Gastroenterology

Gastroenterology

Volume 119, Issue 6, December 2000, Pages 1473-1482
Gastroenterology

Alimentary Tract
Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease,☆☆,

https://doi.org/10.1053/gast.2000.20229Get rights and content

Abstract

Background & Aims: Interleukin 10 (IL-10) is an anti-inflammatory, immunomodulatory cytokine that regulates mucosal inflammation. This study evaluated the safety, tolerance, and efficacy of recombinant human IL-10 (rhuIL-10) for mild to moderately active Crohn's disease. Methods: We conducted a 24-week multicenter, prospective, randomized, double-blind, placebo-controlled, and sequential-escalating-dose study. Ninetyfive patients with Crohn's Disease Activity Index of 200–350, not presently undergoing corticosteroid, mesalamine, or immunosuppressive therapy, were treated with subcutaneous rhuIL-10 (1, 5, 10, or 20 μg/kg) or placebo once daily for 28 consecutive days. Patients were followed up for 20 weeks after treatment. Evaluation of safety and tolerance was the first objective, and efficacy was the second objective. Results: Adverse effects were dose-related, mild-to-moderate in severity, and reversible. Asymptomatic and reversible anemia and thrombocytopenia were observed at higher doses. No withdrawal or delayed adverse effects were evident during 20 weeks of follow-up. At the end of treatment (day 29), intent-to-treat analysis showed that 23.5% (confidence interval [CI], 6.8%–49.9%) of patients receiving 5 μg/kg rhuIL-10 experienced clinical remission and endoscopic improvement; 0% (CI, 0%–14.8%) of patients in the placebo group did. Higher doses of recombinant human IL-10 were less effective than 5 μg/kg. No rhuIL-10 serum accumulation and no antibody against IL-10 were detected after 4 weeks. Conclusions: Subcutaneous rhuIL-10 administered daily for 28 days to patients with mild to moderately active Crohn's disease is safe, well-tolerated, and shows clinical and endoscopic improvement.

GASTROENTEROLOGY 2000;119:1473-1482

Section snippets

Patients

Patients older than 18 years had a diagnosis of mild to moderately active Crohn's disease of the ileum and/or colon and a Crohn's Disease Activity Index (CDAI) score11 between 200 and 350 during the week before study drug initiation. None were receiving corticosteroids or immunosuppressive agents. The CDAI incorporates 8 variables related to the disease: number of liquid or very soft stools, severity of abdominal pain or cramping, general well-being, presence of extraintestinal manifestations,

Patient enrollment

The intent-to-treat data set comprised 95 patients at 25 of 27 participating centers of whom 72 were randomized to rhuIL-10 and 23 to placebo. The distribution among the 4 doses of rhuIL-10 was as follows: 18 patients received 1 μg/kg, 17 received 5 μg/kg, 18 received 10 μg/kg, and 19 received 20 μg/kg. No more than 6 patients were enrolled at any 1 center at each dose level.

Twelve patients (rhuIL-10 groups [n = 10] and placebo [n = 2]) did not complete the 28-day treatment phase, including

Discussion

This study assessed the effects of subcutaneous rhuIL-10 in patients with Crohn's disease. The effect of rhuIL-10 was assessed in adult patients with mild to moderately active Crohn's disease, currently relapsing but not receiving either corticosteroid, mesalamine, or immunosuppressive therapy.

rhuIL-10 was safe and well tolerated. Patient-reported adverse clinical events were mild flu-like symptoms, which were dose-related and reversible. Any serious adverse clinical event reported by patients

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Address requests for reprints to: Richard N. Fedorak, M.D., Division of Gastroenterology, University of Alberta, 519 Robert Newton Research Building, Edmonton, Alberta, Canada T6G 2C2. e-mail: [email protected]; fax: (403) 407-3744.

☆☆

Supported by Schering-Plough Research Institute (Kenilworth, New Jersey).

The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group consists of the following centers and investigators [the number of patients enrolled at each center is given in brackets]: Richard N. Fedorak, M.D., University of Alberta, Edmonton, Alberta, Canada [23]; Alfred Gangl, M.D., and Christoph Gasche, M.D., University Clinic for Internal Medicine IV, Vienna, Austria [9]; Charles O. Elson, M.D., University of Alabama at Birmingham, Birmingham, Alabama [6]; Paul Rutgeerts, M.D., UZ Gasthuisberg, Leuven, Belgium [6]; Stefan Schreiber, M.D., Universitatsklinikum Charite, Berlin, Germany [6]; Gary Wild, M.D., McGill University, Montreal, Quebec, Canada [5]; Steven B. Hanauer, M.D., University of Chicago, Chicago, Illinois [4]; Charles A. Sninsky, M.D., University of Florida, Gainesville, Florida [4]; John H. P. Wilson, M.D., University Hospital Rotterdam, The Netherlands [4]; Herbert Tilg, M.D., University Clinic of Internal Medicine, Innsbruck, Austria [3]; Kim Isaacs, M.D., University of North Carolina Chapel Hill, North Carolina [3]; Meron Jacyna, M.D., Northwick Park Hospital, Harrow, England [3]; Jean-Frederic Colombel, M.D., Hopital Claude Huriez, Lille, France [3]; Sander J. H. van Deventer, M.D., Academische Medisch Centrum, Amsterdam, The Netherlands [2]; John P. Wright, M.D., Kingsbury Hospital, Cape Town, South Africa [2]; Jan Irvine, M.D., McMaster University Medical Center, Hamilton, Ontario, Canada [2]; Douglas S. Levine, M.D., Washington School of Medicine, Seattle, Washington [2]; William J. Tremaine, M.D., Mayo Clinic, Rochester, Minnesota [1]; Bret A. Lashner, M.D., The Cleveland Clinic, Cleveland, Ohio [1]; Andrew S. Warner, M.D., Lahey Hitchcock Clinic, Burlington, Massachusetts [1]; Lloyd F. Mayer, M.D., Mt. Sinai School of Medicine, New York, New York [1]; Jacob C. Koningsberger, M.D., Academisch Ziekenhuis, Utrecht, The Netherlands [1]; Andre van Gossum, M.D., Hospital Erasme, Brussels, Belgium [1]; Ranger Befrits, M.D., Karolinska Hospital, Stockholm, Sweden [1]; Kai Deusch, M.D., Klinikum der Eberhard-Karis-University, Tuebingen, Germany [1]; Stephen Targan, M.D., Cedar-Sinai Medical Center, Los Angeles, California [0]; and Peter Gibson, M.D., Royal Melburne Hospital, Victoria, Australia [0].

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