The    new england journal    of  medicine
n engl j med  348;1
january  2, 2003
24 Natalizumab for Active Crohn’s Disease
Subrata Ghosh, M.D., Eran Goldin, M.D., Fiona H. Gordon, M.D.,
Helmut A. Malchow, Dr. Med., Jørgen Rask-Madsen, M.D.,
Paul Rutgeerts, M.D., Ph.D., Petr Vyhnálek, M.D., Zdena Zádorová, M.B., B.Chir.,
Tanya Palmer, B.Sc., and Stephen Donoghue, Ph.D.,for the Natalizumab Pan-European Study Group*
From the Western General Hospital, Edin-burgh, United Kingdom (S.G.); Hadassah University Hospital,
Jerusalem, Israel (E.G.);Royal Free Hospital, London (F.H.G.); Klin-ikum Leverkusen, Leverkusen, Germany (H.A.M.); Herlev Hospital, Copenhagen,Denmark (J.R.-M.); University Hospital,Leuven, Belgium (P.R.); Nemocnice Par-dubice, Pardubice, Czech Republic (P.V .);Kralovske Vinohrady, Prague, Czech Repub-lic (Z.Z.); and Elan Pharmaceuticals, Steve-nage, United Kingdom (T .P., S.D.). Address reprint requests to Dr. Ghosh at Imperial College London, Hammersmith Hospital,London W12 0NN, United Kingdom, or at s.ghosh@ic.ac.uk.
*Members of the Natalizumab Pan-Europe-an Study Group are listed in the Appendix.N Engl J Med 2003;348:24-32.
Copyright © 2003 Massachusetts Medical Society.
background
In chronic inflammatory conditions such as Crohn’s disease, the migration of leuko-cytes from the circulation into the parenchyma and their activation within inflammato-ry sites are mediated in part by  a  4  integrins.
methods
We conducted a double-blind, placebo-controlled trial of the  a  4  integrin–specific hu-manized monoclonal antibody natalizumab in 248 patients with moderate-to-severe Crohn’s disease. Patients were randomly assigned to receive one of four treatments:two infusions of placebo; one infusion of 3 mg of natalizumab per kilogram of body weight, followed by placebo; two infusions of 3 mg of natalizumab per kilogram; or two infusions of 6 mg of natalizumab per kilogram. Infusions were given four weeks apart. Outcomes included changes in scores for the Crohn’s Disease Activity Index (higher scores indicate more severe disease), the health-related quality of life, and C-reactive protein levels.
results
The group given two infusions of 6 mg of natalizumab per kilogram did not have a sig-nificantly higher rate of clinical remission (defined by a score of less than 150 on the Crohn’s Disease Activity Index) than the placebo group at week 6 (the prospectively de-fined primary end point in the efficacy analysis). However, both groups that received two infusions of natalizumab had higher remission rates than the placebo group at multiple time points. Natalizumab also produced a significant improv
ement in re-sponse rates (defined by a reduction of at least 70 points in the score on the Crohn’s Disease Activity Index). The highest remission rate was 44 percent and the highest re-sponse rate was 71 percent (at week 6 in the group given two infusions of 3 mg per kil-ogram). Overall, the two infusions of 6 mg of natalizumab per kilogram and of 3 mg per kilogram had similar effects. The quality of life improved in all natalizumab groups; C-reactive protein levels improved in groups receiving two infusions of natali-zumab. The rates of adverse events were similar in all four groups.
conclusions
Treatment with the selective adhesion-molecule inhibitor natalizumab increased the rates of clinical remission and response, improved the quality of life and C-reactive protein levels, and was well tolerated in patients with active Crohn’s disease.
