The 11-year long-term follow-up study from the randomized BENEFIT CIS trial

Ludwig Kappos, Gilles Edan, Mark S Freedman, Xavier Montalbán, Hans-Peter Hartung, Bernhard Hemmer, Edward J Fox, Frederik Barkhof, Sven Schippling, Andrea Schulze, Dirk Pleimes, Christoph Pohl, Rupert Sandbrink, Gustavo Suarez, Eva-Maria Wicklein, BENEFIT Study Group, S Strasser-Fuchs, T Berger, K Vass, C Sindic, B Dubois, D Dive, V Delvaux, J Debruyne, L Metz, G Rice, M Kremenchutzky, P Duquette, Y Lapierre, M Freedman, A Traboulsee, P O'Connor, P Stourac, R Talab, M Valis, O Zapletalova, I Kovarova, E Medova, J Fiedler, J Frederiksen, B Brochet, T Moreau, P Vermersch, J Pelletier, G Edan, M Clanet, B David, P Clavelou, C Lebrun-Frenay, O Gout, M Kallela, T Pirttila, J Ruutiainen, Jp Erälinna, K Koivisto, M Reunanen, I Keskinarkus, I Elovaara, A Villringer, H Altenkirch, L Bauer, M Ghazi, C Pohl, K Wessel, H-P Hartung, W Steinke, B Kieseier, H Kolmel, P Oschmann, M Berghoff, R Diem, B Kitze, A Dressel, F Hoffmann, K Baum, S Jung, H Felicitas Petereit, D Reske, M Sailer, J Kohler, B Tackenberg, L Klotz, R Hohlfeld, T Kuempfel, K-H Henn, A Steinbrecher, K Angstwurm, H Tumani, R Gold, P Rieckmann, C Kleinschnitz, R Komoly, G Gacs, G Jakab, G Panczel, T Csepany, L Csiba, L Vecsei, A Miller, D Karussis, J Chapman, A Ghezzi, G Comi, V Martinelli, P Gallo, V Cosi, R Bergamaschi, L Durelli, P Cavalla, Ch Polman, F Barkhof, B Uitdehaag, B Anten, R Hupperts, L Visser, K-M Myhr, A Szczudlik, K Selmaj, Z Stelmasiak, H Barosik-Psujek, R Podemski, Z Maciejek, S Wawrzyniak, L Cunha, S Sega-Jazbec, X Montalbán, T Arbizu, A Saiz Hinarejos, J Barcena, S Martínez Yélamos, R Arroyo, O Fernandez, G Izquierdo Ayuso, B Casanova I Estruch, J Lycke, L Kappos, A de Vera, S Wu, E-W Radue, J Kuhle, H Mattle, K Beer, R Coleman, Dh Miller, J Chataway, J O'Riordan, S Howell, G Edan, M Freedman, H-P Hartung, L Kappos, Dh Miller, X Montalbán, Ch Polman, L Bauer, M Ghazi, C Pohl, Ch Polman, F Barkhof, B Uitdehaag, L Kappos, A de Vera, S Wu, F Barkhof, E-W Radue, Hf McFarland, J Kesselring, Aj Petkau, Kv Toyka, Ludwig Kappos, Gilles Edan, Mark S Freedman, Xavier Montalbán, Hans-Peter Hartung, Bernhard Hemmer, Edward J Fox, Frederik Barkhof, Sven Schippling, Andrea Schulze, Dirk Pleimes, Christoph Pohl, Rupert Sandbrink, Gustavo Suarez, Eva-Maria Wicklein, BENEFIT Study Group, S Strasser-Fuchs, T Berger, K Vass, C Sindic, B Dubois, D Dive, V Delvaux, J Debruyne, L Metz, G Rice, M Kremenchutzky, P Duquette, Y Lapierre, M Freedman, A Traboulsee, P O'Connor, P Stourac, R Talab, M Valis, O Zapletalova, I Kovarova, E Medova, J Fiedler, J Frederiksen, B Brochet, T Moreau, P Vermersch, J Pelletier, G Edan, M Clanet, B David, P Clavelou, C Lebrun-Frenay, O Gout, M Kallela, T Pirttila, J Ruutiainen, Jp Erälinna, K Koivisto, M Reunanen, I Keskinarkus, I Elovaara, A Villringer, H Altenkirch, L Bauer, M Ghazi, C Pohl, K Wessel, H-P Hartung, W Steinke, B Kieseier, H Kolmel, P Oschmann, M Berghoff, R Diem, B Kitze, A Dressel, F Hoffmann, K Baum, S Jung, H Felicitas Petereit, D Reske, M Sailer, J Kohler, B Tackenberg, L Klotz, R Hohlfeld, T Kuempfel, K-H Henn, A Steinbrecher, K Angstwurm, H Tumani, R Gold, P Rieckmann, C Kleinschnitz, R Komoly, G Gacs, G Jakab, G Panczel, T Csepany, L Csiba, L Vecsei, A Miller, D Karussis, J Chapman, A Ghezzi, G Comi, V Martinelli, P Gallo, V Cosi, R Bergamaschi, L Durelli, P Cavalla, Ch Polman, F Barkhof, B Uitdehaag, B Anten, R Hupperts, L Visser, K-M Myhr, A Szczudlik, K Selmaj, Z Stelmasiak, H Barosik-Psujek, R Podemski, Z Maciejek, S Wawrzyniak, L Cunha, S Sega-Jazbec, X Montalbán, T Arbizu, A Saiz Hinarejos, J Barcena, S Martínez Yélamos, R Arroyo, O Fernandez, G Izquierdo Ayuso, B Casanova I Estruch, J Lycke, L Kappos, A de Vera, S Wu, E-W Radue, J Kuhle, H Mattle, K Beer, R Coleman, Dh Miller, J Chataway, J O'Riordan, S Howell, G Edan, M Freedman, H-P Hartung, L Kappos, Dh Miller, X Montalbán, Ch Polman, L Bauer, M Ghazi, C Pohl, Ch Polman, F Barkhof, B Uitdehaag, L Kappos, A de Vera, S Wu, F Barkhof, E-W Radue, Hf McFarland, J Kesselring, Aj Petkau, Kv Toyka

