Disease-modifying treatments for relapsing remitting multiple sclerosis, including rituximab. A health technology assessment.
Health technology assessment
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We have systematically collected and reviewed the evidence for clinical effectiveness and general safety issues for disease modifying treatments for relapsing remitting multiple sclerosis, synthesised evidence from randomised controlled trials and non-randomised registry-based studies using net-work meta-regression, and carefully interpreted the findings.
Key message
We have systematically collected and reviewed the evidence for clinical effectiveness and general safety issues for disease modifying treatments for relapsing remitting multiple sclerosis, synthesised evidence from randomised controlled trials and non-randomised registry-based studies using network meta-regression, and carefully interpreted the findings. We included rituximab in our analysis as it is used off-label for the treatment of patients with RRMS, even though it does not hold marketing authorisation for RRMS.
We included 35 randomised controlled trials and 11 non-randomised registry-based studies, with a total of almost 30 000 patients. We compared estimates of our predefined outcomes from meta-analysis of randomised controlled trials, of non-randomised registry-based studies, the network meta-regression, and other network meta-analytical models, and judged that the estimates are mutually consistent in most cases, and that where there is inconsistency, it could be explained.
Based on the available evidence and the meta-analysis used: alemtuzumab is most likely to be the best treatment with respect to annual relapse rate; ocrelizumab and alemtuzumab are equally likely to be the best treatments with respect to risk of disability progression. Further, we estimate that rituximab is likely to have the lowest risk of serious adverse events and treatment withdrawal due to adverse events. However, the evidence for rituximab is from one small randomised trial of short duration and one non-randomised study, making this finding uncertain.
Summary
Background
Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration (1). It affects axons in the brain and spinal cord by damaging the myelin sheath that covers the axon part of the nerve cells. The myelin sheath protects and aids signal transduction in the CNS (1).
MS is classified into different categories according to course of disease (2). The relapsing-remitting course (RRMS) is the most common, characterised by relapses, followed by complete or partial remission, with stable neurological status until eventually new relapses. Repeated relapses increases the risk of developing a secondary progressive (SPMS) course. A progressive course is characterised by steadily increasing objectively documented neurological disability independent of relapses. Primary progressive multiple sclerosis, PPMS, (a progressive course from disease onset) and secondary progressive multiple sclerosis, SPMS (a progressive course following an initial relapsing-remitting course) are distinguished. Disease-modifying treatments (DMT) are the standard treatment for patients with RRMS.
NIPH conducted a Health Technology Assessment (HTA), including a network meta-analysis, on 11 different medicines for RRMS in 2016 (3). An updated report was commissioned in 2018, requesting that two new medicines with marketing authorisation for RRMS (cladribine and ocrelizumab), as well as rituximab (used off-label for the indication) were added to those included in the 2016 report. Rituximab holds marketing authorisation for several auto immune diseases, such as rheumatoid arthritis, B cell non-Hodgins's lymphomas and a few other types of cancer. Interferons were not included due to low priority use.
Results of safety and clinical effectiveness
Considering all combinations of dose, regimen and method of administration for the treatments of interest and of the controls or comparators reported in the literature, we conducted network meta-analyses of up to 29 different treatments for each outcome. We only present results for the treatments (i.e., combinations of active drug, dose, regimen, and method of administration) considered relevant for Norwegian clinical practice. In addition, we present results on one selected interferon (IFN) for reference purposes. We summarized the results above. In the chapter Clinical effectiveness and safety, we present effect estimates for each comparison as well as a ranking list of the included interventions.
Below we present the results as radar plots that show, for each treatment, probabilities that the treatment is superior with respect to the selected outcomes. Treatments with larger polygons are likely to be better than treatments with smaller polygons. Not all outcomes were available for all treatments.
Method
We have performed a Health Technology Assessment in accordance with the handbook "Slik oppsummerer vi forskning", by Norwegian Institute of Public Health (4).
Literature
We performed several systematic searches, described in Methods (pp 75). We included both randomised controlled trials (RCT) and registry based non-randomised studies (NRS), 35 and 11 articles, respectively.
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Population |
Men and women aged 18 and above diagnosed with multiple sclerosis who were treatment naïve or not. The eligible multiple sclerosis diagnoses were relapse-remitting multiple sclerosis (RRMS) at the start of the trial. |
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Interventions |
All disease-modifying treatments approved by the National System for Managed Introduction of New Health Technologies within the Specialist Health Service, including ocrelizumab, except interferons and peg-interferon (due to low priority use). In addition, rituximab was included as an off-label medicine for the indication. |
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Comparators |
All included interventions as well as interferons or placebo. |
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Outcome |
· Annualised clinical relapse rate (ARR) · Risk of confirmed disability progression, defined as a sustained increase in patient’s EDSS score (scale from 0.5 to 10). (Typically assessed as disability progression sustained over 12 or 24 weeks (12- or 24-CDP). We chose to estimate a single disability progression outcome, and used the longest confirmation time when a study reported more than one.) · Change in EDSS score · Risk of new lesions (detected using Magnetic Resonance Imaging (MRI)) · Risk of mortality · Risk of serious adverse events (SAE) · Risk of treatment withdrawal due to adverse events (AE) · Risk of selected serious adverse events (cancer, progressive multifocal leukoencephalopathy (PML), thyroid diseases, infections) Annualised relapse rate and confirmed disability progression were the clinical effect estimates used in the health economic evaluation. |
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Study design |
Randomised controlled trials and non-randomised controlled trials (limited to include studies using national- or hospital-based registers, or chart reviews as data source). |
Data analyses
We performed network meta-analyses to facilitate multiple treatment comparison via synthesis of all available evidence. We used the GRADE approach for network meta-analysis to assess the certainty of the effect estimates.
