Ulcerative Colitis
Conditions
Keywords
Ulcerative Colitis, medically refractory ulcerative colitis, UC, refractory ulcerative colitis
Brief summary
The purpose of this study is to determine the safety and efficacy of using remestemcel-L, an ex vivo culture-expanded adult allogeneic bone marrow derived mesenchymal stem cell product (MSCs) delivered by targeted endoscopic delivery to treat people for medically refractory ulcerative colitis. This study will enroll adult patients with medically refractory ulcerative colitis who are planning to switch biologic therapy or undergo colectomy as the next stage in their treatment plan.
Detailed description
Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon and rectum, which continues to increase in incidence for unknown reasons, resulting in a significant burden to the healthcare system. UC is characterized by persistent mucosal inflammation of the colon and rectum with a chronic remitting and relapsing behavior which leaves patients on chronic immunosuppression and hospitalizations to treat the disease symptoms, but unable to cure the disease. Despite the ever-growing armamentarium of immunosuppressive medication, up to 30% of patients still require a colectomy for medically refractory disease. Participants with medically refractory ulcerative colitis will be treated by targeted endoscopic delivery of remestemcel-L, an ex vivo culture expanded allogeneic bone marrow derived mesenchymal stem cell product at a dose of 150 or 300 million. This will be injected into the submucosal layer of the colon and rectal wall. Patients will receive a second dose of remestemcel-L at a dose of 150 or 300 million MSCs (same dose as initial). If at 3 months post injection of remestemcel-L there is clinical remission, escalation of medical management and/or surgery will be delayed and patients observed. If there is worsening or no improvement in treated patients, then patients will proceed with escalation of medical management or colectomy as per standard of care. Control patients without improvement will cross over to receive remestemcel-L at 3 months and may be retreated at 6 months. All patients will be followed for two years post initial treatment. There will be a total of 4 cohorts of 3 patients (2 treatment:1 control) receiving the 150 million MSC dose of study drug and a total of 4 cohorts of 3 patients (2 treatment:1 control) receiving 300 million MSCs dose of study drug. This study plans to enroll a total of 24 participants. The primary endpoint of this study is to determine the safety and feasibility of endoscopic injection of remestemcel-L, an ex vivo culture expanded allogeneic bone marrow derived mesenchymal stem cell product for treatment of medically refractory ulcerative colitis.
Interventions
DRUGRemestemcel-L
An ex vivo culture-expanded adult allogeneic bone marrow derived mesenchymal stem cell product for the treatment of medically refractory ulcerative colitis
OTHERPlacebo
Normal saline
Sponsors
The Cleveland Clinic
Mesoblast, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Males and Females 18-75 years of age. 2. Ulcerative colitis of at least 6 months duration with medically refractory symptoms 3. Exposure to corticosteroids, 5-ASA drugs, thiopurines, methotrexate, anti-TNF therapy, anti-integrin and anti-interleukin in the past are permitted but a washout period of 4 weeks for any monoclonal antibody is necessary. 1. If receiving conventional immunomodulators (ie, AZA, 6-MP, or MTX), must have been taking them for ≥12 weeks, and on a stable dose for at least 4 weeks. 2. If AZA, 6-MP, or MTX has been recently discontinued, it must have been stopped for at least 4 weeks. 3. If receiving oral 5-ASA compounds, the dose must have been stable for at least 4 weeks. 4. If receiving oral corticosteroids, the dose must be ≤20 mg/day prednisone or its equivalent and must have been stable for at least 4 weeks. 5. If receiving budesonide, the dose must have been stable for at least 2 weeks. 6. If oral 5-ASA compounds or oral corticosteroids (including budesonide) have been recently discontinued, they must have been stopped for at least 2 weeks. 4. The following medications/therapies must have been discontinued before first administration of study agent: 1. TNF-antagonist therapy (eg, infliximab, etanercept, certolizumab, adalimumab, golimumab), vedolizumab, ustekinumab for at least 4 weeks. 2. Cyclosporine, tacrolimus, or sirolimus, for at least 4 weeks. 3. 6-thioguanine (6-TG) must have been discontinued for at least 4 weeks. 4. Rectal corticosteroids (ie, corticosteroids \[including budesonide\] administered to the 5. rectum or sigmoid colon via foam or enema or suppository) for at least 2 weeks. 6. Rectal 5-ASA compounds (ie, 5-ASAs administered to the rectum or sigmoid colon viafoam or enema or suppository) for at least 2 weeks. 7. Parenteral corticosteroids for at least 2 weeks. 8. Total parenteral nutrition (TPN) for at least 2 weeks. 9. Antibiotics for the treatment of UC (eg, ciprofloxacin, metronidazole, or rifaximin) for at least 2 weeks. 5. No colonic dysplasia and malignancy as ruled out by colonoscopy within 30 days of MSC delivery 6. Ability to comply with protocol 7. Competent and able to provide written informed consent 8. Must have lost response to at least one monoclonal antibody (anti-TNF, anti-interleukin, or anti-integrin therapy), tofacitinib, or have a contra-indication to biologic therapy 9. If patient is of reproductive capacity, willing to use adequate birth control measures while they are in the study
