BENEFIT Study (Betaferon® / Betaseron® in Newly Emerging Multiple Sclerosis for Initial Treatment) and BENEFIT Follow-up Study

Open-label, Multi-center Phase III Extension of the Double-blind, Placebo-controlled BENEFIT Study (no. 92012/304747) to Obtain Long-term Follow-up Data of Patients With Clinically Definite Multiple Sclerosis (MS) and Patients With a First Demyelinating Event Suggestive of MS Treated With 8 MIU (250 µg) Interferon Beta-1b (Betaferon® / Betaseron®) Given Subcutaneously Every Other Day for at Least 36 Months.

This study will primarily compare the long-term effects of an early and continued treatment with Betaferon/Betaseron (patients who were treated with active medication during the double-blind BENEFIT study) to treatment initiated either after Clinically Definite Multiple Sclerosis (CDMS) has been diagnosed or after two years (those patients who were treated with placebo during the double-blind BENEFIT study).

Analyses are based on the integrated data of the initial BENEFIT study and this follow-up study.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Interferon beta-1b (Betaseron, BAY86-5046); Drug: Interferon beta-1b (Betaseron, BAY86-5046)

Detailed Description

The study has previously been posted by Schering AG, Germany. Schering AG, Germany has been renamed to Bayer HealthCare Pharmaceuticals Inc..

Bayer HealthCare Pharmaceuticals Inc. is the sponsor of the trial.

• Study Type: Interventional
• Enrollment (Actual): 468
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
  • Innsbruck, Austria, 6020
  • Wien, Austria, 1090
• Belgium
  • Bruxelles, Belgium, 1200
  • Gent, Belgium, 9000
  • Leuven, Belgium, 3000
  • Liège 1, Belgium, 4000
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T 2B5
  • Ontario
    • London, Ontario, Canada, N6A 5A5
    • Ottawa, Ontario, Canada, K1H 8L6
    • Toronto, Ontario, Canada, M5B 1W8
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
• Czech Republic
  • Brno, Czech Republic, 63900
  • Hradec Kralove, Czech Republic, 50005
  • Ostrava, Czech Republic, 70852
  • Plzen, Czech Republic, 30460
  • Prag, Czech Republic, 10034
  • Prag, Czech Republic, 12808
• Denmark
  • Glostrup, Denmark, 2600
• Finland
  • Helsinki, Finland, 00100
  • Kuopio, Finland, 70210
  • Oulu, Finland, 90029
  • Seinäjoki, Finland, 60220
  • Tampere, Finland, 33521
  • Turku, Finland, 20100
• France
  • Clermont ferrand, France, 63003
  • Dijon, France, 21033
  • Lille, France, 59037
  • Nancy, France, 54035
  • Nice, France, 06000
  • Paris, France, 75019
  • Toulouse, France, 31059
  • Bretagne
    • Rennes, Bretagne, France, 35038
  • Gironde
    • Bordeaux, Gironde, France, 33076
• Germany
  • Berlin, Germany, 12200
  • Berlin, Germany, 13585
  • Baden-Württemberg
    • Ulm, Baden-Württemberg, Germany, 89081
  • Bayern
    • München, Bayern, Germany, 81377
    • Regensburg, Bayern, Germany, 93053
    • Würzburg, Bayern, Germany, 97080
  • Brandenburg
    • Hennigsdorf, Brandenburg, Germany, 16761
  • Hessen
    • Gießen, Hessen, Germany, 35392
    • Marburg, Hessen, Germany, 35039
    • Offenbach, Hessen, Germany, 63069
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17475
  • Niedersachsen
    • Braunschweig, Niedersachsen, Germany, 38126
    • Göttingen, Niedersachsen, Germany, 37099
  • Nordrhein-Westfalen
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40225
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40479
    • Köln, Nordrhein-Westfalen, Germany, 50931
    • Münster, Nordrhein-Westfalen, Germany, 48149
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55101
  • Saarland
    • Homburg, Saarland, Germany, 66424
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 06120
    • Magdeburg, Sachsen-Anhalt, Germany, 39120
  • Thüringen
    • Erfurt, Thüringen, Germany, 99089
• Hungary
  • Budapest, Hungary, 1145
  • Budapest, Hungary, 1204
  • Budapest, Hungary, 1076
  • Debrecen, Hungary, 4032
  • Csongrad
    • Szeged, Csongrad, Hungary, 6720
• Israel
  • Haifa, Israel, 34362
  • Tel Hashomer, Israel, 52621
• Italy
  • Milano, Italy, 20132
  • Padova, Italy, 35128
  • Pavia, Italy, 27100
  • Torino, Italy, 10126
  • Varese
    • Gallarate, Varese, Italy, 21013
• Netherlands
  • Sittard, Netherlands, 6131 BK
  • Tilburg, Netherlands, 5022 GC
• Norway
  • Bergen, Norway, N-5021
• Poland
  • Bydgoszcz, Poland, 85681
  • Krakow, Poland, 31503
  • Lodz, Poland, 90153
  • Lublin, Poland, 20090
  • Wroclaw, Poland, 50420
• Portugal
  • Coimbra, Portugal, 3000
• Slovenia
  • Lubljana, Slovenia, 1525
• Spain
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08035
  • Madrid, Spain, 28040
  • Malaga, Spain, 29010
  • Sevilla, Spain, 41071
  • Valencia, Spain, 46026
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
• Sweden
  • Göteborg, Sweden, 41685
• Switzerland
  • St. Gallen, Switzerland, 9007
  • Basel-Stadt
    • Basel, Basel-Stadt, Switzerland, 4031
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
  • London, United Kingdom, W6 8RF
  • Sheffield, United Kingdom, S10 2JF
  • Scotland
    • Dundee, Scotland, United Kingdom, DD1 9SY

