Follow-up Study After 11 Years of Patients Who Were Included in the BENEFIT Trial (304747) With a First Demyelinating Event Suggestive of Multiple Sclerosis

NCT01795872 | Completed Phase 4

• 2 other identifiers: 164012012-005262-35
• Study Type: interventional
• Target: 278
• Locations: 20 countries
• Sites: 77

Brief Summary

This study assesses clinical and imaging long-term data, after early or delayed interferon-beta-1b treatment in patients with a first demyelinating event suggestive of multiple sclerosis (MS), 11 years after enrollment in the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study (304747). The main objectives are to describe the disease course, change in disability, cognitive function, resource use and employment status, in relation to Interferon beta-1b in the long term.

Conditions

Multiple Sclerosis

Outcome Measures

Primary Outcomes (21)

• Time to First Relapse by Kaplan-Meier Estimates

  Relapses are key features of the clinical presentation of multiple sclerosis. Relapses were assessed retrospectively based on clinical records and subject history. Time to first relapse is the difference from date of first relapse to the date of the BENEFIT baseline visit +1 or time to first relapse is the difference from date of last clinical visit to the date of the BENEFIT baseline visit + 1 (right censored).

  Up to Year 11 (Day 3960)

• Time to Clinically Definite Multiple Sclerosis (CDMS) Represented by Kaplan-Meier Estimates

  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 and a total EDSS of \>=2.5. The validity of CDMS diagnoses was confirmed by a central committee. The EDSS scale quantifies disability in multiple sclerosis (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 = the difference from date of CDMS to the date of Day 1 + 1 or time to CDMS = the difference from date of last clinical visit to the Day 1+1 (right censored).

  Up to Year 11 (Day 3960)

• Number of Subjects With Diagnosis of Multiple Sclerosis Within Eleven years after Clinically-Isolated Syndrome (CIS) According to McDonald 2001 and 2010 Criteria

  MS according to the criteria by McDonald was reached if, in addition to the single clinical demyelinating event, both dissemination in space (DIS) and dissemination in time (DIT) were established by magnetic resonance imaging (MRI) criteria or a new relapse. Number of subjects with diagnosis of MS within 11 years after CIS according to McDonald 2001 and 2010 criteria were reported.

  Year 11

• Disease Course as Assessed at the Time of BENEFIT 11

  Current diagnosis of MS type were categorized with regard to McDonald 2001 and McDonald 2010 criteria were recorded. CIS and silent disease (no relapse, no sustained EDSS progression and no new MRI lesion), McDonald MS not fulfilling the criteria for CDMS, RRMS (CDMS with relapses without evidence for a secondary disease course), SPMS (CDMS with relapses and evidence for a progressive disease course), Revised diagnosis (other reason than MS found for CIS) and Not assessable. Not assessable means McDonald 2001 and McDonald 2010 criteria could not be judged due to missing MRI scan at BENEFIT 11. Number of subjects with current diagnosis of MS at the time of BENEFIT 11 was assessed.

  Year 11

• Percentage of Subjects Converting to Secondary Progressive Multiple Sclerosis (SPMS)

  SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks. Percentage of subjects converting to SPMS were stratified by actual treatment group and baseline EDSS. Baseline EDSS defined as lowest of the EDSS scores obtained during BENEFIT screening or baseline (less than or equal to \[\<=\] median or greater than \[\>\] median).

  Year 11

• Time to Secondary Progressive Multiple Sclerosis (SPMS) Represented by Kaplan-Meier Estimates

  SPMS was defined for this study as progressive deterioration observed and sustained for at least 6 months with or without superimposed attacks. Time to SPMS was represented by Kaplan-Meier estimates.

  Up to Year 11 (Day 3960)

• Expanded Disability Status Scale (EDSS) at Year 11

  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. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS.

  Year 11

• Number of Subjects With Confirmed and Sustained 1-point Expanded Disability Status Scale (EDSS) Progression at Year 11

  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. EDSS progression was defined as an increase in the EDSS of at least 1.0 point compared to initial EDSS score or an increase in the EDSS of at least 1.5 points compared to initial EDSS score, if this score was = 0 points. Confirmed EDSS progression status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS progression observed at two consecutive scheduled visits at least 140 days apart from each other. A confirmed EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies or EDSS progression in BENEFIT 11. A sustained EDSS progression is defined as a confirmed EDSS progression in any of the previous BENEFIT studies sustained up to and including the BENEFIT 11 visit.

