Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicentre Australian Phase 2 Study to Evaluate Safety and Efficacy of Mesenchymal Stromal Cells for Treating Biologic Refractory Crohn's Disease
Brief Summary: Despite the advent of newer biologic therapies such as infliximab for Crohn's disease, a form of autoimmune inflammatory bowel disease, a proportion of patients are refractory to such therapy and require surgery. The hypothesis is that mesenchymal stromal cell therapy using third party human cultured cells will be safe and effective


Options:
A: Inclusion Criteria:

* Ages 15 to 60 years old
* Meet at least 4 of 11 American College of Rheumatology (ACR) Classification criteria for systemic lupus erythematosus (SLE) (see Appendix 16.2)
* Meet one of following five:

  1. For lupus nephritis, participants must fail pulse cyclophosphamide (500 to 1000 mg/m2 monthly for a minimum of 6 months). Failure is defined as meeting criteria to be considered as BILAG renal category A.
  2. For visceral organ involvement other than nephritis, participants must be BILAG cardiovascular/respiratory category A, vasculitis category A, or neurologic category A and must fail at least 3 months of oral or IV cyclophosphamide and be corticosteroid dependent. Steroid dependence being defined as at least 3 months of steroid therapy and inability to wean corticosteroid to less than 20 mg/day of prednisone or equivalent.
  3. For cytopenias that are immune mediated, participants must be BILAG hematologic category A. Participants must fail corticosteroids (either oral prednisone \> 0.5 mg/kg/day for more than 6 months or pulse methylprednisolone for at least one cycle of three days), and at least one of the following: azathioprine at 2 mg/kg/day for at least 3 months, mycophenolate mofetil 2 grams daily for more than 3 months, cyclophosphamide intravenously or orally for at least 3 months, or cyclosporine at least 3 mg/kg/day for at least 3 months, danazol for at least 3 months, or splenectomy.
  4. For mucocutaneous disease, participants must meet BILAG mucocutaneous category A, be unable to be weaned from prednisone to less than 0.5 mg/kg/day for more than 6 months and obvious cushingoid habitus, and have received at least one of the following: azathioprine at 2 mg/kg/day for at least 3 months, methotrexate at 15mg/week for at least 3 months, cyclophosphamide intravenously or orally for at least 3 months, or cyclosporine at least 3 mg/kg/day for at least 3 months.
  5. For arthritis/myositis, participants must meet BILAG musculoskeletal category A, be unable to be weaned from prednisone to less than 0.5 mg/kg/day for more than 6 months and obvious cushingoid habitus, and have received at least one of the following: azathioprine at 2 mg/kg/day for at least 3 months, methotrexate at 15mg/ week for at least 3 months, cyclophosphamide intravenously or orally for at least 3 months, or cyclosporine at least 3 mg/kg/day for at least 3 months.
* Able to give informed consent.
* If indication for hematopoietic stem cell transplant (HSCT) is nephritis, a renal biopsy must demonstrate the potential of a reversible (non-fibrotic) component indicating that if successful the participant would not be likely to be permanently dialysis-dependent after transplant.
* Since the BILAG is only one of multiple indices for SLE, patients may also be candidates if despite prior immune suppression therapy as described above, patients are still on active immune suppression (more than 10mg a day of prednisone).
* Patients with SLE whose major manifestation is Antiphospholipid syndrome (APS) may be candidates without prior immune suppression therapy if they have had a visceral organ thrombotic or embolic event despite anticoagulation.
* Patients with SLE whose major manifestation is Antiphospholipid syndrome (APS) may be candidates without prior immune suppression therapy if they have had a visceral organ thrombotic or embolic event despite anticoagulation.

Exclusion Criteria:

* HIV positive
* Ongoing malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the participant is judged to be cured by local surgical therapy, such as head and neck cancer, or stage I or II breast cancer will be considered on an individual basis by the investigators doing the final screening for participant qualification.
* Positive pregnancy test, inability or unwillingness to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
* Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
* Diffusing capacity of lung for carbon monoxide (DLCO) \< 45% of predicted unless attributed to active lupus.
* Resting left ventricular ejection fraction (LVEF) \< 40% unless attributed to active lupus.
* Known hypersensitivity to E Coli derived proteins.
* Transaminases greater than 2 times normal unless attributed to active lupus.
* Positive tuberculosis skin test
* Any active infection
* Any co-morbid illness that in the opinion of the investigator would jeopardize the ability of the subject to tolerate the study.
* Failure to collect at least 2.0 x 106 cluster of differentiation 34 (CD34+) cells/kg
* Antinuclear antibody (ANA)-negative
B: Inclusion Criteria:

* Colonic or small bowel Crohn's disease based on endoscopic appearances and histology
* Refractory to induction with infliximab or adalimumab; or have lost response to these agents; or have had side effects precluding their further use
* Where there has been loss of response to one of these agents, the other must be tried before being eligible
* Crohn's disease activity score (CDAI) 250 or more.
* C-reactive protein \>10mg/L
* Surgery must have been offered to the subject (if appropriate) and declined
* Signed informed consent

Exclusion Criteria:

* Active sepsis, perforating disease. Coexistent perianal fistulous disease is permitted, providing no co-existent infection within previous 4 weeks
* Chronic stricturing disease in isolation
* Coexistent CMV disease
* Prior history of malignancy
* Pregnant or unwilling to practice contraceptive therapy or breast feeding females
* Last biologic therapy must be greater than 4 weeks prior, must be on stable corticosteroid dose for 14 days prior, during therapy and for 14 days after therapy, must be on stable immunomodulator dose (eg, azathioprine) for 14 days prior, during therapy and for 14 days after.
C: Inclusion Criteria:

* Clinical diagnosis of Crohn´s Disease
* presence of complex Crohn´s Disease fistulas
* fistulas refractory to standard surgical intervention, including long-term seton and regular curettage, and/or medical treatment.

Exclusion Criteria:

- Fistulas developed following proctectomy were excluded.
D: Inclusion Criteria

1. Men and Women 18-75 years of age with a diagnosis of Crohn's disease for at least six months duration.
2. Single and Multi-tract Perianal fistula, with or without previous failed surgical repair.
3. Have no contraindications to MR evaluations: e.g. pacemaker or magnetically active metal fragments, claustrophobia
4. Ability to comply with protocol
5. Competent and able to provide written informed consent
6. Concurrent Crohn's-related therapies with stable doses (\>2 months) corticosteroids, 5- ASA drugs, immunomodulators, anti-TNF therapy, anti-integrin and anti-interleukin therapies are permitted

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 subject.
3. Specific exclusions:

   1. Hepatitis B or C
   2. HIV
   3. Abnormal AST or ALT at screening(defined as \>/= 2x ULN)
4. History of cancer including melanoma (with the exception of localized skin cancers) within one year of screening.
5. History of colorectal cancer within 5 years
6. Investigational drug within one month of treatment
7. Pregnant or breast feeding or trying to become pregnant.
8. Presence of a rectovaginal or perineal body fistula
9. Change in Crohn's immunosuppressive regimen within the 2 months prior to enrollment
10. Uncontrolled intestinal Crohn's disease which will require escalation for medical therapy or surgery within 2 months of enrollment
11. Severe anal canal disease that is stenotic and requires dilation
12. Female participant unwilling to agree to use acceptable contraception methods during participation in study

Answer: B