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SENTINEL

Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis

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Year of Publication: 2006

Authors: R.A. Rudick, W.H. Stuart, P.A. Calabresi, ..., for the SENTINEL Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2006;354:911-23

Link: https://doi.org/10.1056/NEJMoa044396

PDF: https://doi.org/10.1056/NEJMoa044396

Clinical Question

Does adding natalizumab to interferon beta-1a provide additional benefit over interferon beta-1a alone in patients with relapsing MS who have breakthrough disease?

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).

      

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial

Randomization: 1

Blinding: Double-blind; separate examining and treating neurologists

Enrollment Period: Beginning January 2002

Follow-up Duration: Up to 116 weeks (stopped early due to PML)

Centers: 124

Countries: Europe, USA

Sample Size: 1171

Analysis: Intention-to-treat; Poisson regression for relapse rate; Kaplan-Meier and Cox regression for disability; Hochberg procedure for multiple comparisons

Inclusion Criteria

Age 18-55
Relapsing-remitting MS
EDSS 0-5.0
MRI consistent with MS
On interferon beta-1a >=12 months
>=1 relapse in prior 12 months

Exclusion Criteria

Primary progressive, secondary progressive, or progressive relapsing MS
Relapse within 50 days of randomization
Other DMT besides interferon beta-1a

Baseline Characteristics

Characteristic	Control	Active

Arms

Field	Experimental	Control
Intervention	Natalizumab 300 mg IV every 4 weeks added to interferon beta-1a 30 mcg IM weekly	Placebo IV every 4 weeks added to interferon beta-1a 30 mcg IM weekly
Duration

Outcomes

Outcome	Type	Intervention	P-value
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	Primary		P<0.001
Relapse rate at 2 years: 0.34 vs 0.75; 55% reduction, P<0.001	Secondary		P<0.001
Relapse-free at 2 years: 54% vs 32%, P<0.001	Secondary		P<0.001
New/enlarging T2 lesions: 0.9 vs 5.4, P<0.001	Secondary		P<0.001
Gd-enhancing lesions: 0.1 vs 0.9, P<0.001	Secondary		P<0.001
Not reported	Adverse	No adverse event data extracted for this trial

Funding

Biogen Idec and Elan Pharmaceuticals

Based on: SENTINEL (New England Journal of Medicine, 2006)