Natalizumab as treatment for Multiple Sclerosis: a systematic review

Duration: June 2018 – September 2018
Language: English
Publication: LBI-HTA Project report No. 112: https://eprints.aihta.at/1190/

Background:
Multiple Sclerosis (MS) is an autoimmune disease in which focal inflammatory processes within the central nervous system (CNS) trigger the demyelination of the neurons, leading to subsequent axonal damage and neurodegeneration (Dargahi et al., 2017). The clinical manifestations are heterogeneous and depend on the location of the lesions. They could comprise a variety of symptoms including motor deficits, sensory problems, speech and vision impairments and malfunctions of the urogenital system (Gitto, 2017). Furthermore, the majority of the patients suffer from chronic neuropathic pain which is caused by the dysfunction of the nervous system (Murphy et al., 2017).

More than 2.5 million people worldwide are affected from the associated neurological disabilities, whereby three times more women than men are affected (Didonna, Oksenberg, 2017). The etiology of MS is not fully elucidated, although environmental factors as well as hereditary determinants have been identified.

Natalizumab is a humanized monoclonal antibody which is approved for the treatment of the relapsing-remitting form of Multiple Sclerosis and which has been shown to efficiently block the migration of potentially inflammatory cells to the CNS.

A previous systematic review that was published in 2011 by Pucci and colleagues evaluated the efficacy and safety of Natalizumab as add-on treatment or versus a placebo control. It was based on three randomised controlled trials (AFFIRM 2006, SENTINEL 2006 and GLANCE 2009). The authors found significant evidence in favour of Natalizumab for all primary and secondary outcomes. Yet, the therapy has also been associated with an increased risk for developing progressive multifocal leukoencephalopathy (PML) (Pucci et al, 2011).

Aims of project:
The rationale of this review is to provide a more precise estimate of the treatment effect of Natalizumab therapy by including randomised trials that have been undertaken since the publication of the first systematic review and to evaluate potential long-term effects by including observational trials.

Research objectives:

1. To estimate the effect of the treatment with the monoclonal antibody Natalizumab by measuring the number of relapses (Annualized Relapse Rate – ARR) and the proportion of participants who experienced disability worsening (Enhanced Disability Status Score – EDSS) over specified time periods depending on the length of the studies under investigation.
2. In addition, we will consider patient-reported quality of life (QoL).
3. To determine the safety of natalizumab either applied as a first line treatment or as secondary regimen by determining the number of serious adverse events.

Research question:
Is the treatment with natalizumab effective and safe for patients with remitting-relapsing multiple sclerosis in comparison to any alternative therapy?

PICO-question:

Exclusion criteria:

Population:

• Patients with Clinically isolated syndrome (CIS) as not all people diagnosed with CIS will later develop MS.

Types of studies:

• retrospective controlled studies
• prospective controlled trials with a treatment period less than 24 months
• prospective single-arm studies with with a treatment period less than 36 month
• retrospective single-arm studies

Types of publications:

• Unpublished documents
• Abstracts, posters, letters
• Editorials, letters to the editor, comments, other types of correspondence

Methods:

Systematic Review based on published documents:

• Systematic literature search in: Embase, Medline, Cochrane (CENTRAL), Toxline and ClinicalTrials.gov
• Data extraction: the author will include and exclude studies based on the PICO question and perform the data extraction.
• Assessing the risk of bias and strength of evidence: according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Time schedule/ milestones (in months):

References:

Dargahi, N., M. Katsara, T. Tselios, M.-E. Androutsou, M. de Courten, J. Matsoukas, V. Apostopoulos (2017) Multiple Sclerosis: Immunopathology and Treatment Update: Brain Sciences, 7( 7).

Didonna, A., J.R. Oksenberg (2017) in Zagon, I.S., P.J. McLaughlin Multiple Sclerosis: Perspectives in Treatment and Pathogenesis, p3-16.

Gitto, L. (2017) Living with Multiple Sclerosis in Europe: Pharmacological Treatments, Cost of Illness, and Health-related Quality of Life across Countries in Zagon, I.S., P.J. McLaughlin Multiple Sclerosis: Perspectives in Treatment and Pathogenesis, p17-38.

Murphy, K.L., J.R. Bethea, R. Fischer (2017) Neuropathic Pain in Multiple Sclerosis-Current Terapeutic Intervention and Future Treatment Perspectives in Zagon, I.S., P.J. McLaughlin Multiple Sclerosis: Perspectives in Treatment and Pathogenesis, p53-70.

Pucci, E., G. Giuliani, A. Solari, S. Simi, S. Minozzi, C. Di Pietrantonj, I. Galea  (2011) Natalizumab for relapsing remitting multiple sclerosis: Cochrane Database of Systematic Reviews, Oct. 5; (10):, CD007621.