Gastroenterology

Gastroenterology

Volume 114, Issue 6, June 1998, Pages 1133-1142
Gastroenterology

Rapid Communications
A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn's disease,☆☆

https://doi.org/10.1016/S0016-5085(98)70418-4Get rights and content

Abstract

Background & Aims: Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the trafficking and activation of leukocytes and is up-regulated in inflamed mucosa in Crohn's disease. ISIS 2302 is an antisense phosphorothioate oligodeoxynucleotide that inhibits ICAM-1 expression. The aim of this study was to obtain preliminary assessment of tolerability, pharmacology, and efficacy of ISIS 2302 in Crohn's disease. Methods: Twenty patients with active, steroid-treated Crohn's disease were randomized (3:1, ISIS 2302 to placebo) to receive over 26 days 13 intravenous infusions of ISIS 2302 (0.5, 1, or 2 mg/kg) or saline placebo in a double-blinded study. The patients were followed up for 6 months. Results: At the end of treatment, 47% (7 of 15) of ISIS 2302–treated and 20% (1 of 5) of the placebo-treated patients were in remission (Crohn's Disease Activity Index [CDAI] < 150). At the end of month 6, 5 of these 7 ISIS 2302–treated remitters were still in remission, and a 6th patient had a CDAI of 156. Corticosteroid usage was significantly lower (P = 0.0001) in the ISIS 2302–treated patients. These findings were corroborated by significant increases in β7 and αd bearing CD3+ peripheral blood lymphocytes and by decreases in intestinal mucosal ICAM-1 expression during the treatment period. Conclusions: ISIS 2302 seems to be a well-tolerated and promising therapy for steroid-treated Crohn's disease.

GASTROENTEROLOGY 1998;114:1133-1142

Section snippets

Study design

The study was a single-center, double-blinded, placebo-controlled, randomized (3:1; ISIS 2302 to placebo), fixed-dose within patient, and dose-escalation trial, approved by the Ethics Committee of the University of Alberta. We enrolled 20 patients between the ages of 18 and 80 who had moderately active Crohn's disease (Crohn's Disease Activity Index [CDAI], 200–350) despite stable background therapy of moderate-dose corticosteroids (prednisone or equivalent, ≤40 mg/day) and mesalamine drugs for

Patients

Baseline characteristics of the ISIS 2302 and placebo patients are shown in Table 1; none of the differences was statistically significant.

. Baseline characteristics of patients with Crohn's disease receiving ISIS 2302 and placebo

Empty CellISIS 2302Placebo
No. of patients155
Sex (M/F)9/63/2
Age (yr)36.5 (18–78)26.0 (19–33)
Disease duration (yr)8.6 (2–32)5.7 (2–12)
Prednisone dosage (mg/day)15.5 (10–40)13.6 (7.5–30)
CDAI294 (201–428)291 (129–345)
EIS13.05 (1.8–26.1)8.62 (1.6–17.0)
IBDQ163.9 (93–215)182 (156–210)

Discussion

This study provided a novel opportunity to use systemically administered antisense in a human disease process, offering us a means to study a very specific manipulation in the treatment of Crohn's disease: the inhibition of ICAM-1 through an antisense mechanism. In addition to following clinical measures, the study was designed to allow an examination of the effects of ISIS 2302 on peripheral blood lymphocyte and intestinal mucosal ICAM-1 expression and the effects of manipulating ICAM-1 on

Acknowledgements

The authors thank Stanley T. Crooke, M.D., Ph.D., for his thoughtful review of the manuscript; Bonnie Wolschuk, R.N., Kim Doan, B.S., and Diana Martini, M.S., for their expert assistance in the execution of the trial; William Pelkey, Ph.D., and Jan Callahan, Ph.D., for the statistical analyses; and Robert A. Rothlein, Ph.D., and Elizabeth Mainolfi, M.S., of Boehringer Ingelheim Pharmaceuticals Inc., for the sICAM-1 analyses.

References (53)

  • SP Henry et al.

    Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in cynomolgus monkeys

    Toxicology

    (1997)
  • WR Best et al.

    Development of a Crohn's Disease Activity Index: National Cooperative Crohn's Disease Study

    Gastroenterology

    (1976)
  • G Guyatt et al.

    A new measure of health status for clinical trials in inflammatory bowel disease

    Gastroenterolgy

    (1989)
  • EJ Irvine et al.

    Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease

    Gastroenterology

    (1994)
  • JM Leeds et al.

    Quantitation of phosphorothioate oligonucleotides in human plasma

    Anal Biochem

    (1996)
  • ML Dustin et al.

    Induction by IL 1 and interferon gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1)

    J Immunol

    (1986)
  • RM Rothlein et al.

    A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1

    J Immunol

    (1986)
  • MS Diamond et al.

    ICAM-1 (CD54): a counter-receptor for Mac-1 (CD11b/CD18)

    J Cell Biol

    (1990)
  • N Oppenheimer-Marks et al.

    Differential utilization of ICAM-1 and VCAM-1 during the adhesion and transendothelial migration of human T lymphocytes

    J Immunol

    (1991)
  • DM Altmann et al.

    Cotransfection of ICAM-1 and HLA-DR reconstitutes human antigen-presenting cell function in mouse L cells

    Nature

    (1989)
  • GA Van Seventer et al.

    The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor–mediated activation of resting T cells

    J Immunol

    (1990)
  • ML Entman et al.

    Neutrophil induced oxidative injury of cardiac myocytes

    J Clin Invest

    (1992)
  • NK Damle et al.

    Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes

    J Immunol

    (1992)
  • J Poudier et al.

    CD54/Intercellular adhesion molecule 1 and major histocompatibility complex II signalling induces B cells to express interleukin 2 receptors and complements help provided through CD40 ligation

    J Exp Med

    (1994)
  • H Ohtani et al.

    Light and electron microscopic immunolocalization of endothelial leukocyte adhesion molecule–1 in inflammatory bowel disease

    Virchows Arch A Pathol Anat Histopathol

    (1992)
  • S Nakamura et al.

    In situ expression of the cell adhesion molecules in inflammatory bowel disease: evidence of immunologic activation of vascular endothelial cells

    Lab Invest

    (1993)
  • Cited by (0)

    Supported by Isis Pharmaceuticals, Inc., Carlsbad, California.

    ☆☆

    Address requests for reprints to: Bruce R. Yacyshyn, M.D., Department of Gastroenterology, 2E3.11 Walter MacKenzie Health Sciences Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2R7. Fax: (403) 492-2504.

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