Additional file 1: Document S1. of Peginterferon beta-1a improves MRI measures and increases the proportion of patients with no evidence of disease activity in relapsing-remitting multiple sclerosis: 2-year results from the ADVANCE randomized controlled trial

MRI acquisition parameters and analysis. (DOCX 27kb

A Network Meta-Analysis of Efficacy and Evaluation of Safety of Subcutaneous Pegylated Interferon Beta-1a versus Other Injectable Therapies for the Treatment of Relapsing-Remitting Multiple Sclerosis

<div><p>Subcutaneous pegylated interferon beta-1a (peginterferon beta-1a [PEG-IFN]) 125 μg every two or four weeks has been studied in relapsing-remitting multiple sclerosis (RRMS) patients in the pivotal Phase 3 ADVANCE trial. In the absence of direct comparative evidence, a network meta-analysis (NMA) was conducted to provide an indirect assessment of the relative efficacy, safety, and tolerability of PEG-IFN versus other injectable RRMS therapies. Systematic searches were conducted in MEDLINE, Embase, and the Cochrane Library, and conference proceedings from relevant annual symposia were hand-searched. Included studies were randomized controlled trials evaluating ≥1 first-line treatments including interferon beta-1a 30, 44, and 22 μg, interferon beta-1b, and glatiramer acetate in patients with RRMS. Studies were included based on a pre-specified protocol and extracted by a team of independent reviewers and information scientists, utilizing criteria from NICE and IQWiG. In line with ADVANCE findings, NMA results support that PEG-IFN every 2 weeks significantly reduced annualized relapse rate, and 3- and 6-month confirmed disability progression (CDP) versus placebo. There was numerical trend favoring PEG-IFN every 2 weeks versus other IFNs assessed for annualized relapse rate, and versus all other injectables for 3- and 6-month CDP (6-month CDP was significantly reduced versus IFN beta-1a 30 μg). The safety and tolerability profile of PEG-IFN beta-1a 125 μg every 2 weeks was consistent with that of other evaluated treatments. Study limitations for the NMA include variant definitions of relapse and other systematic differences across trials, assumptions that populations were sufficiently similar, and inability to perform NMA of adverse events. With similar efficacy compared to other RRMS treatments in terms of annualized relapse rate and 3- and 6-month CDP, a promising safety profile, and up to 93% reduction in number of injections (which may improve adherence), PEG-IFN every 2 weeks offers a valuable alternative treatment option for patients with RRMS.</p></div

Network Diagram for CDP3M.

<p>Abbreviations: CDP3M, 3-month confirmed disability progression; EOD, every other day; GA, glatiramer acetate; IFN, interferon; OD, once daily; PEG, pegylated; QW, once a week; TIW, 3 times a week.</p

Summary Plot Showing Relative ARR of Peginterferon Beta-1a vs Other Injectables (RR and 95% CrI).

<p>Effect size <1 indicates favorable efficacy of intervention. Abbreviations: ARR, annualized relapse rate; CrI, credible interval; EOD, every other day; GA, glatiramer acetate; IFN, interferon; OD, once daily; PEG, pegylated; QW, once a week; RR, rate ratio; TIW, 3 times a week.</p

Rank Probability of Best Outcomes by Treatment for ARR.

<p>Abbreviations: ARR, annualized relapse rate; CDP3M, 3-month confirmed disability progression; CDP6M, 6-month confirmed disability progression; EOD, every other day; GA, glatiramer acetate; IFN, interferon; μg, microgram; OD, once daily; PEG, pegylated; QW, once a week; SUCRA, surface under the cumulative ranking curve; TIW, 3 times a week</p><p>Rank Probability of Best Outcomes by Treatment for ARR.</p

Summary Plot Showing the CDP3M for Peginterferon Beta-1a vs Comparators (HR and 95% CrI).

<p>Effect size <1 indicates favorable efficacy of intervention. Abbreviations: CDP3M, 3-month confirmed disability progression; CrI, credible interval; EOD, every other day; GA, glatiramer acetate; HR, hazard ratio; IFN, interferon; OD, once daily; PEG, pegylated; QW, once a week; TIW, 3 times a week.</p

Network Diagram for CDP6M.

<p>Abbreviations: CDP6M, 6-month confirmed disability progression; EOD, every other day; GA, glatiramer acetate; IFN, interferon; OD, once daily; PEG, pegylated; QW, once a week; TIW, three times a week.</p

Network Diagram for ARR.

<p>Abbreviations: ARR, annualized relapse rate; EOD, every other day; GA, glatiramer acetate; IFN, interferon; OD, once daily; PEG, pegylated; QW, once a week; TIW, 3 times a week.</p

Annual Risk of AEs by Treatment.

<p>Abbreviations: AE, adverse event; ALT, aminotransferase; GA, glatiramer acetate; IFN, interferon; NR = not reported; PEG, pegylated.</p

Summary Plot Showing the CDP6M for Peginterferon Beta-1a vs Comparators (HR and 95% CrI).

<p>Effect size <1 indicates favorable efficacy of intervention. Abbreviations: CDP6M, 6-month confirmed disability progression; CrI, credible interval; EOD, every other day; GA, glatiramer acetate; HR, hazard ratio; IFN, interferon; OD, once daily; PEG, pegylated; QW, once a week; TIW, 3 times a week.</p