Stem Cells for the Treatment of Pouchitis

Crohn's Disease Clinical Trial

Official title:

A Phase I Study of Bone Marrow Derived Mesenchymal Stem Cells (MSCs) for the Treatment of Medically Refractory Pouchitis

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05578508
• Other study ID #: CCF-Pouchitis
• Status: Withdrawn
• Phase: Phase 1
• Start date: April 2022
• Est. completion date: February 2024

Study information

• Verified date: October 2022
• Source: The Cleveland Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the safety and feasibility of using allogeneic bone marrow derived mesenchymal stem cells (MSCs) to treat people with medically refractory Pouchitis.

Description:

Proctocolectomy with ileal pouch anal anastomosis (IPAA) remains the procedure of choice for patients with chronic ulcerative colitis (CUC). IPAA allows at-risk tissue to be removed with restoration of intestinal continuity while maintaining favorable long-term functional outcomes and quality of life.

While less than 30% of patients experience short-term postoperative morbidity following IPAA, up to 15% of pouches will ultimately fail due to technical or inflammatory complications, the majority of which manifest as a fistula from the pouch to the perianal or vaginal locations. After anastomotic leak, the second leading cause of pouch fistulas is the development of Crohn's disease of the pouch. While the majority of pouches are constructed for CUC, up to 25% will end up having a change in diagnosis to CD which manifests as refractor pouchitis, strictures of the proximal small bowel, or most often as peripouch fistulas. Pouch failure due to refractory pouchitis are notoriously difficult to treat, and reconstructive pouch surgery or transanal repairs are often not offered due to suspicion of recurrent pouchitis following pouch reconstruction. The reality is that patients with refractory pouchitis will end up with a major reconstructive transabdominal operation in a select few for attempt at pouch salvage, or, most likely, a permanent end ileostomy after pouch excision. This can be a devastating outcome in some patients as it impacts body image and quality of life.

Similar to refractory pouchitis, Crohn's related perianal and rectovaginal fistula are other phenotypes of inflammatory bowel disease that are also notoriously difficult to treat with conventional medical and surgical options. Despite an ever expanding repertoire of biologic therapy and surgical intervention, sustained healing rates are less than 30%. This has driven investigators to search for alternative approaches, and in 2003 investigators reported successful healing of a refractory Crohn's rectovaginal fistula following injection of mesenchymal stem cells (MSCs). Following this success, several phase I, II, and III trials designed to study the safety and efficacy of MSCs for perianal CD, all of which have reported encouraging results with superior efficacy compared to conventional medical and surgical therapies. Over 300 perianal CD patients have now been treated without increase in adverse events and no risk of incontinence.

Given the high safety profile, and substantial success in treating perianal CD, the investigators are using a GMP grade allogeneic adipose derived MSCs to establish safety and secondarily monitor for healing in patients with medically refractory pouchitis. This trial will use allogeneic bone marrow derived mesenchymal stem cells (MSCs) to produce regenerative signals which alter the ileal pouch microbiome and local inflammatory mileau. Patients with CD of the pouch suffer chronic immunosuppression and surgical intervention and desperately need an improved therapeutic. The research aims to address the root cause of this inflammation, especially the interactions of the intestinal microbiome and host immune response through a novel therapeutic approach. The specific rationale for MSCs in medical refractory pouchitis is based opon 1) their anti-inflammatory properties; 2) published experience of MSC in this condition and perianal Crohn's fistula demonstrating efficacy and safety; 3) existence of cGMP methods for their isolation and growth.

The study will enroll adult patients with medically refractory pouchitis, whose next option in the treatment plan would be major reconstructive abdominal surgery or pouch excision with a permanent end ileostomy.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: February 2024
• Est. primary completion date: February 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Men and women 18-75 years of age

2. Residents of the United States

3. Medically refractory pouchitis defined as lack of response to antibiotics, immunomodulators, and/or biologics

4. Concurrent therapies with corticosteroids, 5-ASA drugs, thiopurines, MTX, antibiotics, anti-TNF therapy, anti-integrin and anti-interleukin are permitted if have been on them for at least 2 months prior to study enrollment without change

5. No malignant or premalignant intestinal condition, ruled out on colonoscopy within 90 days of MSC delivery

6. Ability to comply with protocol

7. Competent and able to provide written informed consent

8. Must have failed or have a contraindication to standard medical therapy including anti-TNF, anti-interleukin, or anti-integrin agent

Exclusion Criteria:

1. Inability to give informed consent

2. Clinically significant medical conditions within the six months before administration of MSCs: e.g. myocardial infarction, active angina, congestive heart failure or other conditions that would, in the opinion of the investigators, compromise the safety of the patient

3. Specific exclusions:

• HIV

• Hepatitis B or C

• Abnormal CBC at screening

• Abnormal AST or ALT at screening

4. History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment

5. Investigational drug use within thirty (30) days of baseline

6. Pregnant or breastfeeding

7. Multifocal proximal small bowel involvement which resembles Crohn's of the small bowel

8. Evidence of pelvic sepsis and pelvic penetrating fistulizing disease

9. Patients with intestinal diversion above the level of the pouch

10. Neoplasia of pouch

11. Change in medical regimen for pouchitis in the two months prior to study enrollment

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Crohn Disease
• Crohn's Disease
• Inflammatory Bowel Diseases
• Intestinal Diseases
• Pouch, Ileal
• Pouchitis
• Ulcer
• Ulcerative Colitis Chronic

Intervention

Drug:
• Mesenchymal Stem Cells (MSCs)
Endoscopic injection of allogeneic bone marrow derived mesenchymal stem cells (MSCs) to the ileal pouch.

