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    Clinical Trial Results:
    Prospective Phase IV Clinical Trial on Effectiveness and adherence to Rebif Treatment of CIS and RMS Patients in Romania by using Electronic Device RebiSmart®

    Summary
    EudraCT number
    2014-001290-14
    Trial protocol
    RO  
    Global end of trial date
    02 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    08 Sep 2017
    First version publication date
    08 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR 200136_583
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02254304
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Merck KGaA, Communication Center Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Merck KGaA, Communication Center Merck KGaA, +49 6151725200, service@merckgroup.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate effectiveness and adherence to treatment in patients with CIS and in patients with relapsing multiple sclerosis (RMS) using RebiSmart® to self-inject Rebif® in multi dose cartridge.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Dec 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 106
    Worldwide total number of subjects
    106
    EEA total number of subjects
    106
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    106
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted at 7 sites in Romania.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Rebif In RMS Subjects
    Arm description
    Rebif was administered in subjects with Relapsing Multiple Sclerosis (RMS) at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Rebif
    Investigational medicinal product code
    Other name
    Interferon beta-1a
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Rebif was administered in RMS subjects at a dose of 44 mcg subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months

    Arm title
    Rebif in CIS Subjects
    Arm description
    Rebif was administered in subjects with Clinically Isolated Syndromes (CIS) at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Rebif
    Investigational medicinal product code
    Other name
    Interferon beta-1a
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Rebif was administered in CIS subjects at a dose of 44 mcg subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.

    Number of subjects in period 1
    Rebif In RMS Subjects Rebif in CIS Subjects
    Started
    89
    17
    Completed
    75
    13
    Not completed
    14
    4
         Injection site pain and Injection fear
    1
    -
         Protocol deviation
    1
    -
         personal decision
    1
    -
         Adverse event, non-fatal
    2
    1
         Consent withdrawn by subject
    3
    -
         personal causes
    4
    1
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rebif In RMS Subjects
    Reporting group description
    Rebif was administered in subjects with Relapsing Multiple Sclerosis (RMS) at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.

    Reporting group title
    Rebif in CIS Subjects
    Reporting group description
    Rebif was administered in subjects with Clinically Isolated Syndromes (CIS) at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.

    Reporting group values
    Rebif In RMS Subjects Rebif in CIS Subjects Total
    Number of subjects
    89 17 106
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    36.1 ± 10.71 31.6 ± 9.63 -
    Gender, Male/Female
    Units: Subjects
        Female
    58 7 65
        Male
    31 10 41
    Number of Subjects Living in City or Rural Area
    Number of subjects living in city or rural area were presented.
    Units: Subjects
        City
    71 13 84
        Rural
    18 4 22
    Geographical Allocation
    Number of subjects depending upon the geographical location were presented.
    Units: Subjects
        North eastern
    18 3 21
        North western
    23 3 26
        South eastern
    45 10 55
        South western
    3 1 4
    Nicotine Used Status
    Number of subjects with Nicotine used status was categorized under never used, regular user, occasional user and former user.
    Units: Subjects
        Never used
    63 10 73
        Regular user
    19 3 22
        Occasional user
    0 0 0
        Former user
    7 4 11
    Alcohol Consumption
    Units: Subjects
        Subjects consumed alcohol
    3 1 4
        Subjects did not consume alcohol
    86 16 102

    End points

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    End points reporting groups
    Reporting group title
    Rebif In RMS Subjects
    Reporting group description
    Rebif was administered in subjects with Relapsing Multiple Sclerosis (RMS) at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.

    Reporting group title
    Rebif in CIS Subjects
    Reporting group description
    Rebif was administered in subjects with Clinically Isolated Syndromes (CIS) at a dose of 44 microgram (mcg) subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.

    Subject analysis set title
    Rebif in RMS and CIS Subjects
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Rebif was administered in RMS and CIS subjects at a dose of 44 mcg subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.