Exclusion criteria
for all patients to join the protocol 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; 1. HIV 2. Hepatitis B or C 4. Abnormal AST or ALT at screening defined as AST \>100 or ALT \> 100 5. Abnormal basic laboratory values with the following cut-offs: 1. Alkaline phosphate \>200 2. WBC \>13 3. Hemoglobin \<7 4. Platelets \<50 or \> 1 million 5. Creatinine \>1.5 6. History of cancer including melanoma (with the exception of localized skin cancers) within 5 years of study enrollment 7. Investigational drug within one year of study enrollment 8. Pregnant or breast feeding. 9. Fulminant colitis requiring emergency surgery 10. Concurrent active clostridium difficile infection of the colon 11. Concurrent CMV infection of the colon 12. Evidence of colonic perforation 13. Massive hemorrhage from the colon requiring emergent surgery 14. Crohn's colitis or indeterminate colitis 15. Microscopic, ischemic or infectious colitis 16. Neoplasia of the colon and preoperative biopsy 17. Presence of an ostomy 18. Prior small bowel resection 19. Previous colonic resection 20. Colonic stricture that unable to pass an adult colonoscope 21. Active or latent tuberculosis 22. Unable to wean off corticosteroids 23. Patients with extra colonic ulcerative colitis including primary sclerosing cholangitis 24. Patients with history of or current evidence of alcohol or drug abuse or dependence, recreational use of illicit drug or prescription medications, or have use of medical marijuana within 90 days of study entry 25. Patients with known allergy to local anesthetics 26. Patients with a known allergy to DMSO, porcine and/or bovine proteins 27. Patients taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix) to reduce the risk of bleeding/ hemarthrosis 28. If patient is of reproductive capacity, unwilling to use adequate birth control measures while they are in the study Control patients will have additional criteria that need to be met prior to the patients crossing over to receive treatment. Inclusion Criteria for control patients prior to entering the treatment phase: 1. Received placebo at the point of first injection 2. Completed all study visits to date 3. Clinical status has remained the same or improved, not worsened
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment related adverse events | Month 3 | Number of participants with treatment related adverse events post-injection of 150 or 300 million allogeneic bone marrow derived mesenchymal stem cells for the treatment of medically refractory Ulcerative colitis as assessed by protocol CCF-Stem Cells IBD-005. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical and endoscopic remission | Month 3, Month 12 | Number of participants with clinical and endoscopic remission post-injection of 150 or 300 million bone marrow allogeneic derived mesenchymal stem cells for the treatment of medically refractory Ulcerative colitis. Clinical and endoscopic remission is defined as: Clinical remission: Mayo Clinic score of 2 or lower and no subscore higher than 1, and mucosal healing, defined as an endoscopic subscore of 0 or 1 Endoscopic remission: Mayo Clinic scale endoscopic subscore of 0 or 1 |
| Clinical and endoscopic response | Month 3, Month 12 | Number of participants with a clinical and endoscopic response post-injection of 150 or 300 million allogeneic bone marrow derived mesenchymal stem cells for the treatment of medically refractory Ulcerative colitis. Clinical and endoscopic response is defined as: Clinical response: Reduction in the Mayo Clinic score by 3 points and a decrease of at least 30% from the baseline score with a decrease of at least 2 points on the rectal bleeding subscale to an absolute rectal bleeding score of 1 or 2. Endoscopic response: Mayo Clinic scale endoscopic subscore decrease by at least one point |
| Partial clinical and endoscopic response | Month 3, Month 12 | Number of participants with a partial clinical and endoscopic response post-injection of 150 or 300 million allogeneic bone marrow derived mesenchymal stem cells for the treatment of medically refractory Ulcerative colitis. Partial clinical and endoscopic response is defined as: Partial clinical response: Reduction in the Mayo Clinic score that does not meet the following: by 3 points and a decrease of at least 30% from the baseline score with a decrease of at least 2 points on the rectal bleeding subscale to an absolute rectal bleeding score of 1 or 2 Partial endoscopic response: No improvement in Mayo Clinic scale endoscopic subscore that stays the same or decreases |
| Lack of response | Month 3, Month 12 | Number of participants with a lack of response post-injection of 150 or 300 million allogeneic bone marrow derived mesenchymal stem cells for the treatment of medically refractory Ulcerative colitis. Lack of response is defined as: Clinical response: No improvement in Mayo Clinic score Endoscopic response: No improvement or worsening in Mayo Clinic scale endoscopic subscore |
| Mayo clinic score | Month 1 through Month 24 | Mayo clinic score will be used to measure quality of life in participants. \*Score ranges from 0 (least severe) to 12(most severe). |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAmy Lightner
Cleveland Clinic Foundation, Cleveland OH
Outcome results
None listed