Gastroenterology

Gastroenterology

Volume 154, Issue 5, April 2018, Pages 1334-1342.e4
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn’s Disease

https://doi.org/10.1053/j.gastro.2017.12.020Get rights and content

Background & Aims

Therapies for perianal fistulas in patients with Crohn’s disease are often ineffective in producing long-term healing. We performed a randomized placebo-controlled trial to determine the long-term efficacy and safety of a single local administration of allogeneic expanded adipose-derived stem cells (Cx601) in patients with Crohn’s disease and perianal fistulas.

Methods

We performed a double-blind study at 49 hospitals in Europe and Israel, comprising 212 patients with Crohn’s disease and treatment-refractory, draining, complex perianal fistulas. Patients were randomly assigned (1:1) to groups given a single local injection of 120 million Cx601 cells or placebo (control), in addition to the standard of care. Efficacy endpoints evaluated in the modified intention-to-treat population (randomly assigned, treated, and with 1 or more post-baseline efficacy assessment) at week 52 included combined remission (closure of all treated external openings draining at baseline with absence of collections >2 cm, confirmed by magnetic resonance imaging) and clinical remission (absence of draining fistulas).

Results

The study’s primary endpoint, at week 24, was previously reported (combined remission in 51.5% of patients given Cx601 vs 35.6% of controls, for a difference of 15.8 percentage points; 97.5% confidence interval [CI] 0.5–31.2; P = .021). At week 52, a significantly greater proportion of patients given Cx601 achieved combined remission (56.3%) vs controls (38.6%) (a difference of 17.7 percentage points; 95% CI 4.2–31.2; P = .010), and clinical remission (59.2% vs 41.6% of controls, for a difference of 17.6 percentage points; 95% CI 4.1–31.1; P = .013). Safety was maintained throughout week 52; adverse events occurred in 76.7% of patients in the Cx601 group and 72.5% of patients in the control group.

Conclusion

In a phase 3 trial of patients with Crohn’s disease and treatment-refractory complex perianal fistulas, we found Cx601 to be safe and effective in closing external openings, compared with placebo, after 1 year. ClinicalTrials.gov no: NCT01541579.

Section snippets

Study Design and Participants

This is a phase 3, randomized, double-blind, parallel-group, placebo-controlled study (NCT01541579) conducted in 49 hospitals in 7 European countries and Israel from July 6, 2012, to December 13, 2015 (ie, to the end of the 52-week follow-up). The study protocol was approved by the local ethics committee of participating centers and was conducted in accordance with the 2008 Declaration of Helsinki, as well as all relevant international, national, and local rules and regulations. Here, we report

Patients

In total, 212 patients were randomized to Cx601 (n = 107) or control (n = 105) (Supplementary Figure 1). The baseline demographic and clinical characteristics of patients in the Cx601 and control groups were similar, as previously described.17 In the mITT population (n = 204), the mean age of the patients was 38.3 years, 53.9% were male and 92.2% were white. Patients had Crohn’s disease for a mean of 11.6 years and more than 70% of patients had received antibiotics, immunosuppressants, or

Discussion

Complex perianal fistulas are debilitating for patients and challenging for physicians to treat. The ultimate goal of therapy is to provide long-term fistula healing. Using a robust efficacy endpoint combining remission evaluated both clinically and radiologically with MRI, the results of the current study demonstrate that the efficacy of Cx601 observed at 24 weeks was maintained for up to 1 year after administration in patients with Crohn’s disease with treatment-refractory complex perianal

Acknowledgments

ADMIRE CD Study Steering Committee Members:

Julián Panés, Daniel C. Baumgart, Jean F. Colombel, Silvio Danese, Gert Van Assche, and Walter Reinisch.

Global Surgical Coordinator: Damián García-Olmo.