  Year 11

• Number of Subjects With Confirmed 2.5-point Expanded Disability Status Scale (EDSS) Progression at Year 11

  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. EDSS progression was defined as an increase in the EDSS of at least 2.5 points compared to initial EDSS score, if this score was \<= 3.5 points, or an increase in the EDSS of at least 2.0 points compared to initial EDSS score, if this score was \> 3.5 points. Confirmed EDSS increase status in any of the previous BENEFIT studies (304747, 305207, 311129) was defined as an EDSS increase confirmed at scheduled visits after at least 140 days. A confirmed EDSS increase is defined as a confirmed EDSS increase in any of the previous BENEFIT studies or EDSS increase in BENEFIT 11.

  Year 11

• Percentage of Subjects who Ever Reached a Disability Status Scale (DSS) 3 and 6

  The DSS 3, and DSS 6 are important milestones in the course of disability progression and were documented if reached by the subject.

  Year 11

• Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 3 by Kaplan-Meier Estimates

  The DSS 3 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 3 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 3 at Year 11 were estimated by Kaplan-Meier.

  Up to Year 11 (Day 3960)

• Disability Based Efficacy Domain: Time to Disability Status Scale (DSS) 6 by Kaplan-Meier Estimates

  The DSS 6 is an important milestones in the course of disability progression and were documented if reached by the subject. The time point of reaching DSS 6 was obtained retrospectively in the BENEFIT 11 study. Time to respective DSS is the difference between the date of respective DSS and the date of the BENEFIT baseline visit +1. Subjects without event at BENEFIT 11 were censored at the BENEFIT 11 visit. This constituted a right-censored observation. Cumulative probability of reaching DSS 6 at Year 11 were estimated by Kaplan-Meier.

  Up to Year 11 (Day 3960)

• Multiple Sclerosis Functional Composite (MSFC) at Year 11

  The MSFC score consists of three subtests (Timed 25 Foot Walk, 9 Hole Peg Test, 3" Paced Auditory Serial Addition Test \[PASAT\]) whose Z-standardized results (based on baseline values on Day 1 in Study 304747) were combined into a composite score including upper and lower extremities function, and cognitive function. Standardized results (Z-scores) of the subtests 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.

  Year 11

• Multiple Sclerosis Severity Score (MSSS) at Year 11

  The MSSS added the element of disease duration to the EDSS and was designed to provide a measure of disease severity. It was derived from the EDSS during the data evaluation. The MSSS corrects the EDSS for the duration of disease by using an arithmetical method to compare an individual's disability with the distribution of scores in case of having equivalent disease duration.

  Year 11

• Cognitive Function: Paced Auditory Serial Addition Test-3 (PASAT-3) at Year 11

  The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability.

  Year 11

• Cognitive function: Symbol Digit Modalities Test (SDMT)

  The Symbol Digit Modalities Test (SDMT) is a cognitive test for sustained attention, concentration, and information-processing speed, with a high sensitivity. Nine different geometrical symbols have one corresponding number each. One-hundred-ten symbols are presented without these numbers; the subject must find the matching number from the top line and verbalize the number to the examiner. The subject is allowed to proceed for 90 seconds, and the number of correct responses in 90 seconds is counted as the total correct score. Also, the numbers of correct responses at 30 and 60 seconds were recorded in this study. Total score ranged from 0 (worst outcome) to best (outcome).

  Year 11

• 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 with actual treatment in BENEFIT (304747; i.e. IFNB-1b 250 microgram vs. placebo), steroid use during first event (yes vs. no), onset of disease (multifocal vs. monofocal) and number of T2 lesions on BENEFIT screening MRI (categorized as 2-4, 5-8, \>=9) included in the model.

  Year 11

• Relapse Based Efficacy Domain: Annualized Relapse Rate

  The annualized relapse rate is defined as total number of relapses up to Year 11 divided by the total observation time (last clinical visit minus first day of study treatment administration plus 1 of all subjects) in years.

