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

Multiple Sclerosis Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00185211
• Other study ID #: 91031
• Secondary ID: 305207
• Status: Completed
• Phase: Phase 3
• First received: September 9, 2005
• Last updated: December 4, 2013
• Start date: August 2002
• Est. completion date: May 2008

Study information

• Verified date: December 2013
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustria: Federal Ministry for Health and WomenCanada: Health CanadaNetherlands: Dutch Health Care InspectorateSwitzerland: SwissmedicCzech Republic: State Institute for Drug ControlGermany: Federal Institute for Drugs and Medical DevicesDenmark: Danish Medicines AgencySpain: Ministry of Health and ConsumptionFrance: French Data Protection AuthorityFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Finland: Finnish Medicines AgencyHungary: National Institute of PharmacyItaly: Ministry of HealthNorway: Norwegian Medicines AgencyPortugal: National Pharmacy and Medicines InstitutePoland: Ministry of HealthSweden: Medical Products AgencySlovenia: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 468
• Est. completion date: May 2008
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 48 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

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
• 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)

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

Austria,  Belgium,  Canada,  Czech Republic,  Denmark,  Finland,  France,  Germany,  Hungary,  Israel,  Italy,  Netherlands,  Norway,  Poland,  Portugal,  Slovenia,  Spain,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (14)

Barkhof F, Polman CH, Radue EW, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalbán 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: — View Citation

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 fi — View Citation

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 co — View Citation

Edan G, Kappos L, Montalbán 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. — View Citation

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-a-glucose serum biomarker for relapse activity and EDSS — View Citation

Hartung HP, Freedman MS, Polman CH, Edan G, Kappos L, Miller DH, Montalbán X, Barkhof F, Petkau J, White R, Sahajpal V, Knappertz V, Beckmann K, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Interferon ß-1b-neutralizing antibodies 5 years after clin — View Citation

Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Radü 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 — View Citation

Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Radü 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 eve — View Citation

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. 20 — View Citation

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. — View Citation

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 Neuro — View Citation

Penner IK, Stemper B, Calabrese P, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán 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. Epub 2012 Apr 4. — View Citation

Polman C, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalbán 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 int — View Citation

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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No

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