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Randomized Controlled Trial
. 2018 Sep 14;18(1):143.
doi: 10.1186/s12883-018-1145-x.

Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing-remitting multiple sclerosis at year 1

Anthony Traboulsee  1 , David K B Li  2 , Mark Cascione  3 , Juanzhi Fang  4 , Fernando Dangond  5 , Aaron Miller  6
Affiliations
Randomized Controlled Trial

Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing-remitting multiple sclerosis at year 1

Anthony Traboulsee et al. BMC Neurol. .

Abstract

Background: In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing-remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1.

Methods: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed.

Results: Patients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006).

Conclusion: Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups.

Keywords: Clinical trials; Disability progression; Interferon-beta subcutaneously; MRI; No evidence of disease activity; Relapsing–remitting multiple sclerosis.

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Conflict of interest statement

Ethics approval and consent to participate

Ethics approval was obtained from appropriate Institutional Ethics Committees/Institutional Review Boards: Royal Melbourne Hospital, Melbourne, Victoria, Australia; Central Sydney Area Health Service, Camperdown, Australia; University of Western Ontario, London, Ontario, Canada; Ottawa General Hospital, Ottawa, Ontario, Canada; University of British Columbia, Vancouver, British Columbia, Canada; Lund University Hospital, Lund, Sweden; Independent Review Board, Amsterdam, Netherlands; Newcastle & North Tyneside Health Authorities, Newcastle upon Tyne, UK; University Hospital, Nottingham, UK; St. Thomas’s Hospital, London, UK; Central Oxford Research Ethics Committee, Headington, Oxford, UK; UZ Leuven, Leuven, Belgium; Limburgs Universitair Centrum, Diepenbeek, Belgium; Université catholique de Louvain, Louvain-la-Neuve, Belgium; Helsinki University Hospitals, Helsinki, Finland; Turku University Central Hospital, Turku, Finland; Würzburg University, Würzburg, Germany; Kantonsspital Basel, Basel, Switzerland; Academisch Ziekenhuis Rotterdam, Rotterdam, Netherlands; St George’s Hospital, London, UK; and Hôpitaux Universitaires de Genève, Geneva, Switzerland.. All patients gave written informed consent.

Consent for publication

Not applicable.

Competing interests

A Traboulsee has acted as a consultant for Biogen, Genzyme, Roche, and Teva, and is Principal Investigator on clinical trials for Biogen, Chugai, Genzyme, and Roche.

D Li is the Director of the UBC MS/MRI Research Group, which has been contracted to perform central analysis of MRI scans for therapeutic trials with Genzyme, Hoffmann-La Roche, Merck Serono, Nuron, Perspectives, and Sanofi-Aventis. He has acted as a consultant to Vertex Pharmaceuticals; has served on scientific advisory boards for Novartis, Nuron, and Roche; has served on a data and safety advisory board for Opexa; and has received research funding from the Canadian Institute of Health Research and Multiple Sclerosis Society of Canada.

M Cascione has received funding/honoraria for research, consultation, and speakers bureau participation from Acorda, Bayer HealthCare, Biogen, EMD Serono, Genentech, Genzyme/Sanofi, Novartis, Pfizer, Roche, and Teva Pharmaceuticals.

J Fang was an employee of EMD Serono, Inc., Rockland, MA, USA (a business of Merck KGaA, Darmstadt, Germany) at the time of writing.

F Dangond is an employee of EMD Serono, Inc., Billerica, MA, USA (a business of Merck KGaA, Darmstadt, Germany).

