disease by Implant of Autologous Mesenchymal Stem Cells Derived From Adipose Tissue

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01157650
• Other study ID #: CSM/CROH
• Secondary ID: 2009-009880-71
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: July 5, 2010
• Last updated: November 7, 2016
• Start date: June 2010
• Est. completion date: September 2013

Study information

• Verified date: November 2016
• Source: Clinica Universidad de Navarra, Universidad de Navarra
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

Primary outcome measure:

Evaluation of viability, security and tolerance of the adipose-derived mesenchymal stem cells implant (ASCs) in fistulizing Crohn's disease patients, collecting the reactions and adverse events occurred during the study.

Secondary outcome measures:

1. Evaluating the Adipose-derived mesenchymal stem cells therapeutic effect, in particular:

• Fistulas healing efficiency

• Changes in quality of life in patients treated

• Changes of systemic Crohn's disease after implant

• Relapse rate monitored among patients who achieved Adipose-derived mesenchymal Stem Cells treatment success.

2. Achieving the biological characterization of the cell product used and its correlation with the therapeutic effect measured with:

• Phenotype study

• Suppressor capacity study.

• Citoquines production analysis

Description:

The aim of this study is to evaluate the role of Autologous Mesechymal Stem Cells derived from adipose tissue in the treatment of fistulous Crohn disease.

15 Crohn's disease patients with one or more enterocutaneous, recto-vaginal or complex perianal fistula, will be included.

The trial is divided in three phases:

I. - Selection: Patients evaluation for study eligibility will take place within two weeks after Informed Consent signature.

Fistulous disease will be evaluated by MRI for perianal and rectovaginal fistulas, and by CT scan in the case of enterocutaneous fistula.

Previous laboratory test and radiological studies are valid for evaluation if they were obtained within two and six months, respectively, prior to this evaluation, and in the absence of clinical changes.

II.- Treatment phase includes:

1. Liposuction procedure to obtain adipose tissue.

2. Processing and production of Autologous Mesenchymal Stem Cells from adipose tissue (ASCs)

3. ASCs implant

III.- Follow up: Study visits post-implant will take place at the 1st week (+/- 3 days), 4th week (+/- 3 days), 8th week (+/- 7 days), 12nd week (+/- 7 days), 24th week (+/- 7 days), and 1 year (+/- 7 days) after implant.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Fistulizing Crohn´s disease patients with 1 or more enterocutaneous fistulas, recto-vaginal fistula or complex perianal fistula. The complex perianal fistula is defined as a fistula presenting one of these conditions:

• Trans-sphincteric, supra-sphincteric or extra-sphincteric tract, determined with:

• Clinical criteria: No palpation of the tract and surgical exploration

• Radiological criteria: Nucleal Magnetic Resonance (NMR)or Echoendoscopy

• Multiple fistulas

• "Horseshoe" fistula

• Any fistula with fecal incontinence associated

• Any fistula with a risk of fecal incontinence as a result of:

• previous anal fistula surgery or other perianal pathology (hemorrhoids, fissures), that involves lesions or muscular complications.

• Obstetric or iatrogenic sphincter lesions

2. Patients with Crohn Disease (CD) at screening and been diagnosed within 12 months before acceptance of clinical, endoscopical, anatomopathological and/or radiological criteria and have a non-active CD.(Crohn´s Disease Activity Index (CDAI)= 200)

3. > 18 Years and both genders eligible.

4. Negative pregnancy test In female fertile subjects

5. Patient must voluntary sign the informed consent before performance of any study-related procedure not part of normal medical care.

6. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements

Exclusion Criteria:

1. Patients with a highly active CD, i.e., if they meet any of the following criteria:

• Presence of severe proctitis (prominent friability, spontaneous bleeding, multiple erosions, deep ulcers) or dominant active luminal disease that requires immediate treatment, revealed by rectosigmoidoscopy

• CDAI =201

2. Presence of abscess or other collections not drained (revealed by basal radiologic study).

3. Presence of setons drainage, unless they are removed before treatment beginning.

4. Rectal and/ or anal stenosis revealed with rectoscopy or EBA.

5. Patients needs surgery in the perianal region for other reasons than fistulas at inclusion or within 26 weeks after treatment administration.

6. Patients who have received infliximab or any other anti-TNF agent within 8 weeks before the cell treatment administration.

7. Patients who have received tacrolimus or cyclosporine within 4 weeks before cell treatment.

8. Patients with a history of alcohol or other addictive substances abuse within 6 months before inclusion.

9. Severe uncontrolled diseases (chronic renal failure, cardio, pulmonary,…).

10. Any type of medical or psychiatric disease which are considered as exclusion criteria, in the investigator's opinion.

11. Patients with diagnosis of malignant neoplasia, except basal cell or epidermoid carcinoma of the skin or previous history of malignant tumours, except those that have no evidence of relapse for at least 5 years.

12. Subjects with congenital or acquired immunodeficiency.

13. Positive serology for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV).

14. Patient had major surgery or serious traumatism within 6 weeks before enrolment.

15. Pregnant or breast-feeding women.

16. Physical or psychical impossibility of following the protocol requirements

17. Patients who are receiving or received other investigational drugs within 30 days prior to basal visit.

18. Impossibility of doing an radiological exploration (reaction to contrast material, pacemakers, claustrophobia,…)

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Other:
• Autologous mesenchymal stem cells
The trial is divided in three phases: I. - Selection: Patients evaluation for study eligibility will take place within two weeks after Informed Consent signature. II.- Treatment phase includes: Liposuction procedure to obtain adipose tissue. Processing and production of Autologous Mesenchymal Stem Cells from adipose tissue (ASCs) ASCs implant III.- Follow up: Study visits post-implant will take place at the 1st week (+/- 3 days), 4th week (+/- 3 days), 8th week (+/- 7 days), 12nd week (+/- 7 days), 24th week (+/- 7 days), and 1 year (+/- 7 days) after implant.

