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Inflammatory bowel disease
Original article
Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II)
  1. Silvio Danese1,
  2. Séverine Vermeire2,
  3. Paul Hellstern3,
  4. Remo Panaccione4,
  5. Gerhard Rogler5,
  6. Gerald Fraser6,
  7. Anna Kohn7,
  8. Pierre Desreumaux8,
  9. Rupert W Leong9,
  10. Gail M Comer10,
  11. Fabio Cataldi10,
  12. Anindita Banerjee11,
  13. Mary K Maguire12,
  14. Cheryl Li11,
  15. Natalie Rath12,
  16. Jean Beebe11,
  17. Stefan Schreiber13
  1. 1 Gastrointestinal Immunopathology Lab and IBD Unit, Humanitas Clinical and Research Center and Humanitas University, Milan, Italy
  2. 2 Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
  3. 3 Nature Coast Clinical Research, Inverness, Florida, USA
  4. 4 Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Canada
  5. 5 Department of Gastroenterology and Hepatology, University of Zürich, Zürich, Switzerland
  6. 6 Division of Gastroenterology, Rabin Medical Center, University of Tel-Aviv, Petah Tikva, Israel
  7. 7 UOC Gastroenterologia, AO San Camillo Forlanini, Rome, Italy
  8. 8 Lille University School of Medicine, University of Lille, Inserm U995, Lille, France
  9. 9 Inflammatory Bowel Diseases Service, Concord Hospital, Sydney, New South Wales, Australia
  10. 10 Formerly of Worldwide Research and Development, Pfizer Inc, Cambridge, Massachusetts, USA
  11. 11 Worldwide Research and Development, Pfizer Inc, Cambridge, Massachusetts, USA
  12. 12 Worldwide Research and Development, Pfizer Inc, Collegeville, Pennsylvania, USA
  13. 13 Department of Medicine I, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel, Germany
  1. Correspondence to Dr Silvio Danese, Department of Gastroenterology, Humanitas Clinical and Research Center and Humanitas University, Via Manzoni 56, 20089 Rozzano, Milan, Italy; sdanese{at}hotmail.com

Abstract

Objective Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported.

Design Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up.

Results 247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis.

Conclusions PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development.

Trial registration number NCT01287897 and NCT01345318.

  • anti-IL6 antibody
  • crohn’s disease
  • inadequate response
  • anti-TNF

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2017-314562

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    Footnotes

    • SD and SS contributed equally.

    • Contributors SD contributed to study concept and design, acquisition of data, interpretation of data, drafting of the manuscript, critical review of the manuscript, statistical analysis, other support (administrative, technical, material) and study supervision. SV, GR and AK contributed to critical review of the manuscript. PH conducted the study per protocol, contributed to patient acquisition and drafting of the manuscript. RP, GF and NR contributed to interpretation of data, drafting of the manuscript and critical review of the manuscript. PD contributed to acquisition of data, interpretation of data, drafting of the manuscript and critical review of the manuscript. RWL contributed to drafting of the manuscript and critical review of the manuscript. GMC, MKM and JB contributed to study concept and design, interpretation of data, drafting of the manuscript and critical review of the manuscript. FC performed data analyses and contributed to study concept and design, acquisition of data, interpretation of data, drafting of the manuscript, critical review of the manuscript, statistical analysis and other support (administrative, technical, material) and led study supervision. AB performed statistical analysis, interpretation of data, drafting of the manuscript and critical review of the manuscript. CL contributed to study concept and design and performed data analyses. SS contributed to study concept and design, acquisition of data, interpretation of data, drafting of the manuscript and critical review of the manuscript.

    • Funding Both studies were sponsored by Pfizer. Authors employed by Pfizer Inc were involved in the study design and in the collection, analysis and interpretation of data. Editorial support under the direction of the authors was provided by Hannah FitzGibbon, PhD, and Neil Cockburn, BSc, of Complete Medical Communications, and funded by Pfizer.

    • Disclaimer GC and FC were employees of Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA, at the time of the study.

    • Competing interests SD is a speaker, consultant and advisory board member for Abbott Laboratories, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Hospira, Johnson and Johnson, Merck & Co, Millennium Takeda, Mundipharma, Novo Nordisk, Nycomed, Pharmacosmos, Pfizer, Schering-Plough, UCB Pharma and Vifor. SV received research support from AbbVie, MSD and Takeda and received consultancy and/or speaker honoraria from AbbVie, Celgene, Centocor, Ferring, Galapagos, Genentech/Roche, Hospira, MSD, Mundipharma, Pfizer, Shire and Takeda. PH is a consultant and/or advisory board participant for, and/or has received speaker honoraria, research support and/or educational grants from, Cubist, Evoke, Ferring, Forest, Furiex, Gilead, GlaxoSmithKline, Intercept, Ironwood, Menarini, Nature Coast Clinical Research, Pfizer, Rhythm, Salix, Synergy, Takeda, Theravance and Vivus. RP is a consultant for and/or received lecture fees from Abbott, AbbVie, Allergan, Amgen, AstraZeneca, Axcan Pharma, Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research, ELAN, Ferring, Genentech, GlaxoSmithKline, Janssen, Millennium, MSD, Ocera Therapeutics, Otsuka America Pharmaceuticals, Pfizer, Shire Pharmaceuticals, Prometheus, Robarts Clinical Trials, Schering-Plough, Synta Pharmaceuticals, Takeda, Teva, UCB Pharma and Warner Chilcott. GR is a consultant for Abbott, AbbVie, Augurix, Boehringer, Calypso, FALK, Ferring, Fisher, Genentech, Essex/MSD, Novartis, Pfizer, Phadia, Roche, Takeda, Tillots, UCB, Vifor, Vital Solutions and Zeller; received speaker honoraria from AstraZeneca, Abbott, AbbVie, FALK, MSD, Phadia, Tillots, UCB and Vifor; and received educational grants and research grants from Abbot, AbbVie, Ardeypharm, Augurix, Calypso, Essex/MSD, FALK, Flamentera, Novartis, Roche, Takeda, Tillots, UCB and Zeller. AK received educational grants from AbbVie, MSD and Takeda. PD participated in advisory boards for, and received fees and grants from, AbbVie, Biofortis, BioMérieux Danone, Ferring, Genfit, Intralytix, Kitozyme, Lesaffre, MSD, Norgine, OmegaPharma International, Pileje, PPM, Roquette, Takeda and TxCell. RWL participated in advisory boards for AbbVie, Aspen, Ferring, Janssen, Hospira and Takeda and received research support from Janssen, NHMRC Career Development Fellowship and Shire. SS received consultancy fees from AbbVie, Bristol-Myers Squibb, Boehringer, Ferring, Genentech/Roche, Pfizer, MSD/Janssen, Takeda and UCB and lecture fees from AbbVie, MSD/Janssen, Takeda and UCB. AB, MKM, CL, NR and JB are all employees of Pfizer Inc and hold stock or options in Pfizer Inc. GMC and FC are former employees of Pfizer Inc and FC is a current employee of Shire Pharmaceuticals. GF has no conflicts of interest to report. GMC has been a consultant for Adare, Albireo, AstraZeneca, CinRx, Cutis, OrphoMed, Second Genome, Strongbridge and Zealand.

    • Ethics approval Institutional review board.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Author note GC and FC were employees of Worldwide Research and Development, Pfizer Inc, Cambridge, MA, USA, at the time of the study.