  Year 11

• Time to use of Ambulatory Device Represented by Kaplan-Meier Estimates

  Date of use of ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to use of ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1.

  Up to Year 11 (Day 3960)

• Time to Dependence of Ambulatory Device for Walking Represented by Kaplan-Meier Estimates

  Date of dependence from ambulatory device is defined as the retrospectively obtained time point of first use/dependence. Time to dependence from ambulatory device is the difference between the date of first use/dependence and the date of the BENEFIT baseline visit +1. Cumulative probability of dependence of ambulatory device for walking represented by Kaplan-Meier estimates at Year 11.

  Up to Year 11 (Day 3960)

• Number of Subjects With Wheelchair Use After 11 years

  Year 11

Secondary Outcomes (29)

• Education Status at Year 11

  Year 11

• Living Conditions at Year 11

  Year 11

• Employment Status at Year 11

  Year 11

• Multiple Sclerosis Impact on Employment at Year 11

  Year 11

• Resource Use: Hospitalization During Last 12 months

  Year 11

Study Arms (1)

Several diagnostic procedures

OTHER

Procedure: Several diagnostic procedures

Interventions

Several diagnostic procedures PROCEDURE

No drug will be assigned, diagnostic assessment within the study.

Several diagnostic procedures

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients with clinical-isolated syndrome or multiple sclerosis who have been treated at least once in BENEFIT Study 304747

You may not qualify if:

• Patients who, according to the investigator's judgment, have medical, psychiatric, or other conditions that compromise the patient's ability to understand the purpose of the study

Sponsors & Collaborators

• Bayer: lead

Study Sites (77)

