Dose-escalating Therapeutic Study of Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Fistulas in Patients With Refractory Perianal Crohn's Disease

In a dose escalation study we will determine the safety and preliminary efficacy of allogeneic bone marrow mesenchymal stem cells (bmMSCs) in the induction of response for active fistulizing Crohn's Disease (CD).

Despite the introduction of anti-TNFa (tumor necrosis factor alpha) therapy, perianal disease still accounts for a high rate of morbidity in patients diagnosed with CD. Recently, a phase II multicenter randomized study was reported showing that expanded adipose tissue derived mesenchymal stem cells (atMSCs) in combination with fibrin glue was an effective and safe treatment for complex perianal fistula. However, dose escalation of allogeneic bone marrow (bm) MSCs for the local treatment of perianal fistulas has not been studied.

In this study, three escalating doses will be tested in a total of three cohorts. MSC implantation will be preceded by surgical localization, curettage of the fistulous tract and closure of the internal opening. Per cohort, patients will be randomized in a 5:2 fashion to receive either 10x10\^6 (cohort 1), 30x10\^6 (cohort 2) or 90x10\^6 (cohort 3) bmMSCs or no cells (control group).

The primary endpoint will be assessed at week 12: i) the number of adverse and serious adverse events and ii) a reduction in the number of draining fistulas, which is defined as absence of discharge and absence of collections of ≥2 cm directly related to the treated fistulas tracts as measured by MRI.

Eligibility Criteria:
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