Locations

Country	Name	City	State
United States	Cleveland Clinic	Cleveland	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
The Cleveland Clinic	Case Western Reserve University

Country where clinical trial is conducted

United States, 

References & Publications (11)

Cho YB, Lee WY, Park KJ, Kim M, Yoo HW, Yu CS. Autologous adipose tissue-derived stem cells for the treatment of Crohn's fistula: a phase I clinical study. Cell Transplant. 2013;22(2):279-85. doi: 10.3727/096368912X656045. Epub 2012 Sep 21. — View Citation

Cho YB, Park KJ, Yoon SN, Song KH, Kim DS, Jung SH, Kim M, Jeong HY, Yu CS. Long-term results of adipose-derived stem cell therapy for the treatment of Crohn's fistula. Stem Cells Transl Med. 2015 May;4(5):532-7. doi: 10.5966/sctm.2014-0199. Epub 2015 Mar 31. — View Citation

Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, Minelli A, Alvisi C, Vanoli A, Calliada F, Dionigi P, Perotti C, Locatelli F, Corazza GR. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. Gut. 2011 Jun;60(6):788-98. doi: 10.1136/gut.2010.214841. Epub 2011 Jan 21. — View Citation

de la Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis. 2013 Mar;28(3):313-23. doi: 10.1007/s00384-012-1581-9. Epub 2012 Sep 29. — View Citation

Dietz AB, Dozois EJ, Fletcher JG, Butler GW, Radel D, Lightner AL, Dave M, Friton J, Nair A, Camilleri ET, Dudakovic A, van Wijnen AJ, Faubion WA. Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn's Disease. Gastroenterology. 2017 Jul;153(1):59-62.e2. doi: 10.1053/j.gastro.2017.04.001. Epub 2017 Apr 9. — View Citation

García-Olmo D, García-Arranz M, García LG, Cuellar ES, Blanco IF, Prianes LA, Montes JA, Pinto FL, Marcos DH, García-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. Epub 2003 May 20. — 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

Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009 Jan;52(1):79-86. doi: 10.1007/DCR.0b013e3181973487. — View Citation

Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim DS, Jung SH, Kim M, Yoo HW, Kim I, Ha H, Yu CS. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula. Stem Cells. 2013 Nov;31(11):2575-81. doi: 10.1002/stem.1357. — View Citation

Molendijk I, Bonsing BA, Roelofs H, Peeters KC, Wasser MN, Dijkstra G, van der Woude CJ, Duijvestein M, Veenendaal RA, Zwaginga JJ, Verspaget HW, Fibbe WE, van der Meulen-de Jong AE, Hommes DW. Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn's Disease. Gastroenterology. 2015 Oct;149(4):918-27.e6. doi: 10.1053/j.gastro.2015.06.014. Epub 2015 Jun 25. — View Citation

Panés J, García-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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse Events	Number of adverse events that occur throughout the study.	Change from Baseline over 12 months after the MSC injection
Primary	Healing	PDAI endoscopic activity less than or equal to 1, Clinical PDAI score less than or equal to 2, and total PDAI less than or equal to 4	Change from Baseline over 12 months after the MSC Injection
Secondary	Endoscopic Remission	PDAI endoscopic activity less than or equal to 1 Mayo Endoscopic score less than or equal to 1, defined as the absence of friability or ulceration	Change from Baseline over 12 months after the MSC Injection
Secondary	Clinical Remission	Clinical PDAI score less than or equal to 2 MDPAI score less than or equal to 4	Change from Baseline over 12 months after the MSC Injection
Secondary	Endoscopic Improvement	Reduction in the endoscopic PDAI score, but still greater than 1 Reduction in the Mayo endoscopic score, but still greater than 1 Reduction in endoscopic MPDAI score by 2 or more points	Change from Baseline over 12 months after the MSC Injection
Secondary	Clinical Improvement	Reduction in the clinical PDAI score of 2 or more points Reduction in the Clinical MPDAI score of 2 or more points Decrease in 24-hour stool frequency	Change from Baseline over 12 months after the MSC Injection
Secondary	Partial Clinical Healing measured with the Pouchitis Disease Activity Index No No response	No improvement in the PDAI overall, endoscopic, or clinical scores No decrease in Mayo endoscopic severity score No decrease in 24 hour stool frequency	Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection
Secondary	Partial Clinical Healing	Decrease in C-reactive protein serum levels by greater than 50%	Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection
Secondary	Partial Clinical Healing	Decreased mucosal ulceration on pouchoscopy	Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection
Secondary	Partial Clinical Healing	Improved healing on endoscopic biopsy or surgical pathology as compared to pre-MSC delivery endoscopic biopsies.	Baseline, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months after MSC injection
Secondary	Assess for alloimmune response	Measure HLA Class B Antibody Screening	Baseline, 1 month, 3 month, 12 month after MSC injection