natalizumab and crohn’s disease
he integrins are a family of cell-
surface glycoproteins involved in the adhe-
sion, migration, and activation of immune cells. The a4 integrins are heterodimeric receptors consisti
ng of an a4 subunit and either a b1 or b7 subunit. Both a4b1 and a4b7 integrin have a role in the migration of leukocytes across the vascular en-dothelium1,2 and contribute to cell activation and survival within the parenchyma.3,4 Specifically, a4b1 integrin (also known as very late antigen 4, or VLA-4) binds to vascular-cell adhesion molecule-1,5 which is up-regulated on the vascular endothelium at many sites of chronic inflammation,6,7 including the in-testine in patients with Crohn’s disease. The a4b1 integrin also binds to certain forms of the extracel-lular-matrix protein fibronectin. The a4b7 dimer interacts with mucosal addressin-cell adhesion molecule and mediates homing of lymphocytes to the gut.8,9 The expression of this adhesion molecule on the vascular endothelium is also increased at sites of inflammation in the intestinal tract of pa-tients with inflammatory bowel disease.10-12 Preclinical studies have shown that monoclonal antibodies against a4 integrin reduce inflammation and symptoms of disease in tamarins with inflam-matory bowel disease.13,14 Natalizumab (Antegren, Elan Pharmaceuticals and Biogen), a recombinant, humanized monoclonal antibody against a4 inte-grin, improved the signs and symptoms of patients with Crohn’s disease or ulcerative colitis in two pilot studies.15,16 We conducted a large, randomized, pla-cebo-controlled trial of this selective adhesion-mol-ecule inhibitor in patients with moderate-to-severe
After receiving approval from the local ethics com-mittee, centers screened male and female patients at least 18 years of age who had clinical evidence of moderate-to-severe Crohn’s disease, defined by a score on the Crohn’s Disease Activity Index of at least 220 but no more than 450. The Crohn’s Dis-ease Activity Index incorporates eight related vari-ables: the number of liquid or very soft stools per day, the severity of abdominal pain or cramping, general well-being, the presence or absence of ex-traintestinal manifestations of disease, the presence or absence of an abdominal mass, the use of anti-diarrheal drugs, hematocrit, and body weight.17,18 Scores range from 0 to 600, with higher scores in-dicating more severe disease activity. A total of 301 patients were screened, and 248 patients underwent randomization at 35 study centers in Belgium, the Czech Republic, Denmark, Germany, Israel, the Netherlands, Sweden, and the United Kingdom between September 1999 and August 2000. Enroll-ment at each center ranged from 1 to 19 patients. All patients gave written informed consent. Patients who had received methotrexate, cyclosporine, or any investigational agents within three months be-fore randomization were excluded; patients who were receiving azathioprine or mercaptopurine were required to have been taking a stable dose for at least four months before randomization. Other criteria for exclusion included prior treatment with any antibody agent, current use of oral predniso-lone at a dose of more than 25 mg per day or anoth-er corticosteroid at an equivalent dose, current use of an elemental diet or parenteral nutrition, infec-tio
us or neoplastic diseases of the bowel, bowel sur-gery within three months before randomization, the presence of an ostomy, the presence of symp-toms due mainly to fibrotic strictures, and a clinical impression that the patient was likely to require ab-dominal surgery soon.
The study data were gathered by the investiga-tors and by an independent organization (PPD De-velopment), and the data were held and analyzed by Elan and Biogen. The principal investigators on the writing team had access to all data.
study design and randomization
Eligible patients were randomly assigned to one of four treatment regimens according to a com-puter-generated, site-stratified, block randomiza-tion schedule. Each group received two intravenous infusions four weeks apart. The four treatment reg-imens consisted of two infusions of placebo, one infusion of natalizumab at a dose of 3 mg per kilo-gram of body weight and one infusion of placebo, two infusions of natalizumab at a dose of 3 mg per kilogram, and two infusions of natalizumab at a dose of 6 mg per kilogram. Neither the study per-sonnel nor the patients were aware of the treatment assignments.
study procedures and end points
The primary efficacy measure was the Crohn’s Dis-ease Activity Index. A clinical remission was defined by a score of less than 150. A clinical response was defined by a decrease in the score of at least 70 points from base line. Additional outcomes includ-
t
The new england journal of medicine
26ed the serum level of C-reactive protein and the
health-related quality of life, as measured by the In-
flammatory Bowel Disease Questionnaire.19 Scores
on this instrument can range from 32 to 224, with
higher scores indicating a better quality of life.
