Natalizumab for active Crohn's disease.
BACKGROUND
In chronic inflammatory conditions such as Crohn's disease, the migration of leukocytes from the circulation into the parenchyma and their activation within inflammatory sites are mediated in part by alpha4 integrins.


METHODS
We conducted a double-blind, placebo-controlled trial of the alpha4 integrin-specific humanized 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 significantly 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 defined 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 improvement in response 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 response rate was 71 percent (at week 6 in the group given two infusions of 3 mg per kilogram). 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 natalizumab. 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.
Ghosh
Subrata
S
Western General Hospital, Edinburgh, United Kingdom. s.ghosh@ic.ac.uk
Goldin
Eran
E
Gordon
Fiona H
FH
Malchow
Helmut A
HA
Rask-Madsen
Jørgen
J
Rutgeerts
Paul
P
Vyhnálek
Petr
P
Zádorová
Zdena
Z
Palmer
Tanya
T
Donoghue
Stephen
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D002097:C-Reactive Protein / Q000032:analysis / Q000187:drug effects; D003424:Crohn Disease / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D000069442:Natalizumab; D011788:Quality of Life; D012074:Remission Induction / Q000379:methods
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D002097:C-Reactive Protein