A Miller has received research support from Biogen, Genzyme/Sanofi, Mallinckrodt (Questcor), Novartis, and Roche/Genentech. He has acted as a consultant for Accordant Health Services (Caremark), Acorda Therapeutics, Alkermes, Biogen, EMD Serono, Sanofi Genzyme, GlaxoSmithKline, Mallinckrodt (Questcor), Novartis, and Roche/Genentech. He has served on the speakers bureau for Biogen, Genentech, and Sanofi Genzyme for unbranded disease awareness programs only.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Time to first relapse over 1 year. Assessed using Cox’s proportional hazards model adjusting for baseline EDSS score (≤3.5 vs. > 3.5), age (< 40 vs. ≥40 years), baseline number of relapses, and baseline burden of disease (total area [mm2] of all MS lesions, outlined on the PD/T2 scan). A significant difference compared with placebo was seen from Month 3 (*p < 0.05) onward with IFN β-1a 44 μg SC tiw, and from Month 6 (**p < 0.01) onward with IFN β-1a 22 μg SC tiw. CI: confidence interval; EDSS: Expanded Disability Status Scale; IFN β-1a: interferon beta-1a; MS: multiple sclerosis; PD: proton density; SC: subcutaneously; tiw: three times weekly
Fig. 2
Fig. 2
Time to 3-month confirmed disability progressiona over 1 year. Assessed using Cox’s proportional hazards model adjusting for baseline EDSS score (≤3.5 vs. > 3.5) and age (< 40 vs. ≥40 years). aEDSS progression was defined as 1-point increase in EDSS score if the baseline EDSS score was < 6.0 or a 0.5-point increase if the baseline EDSS score was ≥6.0. (EDSS scores could be > 5 if scores increased between screening and baseline). CI: confidence interval; EDSS: Expanded Disability Status Scale; IFN β-1a: interferon beta-1a; SC: subcutaneously; tiw: three times weekly
Fig. 3
Fig. 3
Proportions free from relapses, disability progression, and active T2 lesions up to 1 year. Based on a logistic regression adjusting for age (< 40 vs. ≥40 years), sex, baseline EDSS score (≤3.5 vs. > 3.5), number of relapses prior to the study within 24 months, and time since MS onset; p values indicate effect of IFN β-1a SC tiw compared with placebo. Values within parentheses are 95% CI values. Active T2 lesions obtained at 6-month and 1-year scans were included. aEndpoint is missing if the patient withdrew before the first year and did not have any relapses. bEndpoint is missing if the patient withdrew before the first year and did not have 3-month confirmed EDSS progression before withdrawal; EDSS progression was defined as 1-point increase in EDSS score if the baseline EDSS score was < 6.0 or 0.5-point increase if the baseline EDSS score was ≥6.0 (EDSS scores could be > 5 if scores increased between screening and baseline). cEndpoint is missing if the patient withdrew before the first year and did not have any active T2 lesions. CI: confidence interval; EDSS: Expanded Disability Status Scale; IFN β-1a: interferon beta-1a; OR: odds ratio; SC: subcutaneously; tiw: three times weekly
Fig. 4
Fig. 4
Year 1 effect of IFN β-1a 44 μg SC tiw in prespecified subgroups of patients. a ORs of IFN β-1a 44 μg SC tiw compared with placebo for the proportion of patients free from relapse at Year 1. Based on logistic model adjusting for age, number of pre-study relapses, baseline EDSS score, and baseline BOD as covariates. (Age, number of pre-study relapses, baseline EDSS score, and baseline BOD were not covariates used in analysis of the subgroups determined by each of these respective characteristics.) b Rate ratios for placebo compared with IFN β-1a 44 μg SC tiw for the number of active T2 lesions up to Year 1. Based on a negative binomial model adjusting for baseline BOD as covariate, and log number of scans up to Year 1 as an offset variable. Baseline BOD was not a covariate used in the analysis of the baseline BOD subgroups. Active T2 lesions up to 1 year included those lesions detected at the 6-month or 1-year MRI assessments. aMedian baseline EDSS score: 2.5. bMedian baseline BOD: 1992.5 mm2. BOD: burden of disease; CI: confidence interval; EDSS: Expanded Disability Status Scale; IFN β-1a: interferon beta-1a; MRI: magnetic resonance imaging; MS: multiple sclerosis; OR: odds ratio; SC: subcutaneously; tiw: three times weekly
Fig. 5
Fig. 5
Proportion of patients with no evidence of clinical disease activity. Based on (a) absence of all protocol-defined relapses, (b) absence of Scripps-assessed moderate and/or severe relapses, or (c) absence of severe relapses, at 1 year. Based on a logistic model adjusting for age (< 40 vs. ≥40 years), sex, baseline EDSS (≤3.5 vs. > 3.5), number of relapses in 2 years prior to screening, and time since MS onset. Values within parentheses are 95% CI values. aDefined as no relapses and no 3-month confirmed disability progression (1-point increase in EDSS score if the baseline EDSS score was < 6.0 or 0.5-point increase if the baseline EDSS score was ≥6.0). (EDSS score could be > 5 if scores increase between screening and baseline.) bDefined as no relapses and no 3-month confirmed disability progression (1-point increase in EDSS score if the baseline EDSS score was < 6.0 or 0.5-point increase if the baseline EDSS score was ≥6.0). (EDSS score could be > 5 if scores increase between screening and baseline.) Relapses are defined as Scripps-assessed moderate and/or severe. cDefined as no relapses and no 3-month confirmed disability progression (1-point increase in EDSS score if the baseline EDSS score was < 6.0 or 0.5-point increase if the baseline EDSS score was ≥6.0). (EDSS score could be > 5 if scores increase between screening and baseline.) Relapses are defined as Scripps-assessed severe. EDSS: Expanded Disability Status Scale; IFN β-1a: interferon beta-1a; OR: odds ratio; SC: subcutaneously; tiw: three times weekly
Fig. 6
Fig. 6
Proportion of patients with NEDA status up to 1 year. Based on a logistic model adjusting for age (< 40 vs. ≥40 years), sex, baseline EDSS (≤3.5 vs. > 3.5), number of relapses in 2 years prior to screening, and time since MS onset. Active T2 lesions obtained at 6-month and 1-year scans were used. aNEDA defined as no relapses, no 3-month confirmed disability progression, and no active T2 lesions over 1 year; disability progression was defined as a 1-point increase in EDSS score if the baseline EDSS score was < 6.0 or 0.5-point increase if the baseline EDSS score was ≥6.0. (EDSS score could be > 5 if scores increase between screening and baseline.). bNEDA-2, defined as NEDA with relapses defined as Scripps-assessed moderate and/or severe. cNEDA-3, defined as NEDA with relapses defined as Scripps-assessed severe. EDSS: Expanded Disability Status Scale; IFN β-1a: interferon beta-1a; NEDA: no evidence of disease activity; OR: odds ratio; SC: subcutaneously; tiw: three times weekly
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