Safety evaluations, which included all reports of
adverse events and clinical laboratory tests, were
conducted throughout the study. Investigators were
informed of the patients’ absolute neutrophil counts
but not the white-cell or differential counts, so that
the increase in circulating lymphocytes observed in
natalizumab-treated patients would not prompt un-
blinding of the treatment assignments. An inde-
pendent data and safety monitoring committee
oversaw the study. Serum samples were collected
at each visit and analyzed for antibodies against na-
talizumab by an enzyme-linked immunosorbent
assay.
statistical analysis
The prospective primary hypothesis was that two
infusions of 6 mg of natalizumab per kilogram
would result in a higher proportion of patients in
clinical remission (defined as a score of less than
150 on the Crohn’s Disease Activity Index) at week
6 than would two infusions of placebo. All other ef-
ficacy analyses were prespecified as secondary out-
comes. All efficacy analyses were conducted ac-
cording to the intention-to-treat principle, with the
last observation carried forward, and thus included
all 248 patients who underwent randomization. Pa-
tients who dropped out of the study, including those
who received rescue medications, had the data ob-
tained at their last visit carried forward. The analy-
sis of adverse events included all 244 patients who
underwent randomization and received at least one
dose of the assigned treatment. Four patients did
not receive either dose, because after undergoing
randomization, they were found to be ineligible.
All statistical tests were two-sided, with an alpha
level of 0.05. P values for secondary analyses were
not adjusted for multiple comparisons. Remission
and response rates were compared with use of the
Cochran–Mantel–Haenszel chi-square test (general
association),20 according to the country in which
patients were treated. We analyzed scores on the
Crohn’s Disease Activity Index using the area un-
der the curve, and we used linear mixed modeling
of repeated-measurements methods for a post hoc
evaluation of treatment effects.21,22
We estimated that 60 patients would be needed
in each group in order to detect a significant differ-
ence in response rates among the groups at a power
of 80 percent and a 5 percent level of significance.
We assumed that the natalizumab groups would
have a rate of response of 40 percent and the place-
bo group would have a response rate of 15 percent.
The comparisons of changes from base line in
the scores on the inflammatory bowel disease ques-
tionnaire and in the C-reactive protein levels be-
tween each of the three natalizumab groups and
the placebo group were performed with use of the
Wilcoxon–Mann–Whitney test. C-reactive protein
levels were compared in all patients, as well as in a
prospectively identified subgroup with a base-line
graphic characteristics, Crohn’s Disease Activity In-
dex scores, sites of disease, and medications among
the groups at base line (Table 1). Although not sta-
tistically significant, the incidence of fistulizing dis-
ease at base line was higher in the group given two
infusions of 6 mg of natalizumab per kilogram (25
percent, as compared with 10 percent in the placebo
group, 16 percent in the group given one infusion
of 3 mg of natalizumab per kilogram, and 12 per-
cent in the group given two infusions of 3 mg of
natalizumab per kilogram). At base line (week 0),
most patients were receiving other medications for
Crohn’s disease, including 5-aminosalicylate com-
pounds (48 to 62 percent), oral corticosteroids (46
to 63 percent), or azathioprine or mercaptopurine
(18 to 38 percent), with or without other agents. At
base line, 10 to 19 percent of the patients were not
receiving any other therapy for Crohn’s disease, 16
to 24 percent were receiving monotherapy with
5-aminosalicylate compounds, 7 to 25 percent were
receiving monotherapy with oral corticosteroids,
and 0 to 9 percent were receiving monotherapy with
azathioprine or mercaptopurine. Of the 244 patients
who received at least one dose of the assigned study
drug, 27 withdrew from the study before complet-
ing 12 weeks: 10 in the placebo group, 6 in the
group given one infusion of 3 mg of natalizumab
per kilogram, 5 in the group given two infusions of
3 mg of natalizumab per kilogram, and 6 in the
group given two infusions of 6 mg of natalizumab
per kilogram. The reasons for withdrawal were in-
eligibility (in the case of two patients), adverse
events (eight), lack of efficacy (seven), patient’s re-
quest (three), loss to follow-up (two), and investi-
n engl j med jm.org january 2, 2003
natalizumab and crohn’s disease
gator’s decision (five). Lack of efficacy was the rea-son for the withdrawal of three patients in the placebo group (5 percent), as compared with none in the group given one infusion of 3 mg of natali-zumab per kilogram, three in the group given two infusions of 3 mg of natalizumab per kilogram (5 percent), and one in the group given two infu-sions of 6 mg of natalizumab per kilogram (2 per-cent). Similar numbers of patients in each group withdrew because of adverse events (two [3 per-cent], one [1 percent], two [3 percent], and three [6 percent], respectively).
