Definitions of the strength of the recommendations (A, B, C, U) and classification of the evidence (Class I through Class IV) are provided at the end of the "Major Recommendations" field.
Conclusions
- Natalizumab reduces measures of disease activity such as clinical relapse rate, gadolinium (Gd)-enhancement, and new and enlarging T2 lesions in patients with relapsing multiple sclerosis (MS) (Class I studies, Level A).
- Natalizumab improves measures of disease severity such as the Expanded Disability Status Scale (EDSS) progression rate and the T2-hyperintense and T1-hypointense lesion burden seen on magnetic resonance imaging (MRI) in patients with relapsing MS (Class I studies, Level A).
- The relative efficacy of natalizumab compared to other available disease-modifying therapies is unknown (Level U).
- The value of natalizumab in the treatment of secondary progressive multiple sclerosis (SPMS) is unknown (Level U).
- The SENTINEL trial provides evidence for the value of adding natalizumab to patients already receiving interferon-beta-1a (IFNbeta-1a,) 30 micrograms, intramuscularly (IM) once weekly (one Class I study, Level B). It provides no information either about the value of adding IFN-beta therapy to patients already receiving natalizumab in the treatment of relapsing-remitting multiple sclerosis (RRMS) or about the value of continuing IFN-beta therapy once natalizumab therapy is started (Level U).
- There is an increased risk of developing progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy). The two cases seen in MS were treated with a combination of natalizumab and IFN-beta-1a, but the fact that PML occurred only with combination therapy may be a chance development. There may also be an increased risk of other opportunistic infections (Level C). On the basis of clinical trial data, the PML risk has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this estimate could change in either direction with more patient-years of exposure. Since the development of this guideline, two cases of PML have been reported in patients receiving natalizumab monotherapy, one of whom had never previously received any immunomodulatory or immunosuppressive treatment. This observation indicates that natalizumab, by itself, is a risk factor for PML. However, the evidence has not been formally reviewed by the Therapeutics and Technology Assessment Subcommittee (TTA.)
Recommendations
- Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML, it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. This recommendation is very similar to that of the U.S. Food and Drug Administration (FDA).
- Similarly, because combination therapy with IFN-beta and natalizumab may increase the risk of PML, it should not be used. There are also no data to support the use of natalizumab combined with other disease-modifying agents as compared to natalizumab alone. The use of natalizumab in combination with agents not inducing immune suppression should be reserved for properly controlled and monitored clinical trials.
Definitions:
Classification of Recommendations
Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*
Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)
Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. (Studies not meeting criteria for Class I–III).
* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if (1) all criteria are met; (2) the magnitude of effect is large (relative rate improved outcome > 5 and the lower limit of the confidence interval is > 2).
Classification of Evidence for Therapeutic Intervention
Class I: Randomized, controlled clinical trial with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are required:
- Concealed allocation
- Primary outcome(s) clearly defined
- Exclusion/inclusion criteria clearly defined
- Adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.
Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d.
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*
Class IV: Studies not meeting Class I, II or III criteria, including consensus, expert opinion or a case report.
* Objective outcome measurement: An outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).
