PDF: SENTINEL
(2006)Objective
To determine whether natalizumab added to interferon beta-1a provides additional efficacy compared to interferon beta-1a alone in patients with relapsing multiple sclerosis who have had at least one relapse on interferon
Study Summary
• Relapse rate at 2 yr: 0.34 vs 0.75; 55% reduction, P<0.001
• Relapse-free at 2 yr: 54% combination vs 32% interferon alone, P<0.001
• Sustained disability progression at 2 yr (12-wk confirmed): 23% vs 29%; HR 0.76 (0.61-0.96), P=0.02
• New/enlarging T2 lesions: 0.9 vs 5.4, P<0.001
• 2 cases of PML (1 fatal) in natalizumab group — led to temporary market withdrawal
• Study stopped early due to PML cases
Intervention
Natalizumab 300 mg IV every 4 weeks + interferon beta-1a 30 mcg IM weekly vs placebo IV every 4 weeks + interferon beta-1a 30 mcg IM weekly for up to 116 weeks
Inclusion Criteria
Age 18-55; relapsing-remitting MS; EDSS 0-5.0; MRI consistent with MS; on interferon beta-1a for >=12 months; >=1 relapse during 12 months before randomization. Excluded: primary progressive, secondary progressive, or progressive relapsing MS; relapse within 50 days; other DMT besides interferon beta-1a
Study Design
Arms: Array
Patients per Arm: Natalizumab + interferon: 589; Placebo + interferon: 582
Outcome
• Disability progression at 2 yr (co-primary): 23% vs 29%; HR 0.76, P=0.02
• Relapse-free at 2 yr: 54% vs 32%, P<0.001
• New/enlarging T2 lesions: 0.9 vs 5.4, P<0.001
• 2 PML cases (1 fatal)
Bottom Line
Adding natalizumab to interferon beta-1a reduced the annualized relapse rate by 54-55% and disability progression by 24% compared with interferon alone over 2 years. However, 2 cases of progressive multifocal leukoencephalopathy (PML), one fatal, occurred in the natalizumab group, leading to temporary market withdrawal. This trial demonstrated natalizumab's potent efficacy but also established PML as a critical safety concern.
Major Points
- SENTINEL was a 2-year, randomized, double-blind, placebo-controlled phase 3 trial enrolling 1171 analyzable patients at 124 centers in Europe and the US.
- Patients on interferon beta-1a (Avonex) with breakthrough disease (>=1 relapse in prior year) were randomized 1:1 to add natalizumab 300 mg IV or placebo every 4 weeks.
- Annualized relapse rate at 1 year: 0.38 (combination) vs 0.82 (interferon alone); 54% reduction (P<0.001). At 2 years: 0.34 vs 0.75; 55% reduction.
- Cumulative probability of disability progression at 2 years: 23% vs 29%; HR 0.76 (0.61-0.96, P=0.02).
- Relapse-free at 2 years: 54% combination vs 32% interferon alone (P<0.001).
- New/enlarging T2 lesions: 0.9 vs 5.4 (P<0.001). Gd-enhancing lesions: 0.1 vs 0.9 (P<0.001).
- Two patients developed PML (1 fatal) after >2 years of natalizumab, leading to temporary withdrawal from market in February 2005.
- The trial was stopped early due to PML cases. Natalizumab was reintroduced in 2006 with a risk management program (TOUCH).
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind; separate examining and treating neurologists
- Sample Size
- 1171
- Follow-up
- Up to 116 weeks (stopped early due to PML)
- Centers
- 124
- Countries
- Europe, USA
Primary Outcome
Definition: Rate of clinical relapse at 1 year: 0.38 vs 0.82; 54% reduction, P<0.001 | Cumulative probability of 12-week sustained disability progression at 2 years: 23% vs 29%; HR 0.76 (0.61-0.96), P=0.02
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | P<0.001 |
Citation
N Engl J Med 2006;354:911-23