clinical remissions and responses
The group given two infusions of 6 mg of natali-zumab per kilogram did not have a significantly higher rate of clinical remission than the placebo group at week 6 (the prospectively defined primary end point in the efficacy analysis). This group did have significantly higher rates of remission than the placebo group at four and eight weeks. The rate of remission in the placebo group was relatively high at week 6 (27 percent), as compared with week 2 (10 percent), week 4 (14 percent), and week 8 (16 percent). At week 4, before the second infusion, all three natalizumab groups had significantly higher rates of clinical remission than the placebo group, and the group given two infusions of 3 mg of natal-izumab per kilogram also had significantly higher rates at weeks 6, 8, and 12 (Table 2).
The rate of clinical response was significantly higher  in all three natalizumab groups at weeks 4, 6, and 8 than in the placebo group, with the highest rate (71 percent) occurring at six weeks in the group given two infusions of 3 mg of natalizumab per kil-ogram (Table 2). An additional benefit was observed after the second infusion of natalizumab, and this benefit persisted through week 12. Trends toward
*Eight of 248 patients had a Crohn’s Disease Activity Index score of less than 220 at base line. Five of these eight patients were el-igible on the basis of their screening hematocrit, but they had scores of less than 220 when they were subsequently recalculated with use of the base-line hematocrit. The
scores for the other three patients were incorrectly calculated at the time of randomiza-tion but are included in the intention-to-treat analysis.
†The patients were not receiving 5-aminosalicylate compounds, corticosteroids, or immunosuppressants.
The new england journal of medicine
28an improvement in the response rates were ob-
served as early as two weeks after the first treatment.
That natalizumab was better than placebo was
further supported by post hoc analyses of the area
under the curve of the scores on the Crohn’s Dis-
ease Activity Index (P<0.02 for each natalizumab
group), and these differences remained significant
at a level of less than 0.05 after Bonferroni’s adjust-
ment for multiple comparisons for the groups giv-
en two infusions of 3 mg of natalizumab per kilo-
gram (P=0.002) and two infusions of 6 mg of
natalizumab per kilogram (P=0.009). Repeated-
measures analysis of the scores (with use of linear
mixed-model methods) also provided supportive
evidence of the beneficial effects of natalizumab
(P<0.05 for all pairwise comparisons of the three
natalizumab groups with the placebo group at
kilogram
weeks 2, 4, 6, and 8). An analysis of the treatment
effects according to the country in which treatment
was received indicated that the observed benefits of
natalizumab were similar in all geographic areas.
During the 12 weeks of the study 11 patients in the
placebo group used rescue medication (17 percent),
as compared with 14 in the group given one infu-
sion of 3 mg of natalizumab per kilogram (21 per-
cent), 10 in the group given two infusions of 3 mg
of natalizumab per kilogram (15 percent), and 6 in
the group given two infusions of 6 mg of natalizu-
mab per kilogram (12 percent); none of these dif-
ferences were statistically significant.
quality of life
All three natalizumab groups had a significant im-
provement in mean scores on the inflammatory
bowel disease questionnaire at week 6, as com-
pared with the value in the placebo group. By week
12, only the groups that received two infusions of
natalizumab continued to have scores that were *Remission was defined by a score of less than 150 on the Crohn’s Disease Activity Index. A response was defined by a decrease in the score of at least 70 points from base line. P values are for the comparison with the placebo group.
n engl j med jm.org january 2, 2003

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