Please select the eligibility criteria that correspond to the clinical trial below.
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.
Brief Summary: 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.


Options:
A: 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.
B: Inclusion Criteria:

* Men and women \> 18 years of age
* Patient must have had CD (for at least 3 months from the time of initial diagnosis). The diagnosis of CD must have been confirmed by endoscopic and histologic evidence
* CDAI score of \<250 at screening and baseline
* Peri-anal fistulas must be refractory to conventional medical therapy Which means that at some time during the course of the disease, patient must have received both steroids and immunosuppressive agents (for example, azathioprine, 6-mercaptopurine (6-MP), methotrexate, or infliximab) which did not result in an adequate response to treatment
* Patients with previous surgical attempts to eradicate perianal fistulas are eligible for inclusion as are patients with setons in situ. Setons will be removed during the surgical procedure
* Patients included in the study might be receiving 5-aminosalicylic acid (5-ASA), steroids, azathioprine, 6-MP, methotrexate, or any similar drug at the time of enrolment and is allowed to have a history of infliximab treatment, provided the following conditions are fulfilled at screening:
* The dose of 5-ASA (both oral and rectal) must have been stable for at least 4 weeks prior to enrollment
* The dose of steroids must be stable for at least 4 weeks prior to enrollment
* The dose of immunosuppressants (for example azathioprine, 6-MP, or methotrexate) must have been stable for at least 8 weeks prior to enrollment and the patient on therapy for at least three months prior to enrollment
* The last dose of infliximab or other anti-TNF drug is \> 8 weeks prior to enrollment
* No need for immediate surgery (obstruction, strictures or abscess)
* If female and of child-bearing age, patient must be non-pregnant non-breastfeeding, and use adequate contraception
* Patient is willing to participate in the study and has signed the informed consent. Consent must be obtained prior to any study procedure

Exclusion Criteria:

* Patients with evidence of acute peri-anal infection, presence of peri-anal abscesses larger than 2 cm, and anal or rectal stricture
* Patients with evidence of any infections needing antibiotic treatment
* Rectovaginal fistulas, or complex peri-anal fistulas with more than two internal openings
* Patients suffering from renal- or hepatic failure
* Use of any investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer
* Patient is allergic to gadolinium (MRI contrast agent)
* Patient with severe renal insufficiency defined as patients with a glomerular filtration rate (GFR) below 60 mL/min/1.73 m2. GFR = 186.3 x (serum creatinine)-1.154 x (age in years)-0.203 x 1.212 (if patient is black) x 0.742 (if female)
* Due to the high strength electromagnetic fields that will be used during MRI there is a risk of interference with any metallic implants in the body. The following conditions will disqualify patients from having an MRI and will be excluded from this study:

  * Electronically, magnetically, and mechanically activated implants
  * Ferromagnetic or electronically operated stapedial implants
  * Cardiac pacemakers/carotid sinus pacemaker implant
  * Hemostatic clips
  * Metallic splinters in the orbit
  * Insulin pumps and nerve stimulators
  * Lead wires or similar wires
  * Metal intrauterine device
* Change in concomitant medication:

  * Steroids must be stable for at least 4 weeks prior to enrollment
  * 5-ASA should be on a stable dose \> 4 weeks prior to enrollment
  * Immunosuppressants (e.g. azathioprine, 6MP or methotrexate) should be on a stable dose \> 8 weeks prior to enrolment
  * Infliximab or other anti-TNF antibody therapy should not be administered \< 8 weeks prior to enrollment
* Claustrophobia
* Documented HIV (Human Immunodeficiency Virus) infection. Active hepatitis B, hepatitis C or TB
* Patients who currently have or who have had an opportunistic infection (e.g., herpes zoster \[shingles\], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening
* Serious infections (such as pneumonia or pyelonephritis) in the previous 3 months. Less serious infections (such as acute upper respiratory tract infection \[colds\] or simple urinary tract infection) need not be considered exclusions at the discretion of the investigator
* Malignancy within the past 5 years (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence)
* History of lymphoproliferative disease including lymphoma
* Patient is unwilling or unable to comply with the study procedures
C: 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.
D: Inclusion Criteria:

1. Patient with a complex perianal fistula. A complex perianal fistula must meet one of the following:

   * No fistula tract is palpated under the perianal skin or tract parallel to the rectum on examination with a stylet.
   * Associated anal incontinence in transsphincteric fistulas.
   * Risk factors for anal incontinence.
   * At least one prior surgery for a fistulous disease.
   * Suprasphincteric tracts shown by an image test.
2. Women of childbearing age should have a negative serum or urine pregnancy test (sensitive to 25IU of hCG) and not be lactating before study entry. Both men and women should use adequate birth control methods as defined by the investigator.
3. Seton presence is allowed at the time of study entry and until cells (in groups receiving ASCs) or Fibrin adhesive are implanted.
4. No condition that may prevent the patient from following the study procedures until 26 weeks of follow-up are completed is foreseen.
5. Patient should give his/her signed, written informed consent. -

Exclusion Criteria:

1. Patient has been diagnosed with IBD
2. Patient has a rectovaginal fistula
3. Patient is pregnant or lactating woman
4. Patient has acute sepsis at the time of study entry
5. A liposuction to draw at least 100 cc of fat from the abdominal wall is not technically feasible.
6. Patient needs surgery in the perianal region for reasons other than fistulas
7. Presence of two or more complex perianal fistulas
8. Patient has collections \> 2 cm in MRI. If such collections exist, the surgeon may perform a complete toilette of the area.
9. Patient is allergic to local anesthetics or Gadolinium (MRI contrast agent).
10. MRI is not technically feasible.
11. Patient has abused alcohol or other addictive substances within 6 months of study entry.
12. Patient has active or latent infection by HIV, HBV or HCV.
13. Patient has undergone major surgery or sustained a severe trauma, in the investigator's judgment, within 28 days of recruitment.
14. Patient is receiving or has received immunomodulatory treatment for reasons other than the fistula within 6 months of study entry.
15. Patient has a malignant tumour, except for basal or squamous cell carcinoma of the skin, or has a prior history of a malignant tumour, except if the tumour has been in remission for at least the past 5 years.

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Answer: A