Julián Panés1, Damián García-Olmo2, Gert Van Assche3, Jean Frederic Colombel4, Walter Reinisch5, Daniel C Baumgart6, Axel Dignass7, Maria Nachury8, Marc Ferrante3, Lili Kazemi-Shirazi9, Jean C Grimaud10, Fernando de la Portilla11, Eran Goldin12, Marie Paule Richard13, Anne Leselbaum13, Silvio Danese14. 1. Department of Gastroenterology, Hospital Clínic, IDIBAPS, Centro Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain. Electronic address: jpanes@clinic.ub.es. 2. Department of Surgery, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain. 3. Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. 4. Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 5. Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine, Division of Gastroenterology and Hepatology, McMaster University, Hamilton, ON, Canada. 6. Department of Gastroenterology and Hepatology, Charité Medical School-Humboldt-University of Berlin, Berlin, Germany. 7. Department of Medicine Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Germany. 8. Department of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Lille, Lille, France. 9. Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. 10. Department of Hepato-Gastroenterology, Hôpital Nord, Marseille, France. 11. Department of Surgery, Unit of Coloproctology, University Virgen del Rocio Hospital, Centro Superior de Investigaciones, University of Seville, Seville, Spain. 12. Digestive Diseases Institute, Shaare Zedek Medical Center, Jerusalem, Israel. 13. TiGenix, Parque Tecnológico de Madrid, Madrid, Spain. 14. Humanitas University, IBD Center, Department of Gastroenterology, Instituto Clinico Humanitas, Rozzano, Milan, Italy.
Abstract
BACKGROUND:Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease. METHODS: We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579. FINDINGS:212 patients were randomly assigned: 107 to Cx601 and 105 toplacebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2-30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5-31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine). INTERPRETATION:Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both. FUNDING: TiGenix.
RCT Entities:
BACKGROUND: Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease. METHODS: We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579. FINDINGS: 212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2-30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5-31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine). INTERPRETATION:Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both. FUNDING: TiGenix.
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