    Primary: Percentage of Relapse-free RMS Subjects

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    End point title
    Percentage of Relapse-free RMS Subjects [1] [2]
    End point description
    A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to multiple sclerosis (MS), accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. Relapse-free RMS subjects were those who did not had relapse during 12 month treatment period. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Data was planned to be reported for "Rebif in RMS Subjects" arm.
    End point type
    Primary
    End point timeframe
    Month 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Rebif In RMS Subjects
    Number of subjects analysed
    89
    Units: percentage of subjects
        number (not applicable)
    66.3
    No statistical analyses for this end point

    Primary: Time to the First Relapse for CIS Subjects

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    End point title
    Time to the First Relapse for CIS Subjects [3] [4]
    End point description
    A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to MS, accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. Time to the First Relapse was defined as the duration from start of the treatment until first relapse. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Data was planned to be reported for "Rebif in CIS Subjects" arm. 99999 = Median Kaplan Meier time to first relapse and inter-quartile range was not reached in the study because relapse was reported in only 1 subject.
    End point type
    Primary
    End point timeframe
    Baseline up to 12 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Rebif in CIS Subjects
    Number of subjects analysed
    17
    Units: months
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment Adherence

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    End point title
    Percentage of Subjects With Treatment Adherence
    End point description
    According to the World Health Organisation (WHO), treatment adherence is defined as both compliance (taking the medication in the correct dose and according to the schedule prescribed) and persistency (maintenance of the drug regimen over the long-term). Percentage of subjects with treatment adherence under different categories (<=50%, >50-75%, >75-90%, >90%) were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    89
    17
    Units: percentage of subjects
    number (not applicable)
        Adherence <=50%
    2.2
    11.8
        Adherence >50-75%
    2.2
    0
        Adherence >75-90%
    13.5
    0
        Adherence >90%
    80.9
    88.2
        Missing
    1.1
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Relapse by Adherence Category

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    End point title
    Percentage of Subjects With Relapse by Adherence Category
    End point description
    A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to multiple sclerosis (MS), accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. According to the World Health Organisation (WHO), treatment adherence is defined as both compliance (taking the medication in the correct dose and according to the schedule prescribed) and persistency (maintenance of the drug regimen over the long-term). Percentage of subjects with relapses by adherence categories (<=50%, >50-75%, >75-90%, >90%) were presented. Adherence missing are the subjects who withdrew before 12 months and who did not have any relapses before withdrawal. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    89
    17
    Units: percentage of subjects
    number (not applicable)
        Relapse Status Yes, Adherence <= 50% (n=2, 2)
    0
    0
        Relapse Status Yes, Adherence >50-75% (n=2, 0)
    0
    0
        Relapse Status Yes, Adherence >75-90% (12, 0)
    16.7
    0
        Relapse Status Yes, Adherence >90% (n=72, 15)
    19.4
    6.7
        Relapse Status Yes, Adherence Missing (n=1, 0)
    0
    0
        Relapse Status No, Adherence <= 50% (n=2, 2)
    0
    50
        Relapse Status No, Adherence >50-75% (n=2, 0)
    50
    0
        Relapse Status No, Adherence >75-90% (n=12, 0|)
    50
    0
        Relapse Status No, Adherence >90% (n=72, 15)
    72.2
    73.3
        Relapse Status No, Adherence Missing (n=1, 0)
    0
    0
        Relapse Status Missing, Adherence <=50% (n=2, 2)
    100
    50
        Relapse Status Missing, Adherence >50-75% (n=2, 0)
    50
    0
        Relapse Status Missing,Adherence >75-90%(n=12, 2)
    33.3
    0
        Relapse Status Missing, Adherence >90% (n=72, 15)
    8.3
    20
        Relapse Status Missing, Adherence Missing (n=1, 0)
    100
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects who Prematurely Terminated Treatment and Reasons

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    End point title
    Percentage of subjects who Prematurely Terminated Treatment and Reasons
    End point description
    Percentage of subjects who prematurely terminated treatment and reasons were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 12 months
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    89
    17
    Units: percentage of subjects
    number (not applicable)
        Adverse Event
    2.2
    5.9
        Lost to follow-up
    2.2
    11.8
        Protocol Non-compliance
    1.1
    0
        Withdrew Consent
    3.4
    0
        Pain at Injection site and fear of Injection
    1.1
    0
        personal causes
    4.5
    5.9
        personal decision
    1.1
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Free From Clinical Disease Activity

