Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages

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Abstract

Background

We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-β) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs’ recommended dosages.

Methods

We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-β and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis.

Results

We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs.

Conclusions

Meta-analyses confirmed that IFN-β and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear ‘winner’ across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness.

Review registration

PROSPERO CRD42016043278.

Electronic supplementary material

The online version of this article (10.1186/s12883-018-1162-9) contains supplementary material, which is available to authorized users.

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Most cited references 9

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Defining reliable disability outcomes in multiple sclerosis.

Tomas Kalincik, Gary R Cutter, Tim Spelman … (2015)

Prevention of irreversible disability is currently the most important goal of disease modifying therapy for multiple sclerosis. The disability outcomes used in most clinical trials rely on progression of Expanded Disability Status Scale score confirmed over 3 or 6 months. However, sensitivity and stability of this metric has not been extensively evaluated. Using the global MSBase cohort study, we evaluated 48 criteria of disability progression, testing three definitions of baseline disability, two definitions of progression magnitude, two definitions of long-term irreversibility and four definitions of event confirmation period. The study outcomes comprised the rates of detected progression events per 10 years and the proportions of the recorded events persistent at later time points. To evaluate the ratio of progression frequency and stability for each criterion, we calculated the proportion of events persistent over the five subsequent years once progression was achieved. Finally, we evaluated the clinical and demographic determinants characterising progression events and, for those that regressed back to baseline, determinants of their subsequent regression. The study population consisted of 16 636 patients with the minimum of three recorded disability scores, totalling 112 584 patient-years. The progression rates varied between 0.41 and 1.14 events per 10 years, with the length of required confirmation interval as the most important determinant of the observed variance. The concordance among all tested progression criteria was only 17.3%. Regression of disability occurred in 11-34% of the progression events over the five subsequent years. The most important determinant of progression stability was the length of the confirmation period. For the most accurate set of the progression criteria, the proportions of 3-, 6-, 12- or 24-month confirmed events persistent over 5 years reached 70%, 74%, 80% and 89%, respectively. Regression post progression was more common in younger patients, relapsing-remitting disease course, and after a smaller change in disability, and was inflated by higher visit frequency. These results suggest that the disability outcomes based on 3-6-month confirmed disability progression overestimate the accumulation of permanent disability by up to 30%. This could lead to spurious results in short-term clinical trials, and the issue may be magnified further in cohorts consisting predominantly of younger patients and patients with relapsing-remitting disease. Extension of the required confirmation period increases the persistence of progression events.

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Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN).

, Mauro Bergui, P Barbero … (2002)

The three interferon beta preparations approved for treatment of relapsing-remitting multiple sclerosis (MS) differ in dose and frequency of administration. Interferon beta-1a 30 microg is administered once a week, interferon beta-1a 22 microg or 44 microg is given three times a week, and interferon beta-1b 250 microg is administered on alternate days. No clinical study directly comparing the different regimens has been published. The INCOMIN study was designed to compare the clinical and magnetic resonance imaging (MRI) benefits of on-alternate-day interferon beta-1b 250 microg with once-weekly interferon beta-1a 30 microg. INCOMIN was a 2-year, prospective, randomised, multicentre study. 188 patients with relapsing-remitting MS were assigned to interferon beta-1b (n=96) or interferon beta-1a (n=92). Primary outcome measures were the proportion of patients free from relapses and that of patients free from new proton density/T2 lesions at MRI assessment. Several secondary outcome measures were also assessed. Analysis was by intention to treat. Over 2 years, 49 (51%) individuals administered interferon beta-1b remained relapse-free compared with 33 (36%) given interferon beta-1a relative risk of relapse 0.76; 95% CI 0.59-0.9; p=0.03); and 42 (55%) compared with 19 (26%), respectively, remained free from new T2 lesions at MRI (relative risk of new T2 lesion 0.6; 0.45-0.8; p<0.0003). In both groups, the differences between the two treatments increased during the second year. There were also significant differences in favour of interferon beta-1b in most of the secondary outcome measures, including delay of confirmed disease progression. High-dose interferon beta-1b administered every other day is more effective than interferon beta-1a given once a week.

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Is Open Access

Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor.

Maria Elena Flacco, Lamberto Manzoli, Stefania Boccia … (2015)

To map the current status of head-to-head comparative randomized evidence and to assess whether funding may impact on trial design and results.

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Author and article information

Contributors

G. J. Melendez-Torres:

ORCID: http://orcid.org/0000-0002-9823-4790

+44 (0) 24765 74877 , g.melendez-torres@warwick.ac.uk

Xavier Armoiry: x.armoiry@warwick.ac.uk

Rachel Court: r.a.court@warwick.ac.uk

Jacoby Patterson: jacobyvpatterson@gmail.com

Alan Kan: wunfikan@gmail.com

Peter Auguste: p.auguste@warwick.ac.uk

Jason Madan: j.j.madan@warwick.ac.uk

Carl Counsell: carl.counsell@abdn.ac.uk

Olga Ciccarelli: o.ciccarelli@ucl.ac.uk

Aileen Clarke: aileen.clarke@warwick.ac.uk

Journal

Journal ID (nlm-ta): BMC Neurol

Journal ID (iso-abbrev): BMC Neurol

Title: BMC Neurology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2377

Publication date (Electronic): 3 October 2018

Publication date PMC-release: 3 October 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 162

Affiliations

[1 ]ISNI 0000 0000 8809 1613, GRID grid.7372.1, Warwick Evidence, Warwick Medical School, , University of Warwick, ; Coventry, CV4 7AL UK

[2 ]Independent research consultant, Windsor, UK

[3 ]ISNI 0000 0004 1936 7291, GRID grid.7107.1, Institute of Applied Health Sciences, , University of Aberdeen, ; Aberdeen, UK

[4 ]ISNI 0000000121901201, GRID grid.83440.3b, Queen Square Multiple Sclerosis Centre, , University College London Institute of Neurology, ; London, UK

[5 ]ISNI 0000 0004 0495 5357, GRID grid.485385.7, National Institute for Health Research University College London Hospitals Biomedical Research Centre, ; London, UK

Author information

G. J. Melendez-Torres http://orcid.org/0000-0002-9823-4790

Article

Publisher ID: 1162

DOI: 10.1186/s12883-018-1162-9

PMC ID: 6169084

PubMed ID: 30285675

SO-VID: 359fc147-f6f8-4c24-8477-7e83c8076aeb

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 17 January 2018

Date accepted : 21 September 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000664, Health Technology Assessment Programme;

Award ID: ID809

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: multiple sclerosis,clinically isolated syndrome,beta-interferon,glatiramer acetate,systematic review,economic evaluation

Data availability:

ScienceOpen disciplines: Neurology

Keywords: multiple sclerosis, clinically isolated syndrome, beta-interferon, glatiramer acetate, systematic review, economic evaluation

Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 9

Defining reliable disability outcomes in multiple sclerosis.

Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN).

Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor.

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