A randomized placebo-controlled trial of a humanized monoclonal antibody to α4 integrin in active crohn's disease

doi:10.1053/gast.2001.26260

Gastroenterology

Volume 121, Issue 2, August 2001, Pages 268-274

https://doi.org/10.1053/gast.2001.26260 Get rights and content

Abstract

Background & Aims: α4 integrins are important mediators of leukocyte migration across vascular endothelium.This pilot placebo-controlled study aimed to assess the safety and efficacy of natalizumab, a recombinant humanized monoclonal antibody to α4 integrin, in patients with mild to moderately active Crohn's disease.Methods: Thirty patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] ≥151 and ≤450) received a 3-mg/kg infusion of natalizumab (n = 18) or placebo (n = 12) by double-blind randomization.The study's primary endpoint was change in CDAI at week 2.Results: At week 2, the CDAI decreased significantly from baseline after infusion of natalizumab (mean 45 points) but not placebo (mean 11 points).Seven (39%) natalizumab-treated patients achieved remission at week 2, compared with 1 (8%) treated with placebo.In contrast, 4 (33%) of the placebo-treated patients required rescue medication by week 2, compared with 2 (11%) natalizumab-treated patients.Significant increases in circulating B and T lymphocytes were detected only after natalizumab administration.The frequency of commonly reported adverse events did not differ significantly between groups.Conclusions: A single 3-mg/kg natalizumab infusion was well tolerated by Crohn's disease patients, although the dose used may have been suboptimal.Elevated circulating lymphocyte levels after natalizumab suggest interrupted lymphocyte trafficking.Natalizumab therapy in active Crohn's disease merits further investigation.

GASTROENTEROLOGY 2001;121:268-274

Section snippets

Patients

Thirty-five patients with mild to moderately active Crohn's disease, defined by a Crohn's Disease Activity Index (CDAI) score ≥151 and ≤450,¹⁴ were assessed for trial eligibility at an outpatient visit at least 1 week before the planned treatment date.Patients included in the trial were at least 18 years old and had Crohn's disease confirmed by 2 or more of the following diagnostic criteria at least 3 months before study entry: history, radiologic or endoscopic intestinal appearance, histology,

Demography

The demographic characteristics of the 30 patients who received natalizumab or placebo are shown in Table 1.

. Demographic characteristics of patients at study entry

Empty Cell	Placebo (n = 12)	Natalizumab (n = 18)
Characteristic, mean (SD)
Disease duration (yr)	8.4 (6.0)	8.5 (9.6)
Age (yr)	34.4 (8.8)	36.0 (13.2)
Sex (M/F)	5/7	7/11
Weight (kg)	57.5 (8.6)	66.4 (10.6)
Height (m)	161.5 (7.1)	166.5 (8.7)
Ethnicity (white/Asian)	11/1	17/1
Disease site, n (%)
Ileal or ileocecal alone	5 (42)	7 (39)
Colonic alone	3 (25)	5 (28)
Ileal and colonic

Discussion

This study shows that treatment with a single 3-mg/kg infusion of natalizumab (Antegren) is well tolerated by patients with active Crohn's disease.Remission occurred 2 weeks postinfusion in a greater proportion of natalizumab-treated patients than of those who received placebo, but the difference between groups was not significant.Natalizumab-treated patients achieved significant reductions in CDAI 2 and 4 weeks after treatment compared with baseline, although results of between-groups

Acknowledgements

The authors thank Dr.Bruce MacFarlane and Dr.Alistair McNair for kindly referring their patients and Tanya Palmer, Judy Sercombe, Shelley Rana, and Fari Tahami for technical assistance.

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^☆: Address requests for reprints to: Fiona H.Gordon, M.A., M.B.B.Chir., M.R.C.P., Centre for Gastroenterology (10th Floor), Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, England.e-mail: [email protected]; fax: (44) 20-7431-5261.

^☆☆: Supported by Elan Pharmaceuticals Inc., South San Francisco, California.

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Alimentary TractA randomized placebo-controlled trial of a humanized monoclonal antibody to α4 integrin in active crohn's disease☆,☆☆

Abstract

Section snippets

Patients

Demography

Discussion

Acknowledgements

J Biol Chem

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Traffic signals for lymphocyte recirculation and leu-kocyte emigration: the multistep paradigm

Cell

Lymphocyte homing and homeostasis

Science

Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue

Am J Pathol

Inhibition of in vivo lymphocyte migration to inflammation and homing to lymphoid tissues by the TA-2 monoclonal antibody

J Immunol

Attenuation of colitis in the cotton-top tamarin by anti-α4 integrin monoclonal antibody

J Clin Invest

Alimentary Tract
A randomized placebo-controlled trial of a humanized monoclonal antibody to α4 integrin in active crohn's disease☆,☆☆