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    End point title
    Percentage of Subjects Free From Clinical Disease Activity
    End point description
    Data could not be analyzed for this outcome because this is a composite outcome dependent on subjects free from relapses and Expanded Disability Status Scale (EDSS) progression, where EDSS progression requires to be collected every 3/6 months and confirmed 3/6 months later. Since EDSS progression was only done at Month 12, therefore this derived outcome could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to 12 months
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [5] - EDSS progression was only done at Month 12, therefore this derived outcome could not be estimated
    [6] - EDSS progression was only done at Month 12, therefore this derived outcome could not be estimated.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Free from Disability Progression

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    End point title
    Percentage of Subjects Free from Disability Progression
    End point description
    Data could not be analyzed for this outcome because this Expanded Disability Status Scale (EDSS) progression requires EDSS to be collected every 3/6 months and confirmed 3/6 months later. Since EDSS progression was only done at Month 12, therefore this derived outcome could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline up to 12 months
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [7] - EDSS progression was only done at Month 12, therefore this derived outcome could not be estimated.
    [8] - EDSS progression was only done at Month 12, therefore this derived outcome could not be estimated.
    No statistical analyses for this end point

    Secondary: Mean Number of Relapses in RMS Subjects

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    End point title
    Mean Number of Relapses in RMS Subjects [9]
    End point description
    A relapse was defined as the appearance of a new symptom or worsening of an old symptom, attributable to multiple sclerosis (MS), accompanied by an appropriate new neurological abnormality or focal neurological dysfunction lasting at least 24 hours in the absence of fever, and preceded by stability or improvement for at least 30 days. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Month 12
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only arms which are applicable to the endpoint are reported.
    End point values
    Rebif In RMS Subjects
    Number of subjects analysed
    89
    Units: relapses
        arithmetic mean (standard deviation)
    0.2 ± 0.54
    No statistical analyses for this end point

    Secondary: Number of Subjects With Reasons of Missed Injections

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    End point title
    Number of Subjects With Reasons of Missed Injections
    End point description
    Number of subjects with the reasons of missed injections were presented. Aspartate transaminase and alanine transaminase are abbreviated as ALT and AST respectively. Glutamic oxaloacetic transaminase and glutamic pyruvic transaminase are abbreviated as GOT and GPT respectively. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects who missed the injections are evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to 12 months
    End point values
    Rebif in RMS and CIS Subjects
    Number of subjects analysed
    62
    Units: subjects
        Forgot to Injection
    48
        Tired
    23
        Fear of Injection
    11
        Did not want to have Injection
    5
        Pain at Injection site
    5
        Flu-like symptoms
    4
        Adverse event
    2
        Device broken
    1
        Device malfunctions
    1
        Device not functioning
    1
        Difficulty using the device
    1
        Elevated ALT and AST
    1
        Elevated liver enzymes
    2
        Increased GOT and GPT levels
    2
        Local erythema and induration
    1
        Missed study medication
    1
        Forgot the device at home
    1
        No access to medication
    1
        could not came at the scheduled visit
    1
        Patient redrawn intracutaneous
    1
        Stop the treatment
    1
        Technical problems with Rebismart
    1
    No statistical analyses for this end point

    Secondary: Overall Evaluation of RebiSmart use as Assessed by Investigator

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    End point title
    Overall Evaluation of RebiSmart use as Assessed by Investigator
    End point description
    Evaluation of RebiSmart was categorized under very easy, quite easy, Neither easy nor difficult, very difficult and missing. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    89
    17
    Units: subjects
        Very easy
    46
    13
        Quite easy
    32
    1
        Neither easy nor difficult
    9
    1
        Quite difficult
    0
    0
        Very difficult
    1
    2
        Missing
    1
    0
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Visits to Clinic by Subjects due to Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Visits to Clinic by Subjects due to Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of visits to clinic by subjects due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects who visited clinic for MS.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: visits
        arithmetic mean (standard deviation)
    0.2 ± 0.49
    0.1 ± 0.49
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Subjects Visiting Different Types of Doctors During Their Clinical Visit

