Natalizumab reduces the rate of hospitalization in moderate to severe Crohnʼs Patients: Evidence from the Clinical Trial Program (2009)

Crohn's disease (CD) is a disabling disorder often requiring hospitalization. This study evaluated the effect of natalizumab (NAT) therapy on hospitalization rates during both the induction and maintenance treatment phases of three randomized controlled trials. Induction therapy with NAT was studied using pooled data from the ENACT-1 and ENCORE trials of moderate to severe CD patients randomized to intravenous NAT 300mg or placebo (PBO) every 4 weeks for 12 weeks. The maintenance analysis was conducted using data from the ENACT-2 trial and ENABLE, an open label extension. ENACT-2 consisted of NAT responders in ENACT-1 who were re-randomized and received an additional 48 weeks of therapy. Data from patients losing response in ENACT-2 who rolled over into ENABLE supplemented the ENACT-2 data. Hospitalizations were identified from adverse event reports. The rates of all-cause (ACH) and CD-related hospitalizations (CDH) per 100 patients (/100P) over the 84-day induction period and the 336-day maintenance periods were evaluated. Further analyses were performed in an a priori defined subgroup that had received prior anti-TNF alpha therapy. During induction therapy, the all cause hospitalization rate was 11.2 ACH /100P for PBO, compared to 7.3 ACH /100P in the NAT cohort (p= 0.02). During the 48 week maintenance period the rate was 21.3 ACH /100 PBO patients compared to 12.0 ACH /100 NAT patients (p= 0.04). Restricting the sample to patients with prior exposure to anti-TNF therapy resulted in larger differences between treated and untreated patients in both the induction (21.5 ACH /100 PBO patients vs. 9.4 ACH /100 NAT patients; p<0.01) and maintenance populations (41.6 ACH/100 PBO patients vs. 16.8 ACH/100 NAT patients; p= 0.03. Analysis of CD-related hospitalizations yielded similar results, in the overall sample (induction: 8.3 CDH/100 PBO patients vs. 5.7 CDH/100 NAT patients; p= 0.07; maintenance: 13.9 CDH /100 PBO patients vs. 5.8 CDH /100 NAT patients; p= 0.03). In the subset of patients who had previously received anti-TNF therapy, the CD population for which NAT is currently indicated, treatment was associated with a >50% relative risk reduction in hospitalization for both induction and maintenance therapy (induction: 13.3 CDH /100 PBO patients vs. 6.0 CDH/100 NAT patients; p= 0.02; maintenance: 19.9 CDH/100PBO patients vs. 4.9 CDH /100 NAT patients, p= 0.03). Evaluation of surgery rates was hampered by low numbers of events. In the prior anti-TNF therapy subgroup, there was no difference in surgery rates between the treatment groups during induction (rate ratio 1.33, p= 0.81), while during maintenance, NAT was associated with a statistically non-significant 55% reduction in surgeries (p= 0.22). Treatment with NAT was associated with statistically significant and clinically meaningful reductions in the rate of both all cause and CD-related hospitalizations. Furthermore, for patients who had previously received anti-TNF therapy, the approved indication of NAT in CD, both ACH and CDH rates were also markedly lower than those who received placebo. Notably, within the 48-week maintenance period, NAT therapy was associated with a 75% reduction in the incidence of CD-related hospitalization.