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients who have reached scheduled end of study in BENEFIT, either by developing CDMS or by completing 24 months

Exclusion Criteria:

• No participation in the initial BENEFIT study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Initial IFNB-1b (Interferon beta-1b); Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase	Drug: Interferon beta-1b (Betaseron, BAY86-5046); Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase; Drug: Interferon beta-1b (Betaseron, BAY86-5046); Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)
Experimental: Initial Placebo; Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)	Drug: Interferon beta-1b (Betaseron, BAY86-5046); Initial Betaferon/Betaseron treatment (Interferon beta-1b, IFNB-1b), 250 ug administered s.c. (subcutaneous) every other day, continued in Follow-up phase; Drug: Interferon beta-1b (Betaseron, BAY86-5046); Initial placebo treatment; Betaferon/Betaseron, 250 ug administered s.c. (subcutaneous) every other day offered in Follow-up phase (= this trial)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With CDMS at Selected Points in Time	CDMS could be reached due to a qualifying relapse or sustained progression of 1.5 points on the expanded disability status scale (EDSS) as compared to the lowest EDSS obtained during screening or Day 1. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in MS in 8 functional systems, values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on an ordinal scale. Time to CDMS = date of CDMS - date of Day 1 + 1 or time to CDMS = date of last clinical visit - date of Day 1 + 1 (right-censored)	up to 60 months after start of treatment
Time to Confirmed Expanded Disability Status Scale (EDSS) Progression Represented by Kaplan-Meier Estimates of the Cumulative Percentage of Participants With Confirmed EDSS Progression at Selected Points in Time	EDSS progression was defined as an increase in the expanded disability status scale (EDSS) of 1.0 point compared to the lowest EDSS score obtained during the screening or baseline visit, if this score was <= 5.5. A confirmed EDSS progression status was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. The EDSS scale is a method of quantifying disability in multiple sclerosis in eight functional systems and values vary between 0="normal neurological examination" and 10="death due to MS" measured in half-points on a scale.	up to 60 months after start of treatment
Functional Assessment of Multiple Sclerosis (FAMS) Trial Outcome Index (TOI) at Month 60	As an index of health related quality of life in people diagnosed with MS, the FAMS Trial Outcome Index covers overall physical health (sum of sub-scale scores Mobility, Symptoms, Thinking/Fatigue, Additional Concerns) with a score range from 0 to 148. A higher score reflects a higher overall physical health as reported by patients.	60 months after start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse-based Efficacy Domain: Time to Multiple Sclerosis (MS) According to McDonald Criteria	MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space and dissemination in time were established by MRI-criteria or a new relapse. Time to McDonald MS is the difference of date of McDonald MS to the date of Day 1 + 1. For subjects without McDonald MS, time to McDonald MS is the difference from the maximum (date of last magnetic resonance imaging scan, date of last clinical visit) to the date of Day 1 + 1 (right-censored observation).	up to 60 months after start of treatment
Relapse-based Efficacy Domain: Hazard Ratio for Recurrent Relapses	A relapse was defined as the appearance of a new neurological abnormality or the reappearance of a neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event. The time to the onset of recurrent relapses was determined for each subject according to the counting process representation for recurrent events. Time to a relapse was right-censored if a relapse-risk period ended without relapse. Based on the Andersen-Gill model the hazard ratio for recurrent relapses was estimated. Annualized relapse rates are provided as another outcome measure.	up to 60 months after start of treatment
Relapse-based Efficacy Domain (Supportive): Annualized Relapse Rate	The annualized relapse rate is defined as total number of relapses up to month 60 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all participants) in years.	up to 60 months after start of treatment
Disability-based Efficacy Domain: Multiple Sclerosis Functional Composite (MSFC) at Month 60	The MSFC score consists of three sub-tests (Timed-25-Foot-Walk, 9-Hole-Peg-Test, 3" Paced Auditory Serial Addition Test [PASAT]). Standardized results (Z-scores) of the sub-tests and the overall MSFC Z-score as an average of the three Z-scores were derived using baseline data pooled over both treatment arms as reference population. Higher Z-scores reflect a better neurological status.	60 months after start of treatment
MRI (Magnet-Resonance Imaging)-Based Efficacy Domain: Cumulative Number of Newly Active Lesions at Month 60	Newly active lesions are defined as displaying either new Gadolinium (Gd)-enhancement on T1-weighted scans or non-enhancement on T1-weighted scan but new on T2-weighted scan. The numbers of newly active lesions on yearly MRI scans were summed up to the cumulative number.	up to 60 months after start of treatment
MRI-based Efficacy Domain: Absolute Change of T2 Lesion Volume From Screening MRI to Month 60	Absolute change of T2 lesion volume from screening MRI to month 60 was calculated as T2 lesion volume at month 60 minus T2 lesion volume at screening.	60 months after start of treatment
MRI-based Efficacy Domain: Absolute Change of Volume of Black Holes From Screening MRI to Month 60	Absolute change of volume of black holes from screening MRI to month 60 was calculated as volume of black holes at month 60 minus volume of black holes at screening.	60 months after start of treatment
MRI-based Efficacy Domain: Percentage Change of Brain Volume From Screening MRI to Month 60	Two-timepoint percentage brain volume change was estimated with Structural Image Evaluation, using Normalisation, of Atrophy (SIENA) software. The measurements describe the percentage change from screening in brain volume at month 60.	60 months after start of treatment

