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

Study at a glance

From the registry record, last updated by the sponsor on 27 Jul 2015. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title

BENEFIT 11 a Long-term Follow-up Study of the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment, 304747), BENEFIT Follow-up (305207) Studies and BENEFIT Extension (311129) Study to Further Evaluate the Progress of Patients With First Demyelinating Event Suggestive of Multiple Sclerosis

ClinicalTrials.gov ID

NCT01795872

Acronym / sponsor ID

16401

Conditions

Multiple Sclerosis

Phase

Phase 4

Study type

Interventional

Recruitment status

Completed

Enrolment

278 participants (actual)

Lead sponsor

BayerIndustry (pharma, biotech, devices)

Study start

Sep 2013

Primary completion

Apr 2014 (actual)

Study completion

Jun 2014 (actual)

First posted

21 Feb 2013 (estimated)

Results

Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose

Treatment

Allocation

Not applicable

Intervention model

Single group

Masking

None (open label)

Number of arms

1

Who may qualify

Ages

18 years and older

Sex

All

Healthy volunteers

Not accepted

Age groups

Adult, Older adult

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Primary outcome

1. Time to First Relapse by Kaplan-Meier Estimates

   Time frame: Up to Year 11 (Day 3960)

   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).

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

   Time frame: Up to Year 11 (Day 3960)

   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).

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

   Time frame: Year 11

   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.

4. Disease Course as Assessed at the Time of BENEFIT 11

   Time frame: Year 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.

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

   Time frame: Year 11

   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).

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

   Time frame: Up to Year 11 (Day 3960)

   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.

7. Expanded Disability Status Scale (EDSS) at Year 11

   Time frame: 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.

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

   Time frame: 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.

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

   Time frame: 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.

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

    Time frame: Year 11

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

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

    Time frame: Up to Year 11 (Day 3960)

    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.

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

    Time frame: Up to Year 11 (Day 3960)

    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.

13. Multiple Sclerosis Functional Composite (MSFC) at Year 11

    Time frame: 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.

14. Multiple Sclerosis Severity Score (MSSS) at Year 11

    Time frame: 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.

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

    Time frame: 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.

16. Cognitive function: Symbol Digit Modalities Test (SDMT)

    Time frame: Year 11

    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).

17. Relapse-Based Efficacy domain: Hazard Ratio for Recurrent Relapses

    Time frame: Year 11

    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.

18. Relapse Based Efficacy Domain: Annualized Relapse Rate

    Time frame: Year 11

    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.

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

    Time frame: Up to Year 11 (Day 3960)

    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.

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

    Time frame: Up to Year 11 (Day 3960)

    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.

21. Number of Subjects With Wheelchair Use After 11 years

    Time frame: Year 11

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

• Official record on ClinicalTrials.govLast updated by the sponsor 27 Jul 2015.
• Derived from this study: PubMed 27511182Kappos 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.
• Click here to find information about studies related to Bayer Healthcare products conducted in EuropeLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

77 sites in 20 countries: see every site and its status.