Natalizumab for multiple sclerosis.

Rationale: Natalizumab (NTZ) is the first monoclonal antibody approved for the treatment of highly active relapsing-remitting multiple sclerosis (RRMS). Since 2010, several new studies on NTZ for MS have emerged.

Objectives: To evaluate the benefits and harms of NTZ alone or associated with other treatments in people with any form of MS.

Search methods: We searched CENTRAL, PubMed, Embase, and two trials registries together with reference checking and contact with study authors to identify studies for inclusion in the review. The latest search date was 1 February 2024.

Eligibility criteria: We included randomised controlled trials (RCTs) in adults with any subtype of MS comparing NTZ alone or associated with other medications versus inactive control or other approved disease-modifying treatments.

Outcomes: Our outcomes included: relapse, disability worsening, serious adverse events (SAE), quality of life (QoL), number of participants with active magnetic resonance imaging (MRI) lesions (new or enlarged T2 lesions and gadolinium-enhancing (Gd+) lesions), and treatment discontinuation caused by adverse events (AE).

Risk of bias: We assessed risk of bias using the Cochrane RoB 2 tool.

Synthesis methods: Where possible, we performed a meta-analysis for each outcome by calculating risk ratios (RR), mean differences (MD), and hazard ratios (HR) with 95% confidence intervals (CI) for dichotomous outcomes, continuous outcomes, and time-to-event data respectively. Where meta-analysis was precluded by the nature of the data, we summarised the results narratively. We used GRADE to assess the certainty of evidence.

Included studies: We included five parallel-group, multicentre RCTs enrolling a total of 3255 randomised participants who received NTZ 300 mg intravenously (IV) every four weeks or comparators. The included studies were conducted mostly in Europe and North America in white participants. Four of the five included studies were commercially funded.

Synthesis of results: This review includes four comparisons; we have summarised the findings for the three main comparisons here, as evidence for the fourth comparison, NTZ versus interferon-beta in RRMS following NTZ discontinuation, was insufficient to draw conclusions as it was based on a single small study. The certainty of evidence was downgraded primarily due to high risk of bias and imprecision. All results are for NTZ 300 mg IV. NTZ versus placebo for RRMS At two-year follow-up, NTZ reduces the risk of relapse (HR 0.47, 95% CI 0.39 to 0.55; 2 studies, 2113 participants; high-certainty evidence) and sustained disability progression (HR 0.67, 95% CI 0.52 to 0.88; 2 studies, 2113 participants; high-certainty evidence); probably reduces the risk of SAEs (RR 0.83, 95% CI 0.70 to 0.99; 2 studies, 2110 participants; moderate-certainty evidence); improves QoL very slightly as measured by the physical component summary of the 36-Item Short Form Health Survey (SF-36) (higher score indicates improvement) (MD 1.98, 95% CI 1.05 to 2.91; 2 studies, 2113 participants; high-certainty evidence) and mental component summary of the SF-36 (MD 1.38, 95% CI 0.33 to 2.42; 2 studies, 2113 participants; high-certainty evidence); reduces the number of participants with new or enlarging T2-weighted lesions on MRI (RR 0.49, 95% CI 0.45 to 0.53; 2 studies, 2113 participants; high-certainty evidence); reduces the number of participants with Gd+ T1 lesions on MRI (RR 0.12, 95% CI 0.09 to 0.17; 2 studies, 2113 participants; high-certainty evidence); and probably results in little to no difference in discontinuation caused by AEs (RR 1.27, 95% CI 0.90 to 1.79; 2 studies, 2110 participants; moderate-certainty evidence). NTZ versus biosimilar-NTZ for RRMS At one-year follow-up, NTZ may result in little to no difference in risk of SAEs (RR 0.85, 95% CI 0.14 to 4.98; 1 study, 234 participants; low-certainty evidence); probably results in little to no difference in the number of participants with new or enlarging T2-weighted lesions on MRI (RR 1.10, 95% CI 0.80 to 1.50; 1 study, 234 participants; moderate-certainty evidence) and the number of participants with new Gd+ T1 lesions on MRI (RR 1.20, 95% CI 0.64 to 2.25; 1 study, 234 participants; moderate-certainty evidence); and may result in little to no difference in treatment discontinuation caused by AEs (RR 0.64, 95% CI 0.20 to 2.05; 1 study, 234 participants; low-certainty evidence). NTZ versus placebo for secondary progressive multiple sclerosis (SPMS) At two-year follow-up, NTZ may reduce the number of participants who experienced at least one relapse (RR 0.61, 95% CI 0.47 to 0.79; 1 study, 887 participants; low-certainty evidence); may result in little to no difference in sustained disability that worsened during the study (RR 1.05, 95% CI 0.77 to 1.43; 1 study, 887 participants; low-certainty evidence), risk of SAEs (RR 0.92, 95% CI 0.72 to 1.18; 1 study, 888 participants; low-certainty evidence), and treatment discontinuation caused by AEs (RR 1.02, 95% CI 0.57 to 1.85; 1 study, 888 participants; very low-certainty evidence) (evidence for the last outcome is very uncertain); and probably results in little to no difference in QoL as measured by the Multiple Sclerosis Impact Scale physical score (0 to 100, higher scores indicate greater degree of disability) (MD -2.73, 95% CI -5.46 to 0.00; 1 study, 858 participants; moderate-certainty evidence).

Authors' conclusions: For RRMS: compared with placebo at two-year follow-up: moderate- to high-certainty evidence indicates that NTZ reduces the risk of relapses and disability; probably slightly reduces SAEs; results in a very slight improvement in QoL; decreases MRI disease activity; and probably results in little to no difference in treatment discontinuation caused by AEs. Compared with biosimilar-NTZ at one-year follow-up: low- to moderate-certainty evidence suggests that the two drugs may be similar in their effects on SAEs, MRI disease activity, and treatment discontinuation caused by AEs. For SPMS: compared with placebo at two-year follow-up: very low- to moderate-certainty evidence suggests potential decreased relapse rates, but little to no difference between groups in disability progression, risk of SAEs, QoL, and treatment discontinuation caused by AEs. Future studies should focus on directly comparing active agents, assessing long-term effects, exploring alternative treatment options for individuals discontinuing NTZ, adhering to CONSORT guidelines for harm-related reporting, and ensuring adequate representation of non-white populations to enhance generalisability.

Funding: This Cochrane review had no dedicated funding.

Registration: Protocol available via doi.org/10.1002/14651858.CD015123.