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Edan G, Kappos L, Montalban X, Polman CH, Freedman MS, Hartung HP, Miller D, Barkhof F, Herrmann J, Lanius V, Stemper B, Pohl C, Sandbrink R, Pleimes D; BENEFIT Study Group. Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT. J Neurol Neurosurg Psychiatry. 2014 Nov;85(11):1183-9. doi: 10.1136/jnnp-2013-306222. Epub 2013 Nov 11.
• Nagtegaal GJ, Pohl C, Wattjes MP, Hulst HE, Freedman MS, Hartung HP, Miller D, Montalban X, Kappos L, Edan G, Pleimes D, Beckman K, Stemper B, Polman CH, Sandbrink R, Barkhof F. Interferon beta-1b reduces black holes in a randomised trial of clinically isolated syndrome. Mult Scler. 2014 Feb;20(2):234-42. doi: 10.1177/1352458513494491. Epub 2013 Jul 10.
• Penner IK, Stemper B, Calabrese P, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Pleimes D, Lanius V, Pohl C, Kappos L, Sandbrink R. Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. Mult Scler. 2012 Oct;18(10):1466-71. doi: 10.1177/1352458512442438. Epub 2012 Apr 4.
• Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Radu EW, Metzig C, Bauer L, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. 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 Nov;8(11):987-97. doi: 10.1016/S1474-4422(09)70237-6. Epub 2009 Sep 10.
• Hartung HP, Freedman MS, Polman CH, Edan G, Kappos L, Miller DH, Montalban X, Barkhof F, Petkau J, White R, Sahajpal V, Knappertz V, Beckmann K, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Interferon beta-1b-neutralizing antibodies 5 years after clinically isolated syndrome. Neurology. 2011 Aug 30;77(9):835-43. doi: 10.1212/WNL.0b013e31822c90d7. Epub 2011 Aug 17. Erratum In: Neurology. 2011 Sep 27;77(13):1317.
• Freedman MS, Metzig C, Kappos L, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Yarden J, Spector L, Fire E, Dotan N, Schwenke S, Lanius V, Sandbrink R, Pohl C. Predictive nature of IgM anti-alpha-glucose serum biomarker for relapse activity and EDSS progression in CIS patients: a BENEFIT study analysis. Mult Scler. 2012 Jul;18(7):966-73. doi: 10.1177/1352458511432327. Epub 2011 Dec 19.
• Waschbisch A, Sandbrink R, Hartung HP, Kappos L, Schwab S, Pohl C, Wiendl H. Evaluation of soluble HLA-G as a biomarker for multiple sclerosis. Neurology. 2011 Aug 9;77(6):596-8. doi: 10.1212/WNL.0b013e318228c14d. Epub 2011 Jul 27. No abstract available.
• Moraal B, Pohl C, Uitdehaag BM, Polman CH, Edan G, Freedman MS, Hartung HP, Kappos L, Miller DH, Montalban X, Lanius V, Sandbrink R, Barkhof F. Magnetic resonance imaging predictors of conversion to multiple sclerosis in the BENEFIT study. Arch Neurol. 2009 Nov;66(11):1345-52. doi: 10.1001/archneurol.2009.243.
