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P352 Unblinded Results from a dose-escalating placebo-controlled study with allogeneic bone marrow-derived mesenchymal stem cells for the treatment of refractory perianal fistulas in patients with Crohn's disease

I. Molendijk1, B.A. Bonsing2, H. Roelofs3, K.C. Peeters2, M.N. Wasser4, R.A. Veenendaal1, J.J. Zwaginga3, H.W. Verspaget1, W.E. Fibbe3, A.E. van der Meulen - de Jong*1, D.W. Hommes1, 5

1Leiden University Medical Center, Gastroenterology and Hepatology, Leiden, Netherlands, 2Leiden University Medical Centre, Surgery, Leiden, Netherlands, 3Leiden University Medical Center, Immunohematology and Blood Transfusion, Leiden, Netherlands, 4Leiden University Medical Centre, Radiology, Leiden, Netherlands, 5University of California Los Angeles, Digestive Diseases, Los Angeles, United States

Background

Mesenchymal stromal cells (MSCs) have gained interest as potential cellular treatment for perianal fistulizing Crohn's disease (pCD), because of their ability to regenerate damaged tissue and to regulate immune and inflammatory responses.

Methods

In this prospective double blind phase I-II trial 21 patients with 1 or 2 draining perianal fistulas, but without active luminal Crohn's disease and not responding to current therapy modalities, were randomized in a 5:2 fashion to receive either protocolized local injections of 10, 30 or 90x10^6 (resp. cohort 1, 2 or 3) allogeneic bone marrow-derived MSCs (bmMSC) or placebo; collectively called endproduct. Treatment was preceded by MRI- and surgical localization curettage and closure of the internal opening of the fistulous tract. Follow-up visits took place 6, 12 and 24 weeks after bmMSC therapy. Primary endpoints were safety and preliminary efficacy of allogeneic bmMSC treatment. Secondary objectives were the changes in CRP, disease activity (CDAI and PDAI), adapted Vaizey score, quality of life scores (sIBDQ and SF-36), and endoscopic disease severity (CDEIS and SES-CD) from baseline to week 24.

Results

Local infusion of the endproduct was safe as no serious adverse events were detected. In total 32 draining perianal fistulas were observed at physical examination and MRI in the 21 patients included. At week 6, 6/12 of the fistulas in cohort 1, 6/11 in cohort 2 and 2/9 in cohort 3 were completely healed, defined as no discharge upon pressure at physical examination. At week 12 these numbers were 5/12, 6/11 and 3/9, respectively, and 7/12, 6/11, and 3/8 (n=6) at week 24. In cohort 3, 1 inactive fistula at baseline was active at week 24. Reinstalment of seton and/or abscess drainage was needed in 1 patient in cohort 1, 2 in cohort 2 and 1 in cohort 3. Average PDAI of the total cohort decreased from 4.6 at baseline to 3.4 at week 12 and 3.1 at week 24. In addition, mean Vaizey score declined from 3.8 at baseline to 2.6 at week 12 and week 24. Secondary endpoints CRP, disease activity, sIBDQ, SF-36 and endoscopy scores were stable during the study. Important to note that these unblinded data include the patients which received placebo in each cohort.

Conclusion

Local administration of allogeneic bmMSC is safe and feasible in patients with refractory pCD. No serious adverse events were detected during the 24 weeks after cellular treatment. In total 16/31 of the fistulas had completely healed at 24 weeks with the highest cure rate in cohort 1 (10x10^6 bmMSC). Deblinding of the study randomizing bmMSCs will take place the 17th of December 2014.