Authors' objectives: 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.

Authors' results and conclusions: 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.

Authors' methods: We have performed a Health Technology Assessment in accordance with the handbook "Slik oppsummerer vi forskning", by Norwegian Institute of Public Health. Literature: We performed several systematic searches, described in the handbook. We included both randomised controlled trials (RCT) and registry based non-randomised studies (NRS), 35 and 11 articles, respectively. Inclusion criteria: 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. 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. Comparators: All included interventions as well as interferons or placebo. 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. 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.

Project Status: Completed

Year Published: 2019

URL for published report: https://www.fhi.no/en/publ/2019/Disease-modifying-treatments-for-relapsing-remitting-multiple-sclerosis-including-rituximab.-A-health-technology-assessment./

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Norway

Organisation Name: Norwegian Institute of Public Health

Contact Address: P.O. Box 222 Skoyen, N-0123, Oslo