• Polman C, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Selmaj K, Uitdehaag BM, Dahms S, Bauer L, Pohl C, Sandbrink R; BENEFIT investigators. Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b. J Neurol. 2008 Apr;255(4):480-7. doi: 10.1007/s00415-007-0733-2. Epub 2007 Nov 15.
• Caloyeras JP, Zhang B, Wang C, Eriksson M, Fredrikson S, Beckmann K, Knappertz V, Pohl C, Hartung HP, Shah D, Miller JD, Sandbrink R, Lanius V, Gondek K, Russell MW. Cost-effectiveness analysis of interferon beta-1b for the treatment of patients with a first clinical event suggestive of multiple sclerosis. Clin Ther. 2012 May;34(5):1132-44. doi: 10.1016/j.clinthera.2012.03.004. Epub 2012 Apr 27.
• Nielsen JM, Pohl C, Polman CH, Barkhof F, Freedman MS, Edan G, Miller DH, Bauer L, Sandbrink R, Kappos L, Uitdehaag BM. MRI characteristics are predictive for CDMS in monofocal, but not in multifocal patients with a clinically isolated syndrome. BMC Neurol. 2009 May 20;9:19. doi: 10.1186/1471-2377-9-19.
• Barkhof F, Polman CH, Radue EW, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Poppe P, de Vos M, Lasri F, Bauer L, Dahms S, Wagner K, Pohl C, Sandbrink R. Magnetic resonance imaging effects of interferon beta-1b in the BENEFIT study: integrated 2-year results. Arch Neurol. 2007 Sep;64(9):1292-8. doi: 10.1001/archneur.64.9.1292.
• Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Radu EW, Bauer L, Dahms S, Lanius V, Pohl C, Sandbrink R; BENEFIT Study Group. 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 Aug 4;370(9585):389-97. doi: 10.1016/S0140-6736(07)61194-5.
• De Jager PL, Chibnik LB, Cui J, Reischl J, Lehr S, Simon KC, Aubin C, Bauer D, Heubach JF, Sandbrink R, Tyblova M, Lelkova P; Steering committee of the BENEFIT study; Steering committee of the BEYOND study; Steering committee of the LTF study; Steering committee of the CCR1 study, Havrdova E, Pohl C, Horakova D, Ascherio A, Hafler DA, Karlson EW. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol. 2009 Dec;8(12):1111-9. doi: 10.1016/S1474-4422(09)70275-3. Epub 2009 Oct 29.

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (Actual): May 1, 2008
• Study Completion (Actual): May 1, 2008

Study Registration Dates

• First Submitted: September 9, 2005
• First Submitted That Met QC Criteria: September 9, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Estimate): December 30, 2013
• Last Update Submitted That Met QC Criteria: December 4, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interferons; Interferon-beta; Interferon beta-1b
• Other Study ID Numbers: 91031; 305207 (Other Identifier: Company Internal)