Locations

Country	Name	City	State
Spain	Clínica Universitaria de Navarra	Pamplona
Spain	Hospital Provincial de Navarra	Pamplona
Spain	Hospital Virgen del Camino	Pamplona

Sponsors (1)

Lead Sponsor	Collaborator
Clinica Universidad de Navarra, Universidad de Navarra

Country where clinical trial is conducted

Spain, 

References & Publications (21)

Arin Letamendia A, Borda Celaya F, Burusco Paternain MJ, Prieto Martínez C, Martínez Echeverría A, Elizalde Apestegui I, Laiglesia Izquierdo M, Macias Mendizábal E, Tamburri Moso P, Sánchez Valverde F. [High incidence rates of inflammatory bowel disease in Navarra (Spain). Results of a prospective, population-based study]. Gastroenterol Hepatol. 2008 Mar;31(3):111-6. Spanish. — View Citation

Brullet E, Bonfill X, Urrútia G, Ruiz Ochoa V, Cueto M, Clofent J, Martínez Salmerón JF, Riera J, Obrador A. [Epidemiological study on the incidence of inflammatory bowel disease in 4 Spanish areas. Spanish Group on the Epidemiological Study of Inflammatory Bowel Disease]. Med Clin (Barc). 1998 May 16;110(17):651-6. Spanish. — View Citation

García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, Rodríguez-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. — View Citation

García-Olmo D, Trébol J, et al. Treatment of digestiva fistula using Adipose-derived Stem Cells. In: García-Olmo D, García-Verdugo JM, Alemany J, Gutierrez-Fuentes JA, editors. Cell Therapy. Madrid: McGraw-Hill. Interamericana; 2008. p. 289-307.

Gardiner KR, Dasari BV. Operative management of small bowel Crohn's disease. Surg Clin North Am. 2007 Jun;87(3):587-610. Review. — View Citation

Gelbmann CM, Rogler G, Gross V, Gierend M, Bregenzer N, Andus T, Schölmerich J. Prior bowel resections, perianal disease, and a high initial Crohn's disease activity index are associated with corticosteroid resistance in active Crohn's disease. Am J Gastroenterol. 2002 Jun;97(6):1438-45. — View Citation

Hanauer SB, Smith MB. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol. 1993 May;88(5):646-9. — View Citation

Hyder SA, Travis SP, Jewell DP, McC Mortensen NJ, George BD. Fistulating anal Crohn's disease: results of combined surgical and infliximab treatment. Dis Colon Rectum. 2006 Dec;49(12):1837-41. — View Citation

Lapidus A, Bernell O, Hellers G, Löfberg R. Clinical course of colorectal Crohn's disease: a 35-year follow-up study of 507 patients. Gastroenterology. 1998 Jun;114(6):1151-60. — View Citation

Lecomte T, Contou JF, Beaugerie L, Carbonnel F, Cattan S, Gendre JP, Cosnes J. Predictive factors of response of perianal Crohn's disease to azathioprine or 6-mercaptopurine. Dis Colon Rectum. 2003 Nov;46(11):1469-75. — View Citation

Michelassi F, Stella M, Balestracci T, Giuliante F, Marogna P, Block GE. Incidence, diagnosis, and treatment of enteric and colorectal fistulae in patients with Crohn's disease. Ann Surg. 1993 Nov;218(5):660-6. — View Citation

Nivatvongs S, Gordon PH. Crohn's Disease. In: Gordon PH, Nivatvongs S, editors. Principles and practice of surgery for the colon rectum and anus Third ed. New York: Informa Healthcare; 2007. p. 819-908.

Parsi MA, Lashner BA, Achkar JP, Connor JT, Brzezinski A. Type of fistula determines response to infliximab in patients with fistulous Crohn's disease. Am J Gastroenterol. 2004 Mar;99(3):445-9. — View Citation

Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995 Jul 15;123(2):132-42. — View Citation

Poritz LS, Rowe WA, Koltun WA. Remicade does not abolish the need for surgery in fistulizing Crohn's disease. Dis Colon Rectum. 2002 Jun;45(6):771-5. — View Citation

Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn's disease. Dig Dis Sci. 1994 Feb;39(2):374-80. — View Citation

Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer SJ. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999 May 6;340(18):1398-405. — View Citation

Sandborn WJ, Present DH, Isaacs KL, Wolf DC, Greenberg E, Hanauer SB, Feagan BG, Mayer L, Johnson T, Galanko J, Martin C, Sandler RS. Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-controlled trial. Gastroenterology. 2003 Aug;125(2):380-8. — View Citation

Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004 Feb 26;350(9):876-85. — View Citation

Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology. 2002 Apr;122(4):875-80. — View Citation

Thoreson R, Cullen JJ. Pathophysiology of inflammatory bowel disease: an overview. Surg Clin North Am. 2007 Jun;87(3):575-85. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Security and tolerance	Evaluation of viability, security and tolerance of the adipose-derived mesenchymal stem cells implant (ASCs) in fistulizing Chron's disease patients, collecting the reactions and adverse events occurred during the study	3 years	Yes
Secondary	therapeutic effect	Evaluting the ASCs therapeutic effect, in particular: Fistulas healing efficiency; Changes in quality of life in patients treated; Changes of systemic Crohn's disease after implant; Relapse rate monitored among patients who achieved ASCs treatment success.; Achieving the biological characterization of the cell product used and its correlation with the therapeutic effect measured with: Phenotype study; Suppressor capacity study.; Citoquines production analysis	3 years	No