Unknown Facility

Graz, Styria, 8036, Austria

Location

Unknown Facility

Innsbruck, 6020, Austria

Location

Unknown Facility

Bruxelles - Brussel, 1200, Belgium

Location

Unknown Facility

Ghent, 9000, Belgium

Location

Unknown Facility

Leuven, 3000, Belgium

Location

Unknown Facility

Liège, 4000, Belgium

Location

Unknown Facility

Calgary, Alberta, T2N 2T9, Canada

Location

Unknown Facility

London, Ontario, N6A 5A5, Canada

Location

Unknown Facility

Ottawa, Ontario, K1H 8L6, Canada

Location

Unknown Facility

Montreal, Quebec, H2L 4M1, Canada

Location

Unknown Facility

Brno, 625 00, Czechia

Location

Unknown Facility

Hradec Králové, 500 05, Czechia

Location

Unknown Facility

Ostrava-Poruba, 708 52, Czechia

Location

Unknown Facility

Prague, 121 11, Czechia

Location

Unknown Facility

Glostrup Municipality, DK-2600, Denmark

Location

Unknown Facility

Oulu, 90029, Finland

Location

Unknown Facility

Seinäjoki, Finland

Location

Unknown Facility

Tampere, 33521, Finland

Location

Unknown Facility

Turku, 20100, Finland

Location

Unknown Facility

Bordeaux, 33000, France

Location

Unknown Facility

Clermont-Ferrand, 63003, France

Location

Unknown Facility

Dijon, 21033, France

Location

Unknown Facility

Lille, 59037, France

Location

Unknown Facility

Nice, 06200, France

Location

Unknown Facility

Rennes, 35033, France

Location

Unknown Facility

Toulouse, 31059, France

Location

Unknown Facility

Ulm, Baden-Wurttemberg, 89075, Germany

Location

Unknown Facility

München, Bavaria, 81377, Germany

Location

Unknown Facility

Regensburg, Bavaria, 93053, Germany

Location

Unknown Facility

Würzburg, Bavaria, 97080, Germany

Location

Unknown Facility

Hennigsdorf, Brandenburg, 16761, Germany

Location

Unknown Facility

Giessen, Hesse, 35392, Germany

Location

Unknown Facility

Marburg, Hesse, 35039, Germany

Location

Unknown Facility

Offenbach, Hesse, 63069, Germany

Location

Unknown Facility

Göttingen, Lower Saxony, 37099, Germany

Location

Unknown Facility

Greifswald, Mecklenburg-Vorpommern, 17475, Germany

Location

Unknown Facility

Cologne, North Rhine-Westphalia, 50931, Germany

Location

Unknown Facility

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Unknown Facility

Mainz, Rhineland-Palatinate, 55101, Germany

Location

Unknown Facility

Halle, Saxony-Anhalt, 06120, Germany

Location

Unknown Facility

Erfurt, Thuringia, 99089, Germany

Location

Unknown Facility

Münster, 48149, Germany

Location

Unknown Facility

Budapest, 1076, Hungary

Location

Unknown Facility

Budapest, 1145, Hungary

Location

Unknown Facility

Debrecen, 4012, Hungary

Location

Unknown Facility

Szeged, 6720, Hungary

Location

Unknown Facility

Tel Litwinsky, Israel, 5262000, Israel

Location

Unknown Facility

Jerusalem, Israel

Location

Unknown Facility

Orbassano, Torino, 10043, Italy

Location

Unknown Facility

Gallarate, 21013, Italy

Location

Unknown Facility

Milan, 20132, Italy

Location

Unknown Facility

Padua, 35128, Italy

Location

Unknown Facility

Pavia, 27100, Italy

Location

Unknown Facility

Torino, 10126, Italy

Location

Unknown Facility

Sittard, 6131 BK, Netherlands

Location

Unknown Facility

Bergen, 5021, Norway

Location

Unknown Facility

Bydgoszcz, 85-681, Poland

Location

Unknown Facility

Krakow, 30-503, Poland

Location

Unknown Facility

Lodz, 90-153, Poland

Location

Unknown Facility

Lublin, 20-090, Poland

Location

Unknown Facility

Wroclaw, 50420, Poland

Location

Unknown Facility

Coimbra, Coimbra District, 3030-075, Portugal

Location

Unknown Facility

Ljubljana, 1525, Slovenia

Location

Unknown Facility

Seville, Andalusia, 41071, Spain

Location

Unknown Facility

Barcelona, Barcelona, 08035, Spain

Location

Unknown Facility

Barcelona, Barcelona, 08036, Spain

Location

Unknown Facility

L'Hospitalet de Llobregat, Barcelona, 08907, Spain

Location

Unknown Facility

Madrid, Madrid, 28040, Spain

Location

Unknown Facility

Málaga, Málaga, 29010, Spain

Location

Unknown Facility

Valencia, Valencia, 46026, Spain

Location

Unknown Facility

Gothenburg, 413 45, Sweden

Location

Unknown Facility

Basel, Canton of Basel-City, 4031, Switzerland

Location

Unknown Facility

Bern, Canton of Bern, 3010, Switzerland

Location

Unknown Facility

Sankt Gallen, Canton of St. Gallen, 9007, Switzerland

Location

Unknown Facility

Sheffield, South Yorkshire, S10 2JF, United Kingdom

Location

Unknown Facility

Aberdeen, AB25 2ZN, United Kingdom

Location

Unknown Facility

Dundee, DD1 9SY, United Kingdom

Location

Related Publications (1)

• Kappos L, Edan G, Freedman MS, Montalban X, Hartung HP, Hemmer B, Fox EJ, Barkhof F, Schippling S, Schulze A, Pleimes D, Pohl C, Sandbrink R, Suarez G, Wicklein EM; BENEFIT Study Group. The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. Neurology. 2016 Sep 6;87(10):978-87. doi: 10.1212/WNL.0000000000003078. Epub 2016 Aug 10.

  PMID: 27511182 DERIVED

Related Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

MeSH Terms

Conditions

Multiple Sclerosis

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2013
• First Posted: February 21, 2013
• Study Start: September 1, 2013
• Primary Completion: April 1, 2014
• Study Completion: June 1, 2014
• Last Updated: July 27, 2015

Record last verified: 2015-07

Locations

BE (4); PT (1); ES (7); FI (4); NL (1); GB (3); DE (16); IT (6); NO (1); SE (1); HU (4); DK (1); SL (1); FR (7); CA (4); PL (5); AU (2); IL (2); CH (3); CZ (4)