Abstract

Objective: To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay.

Methods: Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayed treatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients on placebo could switch to interferon beta-1b or another treatment. Eleven years after randomization, patients were reassessed.

Results: Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible at participating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk of CDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p = 0.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931 [253, 3,296]; p = 0.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p = 0.0018). Only 25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiple sclerosis. Expanded Disability Status Scale scores remained low and stable, with no difference between treatment arms (median [Q1, Q3]: 2.0 [1.0, 3.0]). The early-treatment group had better Paced Auditory Serial Addition Task-3 total scores (p = 0.0070). Employment rates remained high, and health resource utilization tended to be low in both groups. MRI metrics did not differ between groups.

Conclusions: Although the delay in treatment was relatively short, several clinical outcomes favored earlier treatment. Along with low rates of disability and disease progression in both groups, this supports the value of treatment at CIS.

Clinicaltrialsgov identifier: NCT01795872.

Classification of evidence: This study provides Class IV evidence that early compared to delayed treatment prolongs time to CDMS in CIS after 11 years.

© 2016 American Academy of Neurology.

Figures

Figure 1. Study profile for the entire…
Figure 1. Study profile for the entire BENEFIT Study
aIncludes one patient randomized to receive interferon beta-1b but treated with placebo. bIncludes one patient randomized to receive placebo but treated with interferon beta-1b. cIncludes one patient entered into the BENEFIT follow-up study after premature discontinuation of the BENEFIT Study. dFour lost to follow-up, 2 missing data, 1 noncompliance, 1 treatment failure, 2 refused final visit. eThree lost to follow-up, 1 relocated away from site, 1 pregnancy, 1 unable to attend visit because of job. fTo be eligible for the 11-year follow-up, patients only needed to be randomized and treated in the original BENEFIT Study (i.e., they did not need to be included in the previous BENEFIT analyses). BENEFIT = Betaferon/Betaseron in Newly Emerging MS for Initial Treatment; CDMS = clinically definite multiple sclerosis; DMT = disease-modifying therapy.
Figure 2. Kaplan-Meier estimates of probability of…
Figure 2. Kaplan-Meier estimates of probability of CDMS (A), ARR (B), and EDSS scores (C) in the BENEFIT 11 population
aOne patient in the early-treatment arm was excluded from this analysis because diagnosis of CDMS was unclear. Risk of conversion to CDMS was significantly lower for the early-treatment group compared with the delayed-treatment group. Overall ARR was significantly lower in the early-treatment group compared with the delayed-treatment group. As expected, EDSS scores increased from baseline to year 11, but they tended to remain relatively low for both groups. *p < 0.05; **p < 0.01. ARR = annualized relapse rate; BENEFIT = Betaferon/Betaseron in Newly Emerging MS for Initial Treatment; CDMS = clinically definite multiple sclerosis; CI = confidence interval; EDSS = Expanded Disability Status Scale; HR = hazard ratio; RR = risk ratio.
Figure 3. Mean PASAT-3 total score from…
Figure 3. Mean PASAT-3 total score from baseline to year 11
Over the entire study period, the mean PASAT-3 total score was higher in the early- than the delayed-treatment group (p = 0.0070). PASAT-3 = Paced Auditory Serial Addition Task–3.