In addition to the authors, the ADMIRE CD Study Group Collaborators include the following [to be mentioned as “Collaborators” in PubMed]:

Austria – Anton Stift (Medical University of Vienna); Jörg Tschmelitsch, Karl Mrak (St. Veit/Glan Hospital); Herbert Tilg, Irmgard Kroberger (University Clinic

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    Conflicts of interest The authors disclose the following: Julián Panés has received personal fees from TiGenix, AbbVie, Boehringer Ingelheim, Celgene, Galapagos, Genentech-Roche, GSK, Janssen, MSD, Novartis, Oppilan, Pfizer, Takeda, Theravance, and Vivelix. Damián García-Olmo has received personal fees from TiGenix, and has a patent and a patent pending. Gert Van Assche has received personal fees from TiGenix and grants and personal fees from AbbVie, Takeda, MSD, Janssen, Pfizer, Ferring, and Genentech-Roche. Jean Frederic Colombel reports grants from AbbVie, Janssen and Janssen, and Takeda; other fees from Boehringer Ingelheim, Celgene Corporation, Celtrion, Enterome, Ferring, Genentech, Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres, Shire, Theradiag, Amgen, Intestinal Biotech Development, and Genefit. Walter Reinisch has received personal fees as a speaker from Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; personal fees as a consultant from Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Roland Berger GmbH, Bioclinica, Biogen IDEC, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, Mallinckrodt, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, Parexel, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Sigmoid, Takeda, Therakos, TiGenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; personal fees as an advisor from Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, TiGenix, UCB, Zealand, Zyngenia, and 4SC; and grants from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and MSD. Daniel C. Baumgart reports grants, personal fees, and nonfinancial support from Shire, AbbVie, MSD, Takeda, Biogen, Dr. Falk, Ferring, Recordati, Genentech-Roche, Janssen, Pfizer, BMS; personal fees and nonfinancial support from Foreward Pharma and TiGenix; and grants from Nestle, Hitachi, Shield Therapeutics, and Celgene. Axel Dignass reports consultancy fees from AbbVie, MSD, Ferring, Genentech-Roche, Takeda, Pharmacosmos, Vifor, Falk, Mundipharma, Janssen, Allergosan, Hospira, Robarts, Pfizer, Sandoz/Hexal, and Celgene; grants from Institut für Gemeinwohl and Stiftung Leben mit Krebs; payment for lectures from Falk Foundation, Ferring, MSD, AbbVie, Otsuka, Vifor, Immunodiagnostik, Jansen-Cilag, Med Update GmbH, Medice, Pfizer, Mundipharma, Tillotts, and Hospira; manuscript preparation fees from Falk Foundation, Wiley, Thieme, Allergosan, and Takeda; and educational presentation development fees from Pharmacosmos, Falk Foundation, and Tillotts. Maria Nachury has received personal fees from TiGenix and Boehringer Ingelheim; and personal fees and nonfinancial support from AbbVie, MSD, and Takeda. Marc Ferrante has received nonfinancial support from TiGenix; grants, personal fees, and nonfinancial support from Takeda; and personal fees and nonfinancial support from MSD, Janssen, AbbVie, Chiesi, Tillotts, Ferring, Falk, Mitsubishi, Zeria, and Boehringer Ingelheim. Lili Kazemi-Shirazi reports nonfinancial and other support from TiGenix study; other support from SigmaTau and Sanofi; personal fees from MSD, AbbVie, Ferring, MerckSerono/Dr Falk, Chiesi, Novartis, Roche, Abbott, Phadia Austria/Thermo Fisher Scientific, and CSL-Behring; and nonfinancial support from Mylan, Abbott, MSD, Gilead, MerckSerono/Dr Falk, and Novartis. Marie Paule Richard, Mary Carmen Diez, Ignacio Tagarro, and Anne Leselbaum have received personal fees from TiGenix. Silvio Danese has received personal fees from AbbVie, Allergan, Sandoz, UCB, Boehringer Ingelheim. Vifor, Celltrion, Sandoz, MSD, Takeda, Janssen, Mundipharma, Hospira, Ferring, Merck, and Pfizer. Jean C. Grimaud, Fernando de la Portilla, and Eran Goldin declare no competing interests.

    Funding This study was sponsored by TiGenix S.A.U. Writing assistance was provided by David Harrison (Cerebellum Communications Ltd.), who was funded by TiGenix S.A.U.

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