References

    1. Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–1517.
    1. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol 2012;11:157–169.
    1. Miller DH, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis: part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4:281–288.
    1. Comi G, Filippi M, Barkhof F, et al. . Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001;357:1576–1582.
    1. Comi G, Martinelli V, Rodegher M, et al. . Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009;374:1503–1511.
    1. Edan G, Kappos L, Montalban X, et al. . Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT. J Neurol Neurosurg Psychiatry 2014;85:1183–1189.
    1. Jacobs LD, Beck RW, Simon JH, et al. . Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000;343:898–904.
    1. Kappos L, Polman CH, Freedman MS, et al. . Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006;67:1242–1249.
    1. Kappos L, Freedman MS, Polman CH, et al. . Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT Study. Lancet 2007;370:389–397.
    1. Kappos L, Freedman MS, Polman CH, et al. . Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 2009;8:987–997.
    1. Kinkel RP, Dontchev M, Kollman C, Skaramagas TT, O'Connor PW, Simon JH. Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance. Arch Neurol 2012;69:183–190.
    1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983;33:1444–1452.
    1. Fischer JS, Rudick RA, Cutter GR, Reingold SC. The Multiple Sclerosis Functional Composite Measure (MSFC): an integrated approach to MS clinical outcome assessment. National MS Society Clinical Outcomes Assessment Task Force. Mult Scler 1999;5:244–250.
    1. EuroQol Group. EuroQol—a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199–208.
    1. Cella DF, Dineen K, Arnason B, et al. . Validation of the Functional Assessment of Multiple Sclerosis quality of life instrument. Neurology 1996;47:129–139.
    1. Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing depressive symptoms in five psychiatric populations: a validation study. Am J Epidemiol 1977;106:203–214.
    1. Penner IK, Raselli C, Stocklin M, Opwis K, Kappos L. The FSMC (Fatigue Scale for Motor and Cognitive Functions): a new patient-reported outcome measure for cognitive and motor fatigue in multiple sclerosis. Mult Scler 2006;12(suppl 1):S151.
    1. Penner IK, Raselli C, Stocklin M, Opwis K, Kappos L, Calabrese P. The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler 2009;15:1509–1517.
    1. Parmenter BA, Weinstock-Guttman B, Garg N, Munschauer F, Benedict RH. Screening for cognitive impairment in multiple sclerosis using the Symbol Digit Modalities Test. Mult Scler 2007;13:52–57.
    1. Smith A. Symbol Digit Modalities Test (SDMT) Manual (Revised). Los Angeles: Western Psychological Services; 1982.
    1. Lechner-Scott J, Kappos L, Hofman M, et al. . Can the Expanded Disability Status Scale be assessed by telephone? Mult Scler 2003;9:154–159.
    1. Collins C, Ivry B, Bowen JD, et al. . A comparative analysis of Patient-Reported Expanded Disability Status Scale tools. Mult Scler Epub 2015 Nov 12. pii: 1352458515616205.
    1. Poser CM, Paty DW, Scheinberg L, et al. . New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–231.
    1. Karampampa K, Gustavsson A, Miltenburger C, Kindundu CM, Selchen DH. Treatment experience, burden, and unmet needs (TRIBUNE) in multiple sclerosis: the costs and utilities of MS patients in Canada. J Popul Ther Clin Pharmacol 2012;19:e11–e25.
    1. Karampampa K, Gustavsson A, Miltenburger C, Eckert B. Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from five European countries. Mult Scler 2012;18(2 suppl):7–15.
    1. Scalfari A, Neuhaus A, Daumer M, Muraro PA, Ebers GC. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry 2014;85:67–75.
    1. Eriksson M, Andersen O, Runmarker B. Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 2003;9:260–274.
    1. Tremlett H, Yinshan Z, Devonshire V. Natural history of secondary-progressive multiple sclerosis. Mult Scler 2008;14:314–324.
    1. Rovaris M, Confavreux C, Furlan R, Kappos L, Comi G, Filippi M. Secondary progressive multiple sclerosis: current knowledge and future challenges. Lancet Neurol 2006;5:343–354.
    1. Tremlett H, Zhao Y, Rieckmann P, Hutchinson M. New perspectives in the natural history of multiple sclerosis. Neurology 2010;74:2004–2015.
    1. Steinvorth SM, Rover C, Schneider S, Nicholas R, Straube S, Friede T. Explaining temporal trends in annualised relapse rates in placebo groups of randomised controlled trials in relapsing multiple sclerosis: systematic review and meta-regression. Mult Scler 2013;19:1580–1586.
    1. Comi G, De SN, Freedman MS, et al. . Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012;11:33–41.
    1. Comi G, Martinelli V, Rodegher M, et al. . Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome. Mult Scler 2013;19:1074–1083.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