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Subjects Visiting Different Types of Doctors During Their Clinical Visit
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Subjects who took consultations with specialists, general practitioners for MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here "Number of Subjects Analyzed" signifies number of subjects who visited to doctors for MS.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    16
    1
    Units: subjects
        General practitioner
    1
    1
        Specialist
    15
    0
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Visits by Healthcare Professional to Subject's Home

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Visits by Healthcare Professional to Subject's Home
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of visits by healthcare professional to subject's home were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: visits
        arithmetic mean (standard deviation)
    0 ± 0.11
    0 ± 0
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Times Subjects Visited Emergency Room due to Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Times Subjects Visited Emergency Room due to Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of times subjects visited emergency room due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: emergency room visits
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Days Subjects Hospitalized due to Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Days Subjects Hospitalized due to Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of days subjects hospitalized due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: days
        arithmetic mean (standard deviation)
    0.1 ± 0.75
    0 ± 0
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire -Number of Subjects Who Paid Someone to Assist Them due to Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire -Number of Subjects Who Paid Someone to Assist Them due to Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects who paid someone to assist them due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: subjects
    2
    1
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Days per Week Assistant Worked For Subject due to Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Days per Week Assistant Worked For Subject due to Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of days per week assistant worked for subject due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.Here "99999" signifies data was not available because standard deviation could not be estimated as there was only 1 subject analysed.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    2
    1
    Units: days per week
        arithmetic mean (standard deviation)
    2.5 ± 2.12
    2 ± 99999
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Hours per Day Assistant Worked for Subject due to Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Hours per Day Assistant Worked for Subject due to Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of hours per week assistant worked for subject due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure. Here "99999" signifies data was not available because standard deviation could not be estimated as there was only 1 subject analysed.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    2
    1
    Units: hours per day
        arithmetic mean (standard deviation)
    2 ± 1.41
    4 ± 99999
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Subjects Whose Relatives or Friends Missed Work due to Subjects Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Subjects Whose Relatives or Friends Missed Work due to Subjects Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects whose relatives or friends missed work due to subjects' MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: subject
    1
    1
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Working Days Missed by Relative or Friend due to Subjects' Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Working Days Missed by Relative or Friend due to Subjects' Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of working days missed by relative or friend due to subjects' MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure. Here "99999" signifies Standard deviation could not be estimated as there was only 1 subject analyzed.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    1
    1
    Units: days
        arithmetic mean (standard deviation)
    1 ± 99999
    3 ± 99999
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Subjects Who Missed any Full Days From Work due to Multiple Sclerosis (MS).

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Subjects Who Missed any Full Days From Work due to Multiple Sclerosis (MS).
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects who missed any full days from work due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: subjects
    2
    2
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Full Days Missed From Work by Subjects

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Full Days Missed From Work by Subjects
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of full days missed from work by subjects were presented. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    2
    2
    Units: days
        arithmetic mean (standard deviation)
    46.5 ± 61.52
    3.5 ± 2.12
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Subjects Who Missed any Partial Days From Work due to Multiple Sclerosis (MS).

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Subjects Who Missed any Partial Days From Work due to Multiple Sclerosis (MS).
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects who missed any partial days from work due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: subjects
    1
    2
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Hours per day Missed From Work by Subjects

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Hours per day Missed From Work by Subjects
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of hours per day missed from work by subjects were presented. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here "99999" signifies data was not available because standard deviation could not be estimated as there was only 1 subject analysed.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    1
    2
    Units: hours per day
        arithmetic mean (standard deviation)
    8 ± 99999
    3 ± 2.83
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Subjects Accomplished Less Work due to Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Subjects Accomplished Less Work due to Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Number of subjects accomplished less work due to MS were presented. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    88
    17
    Units: subjects
    7
    1
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization Questionnaire - Number of Subjects With Percentage of Work completed Despite of Multiple Sclerosis (MS)

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    End point title
    Healthcare Resource Utilization Questionnaire - Number of Subjects With Percentage of Work completed Despite of Multiple Sclerosis (MS)
    End point description
    Subjects was assessed at Month 12 utilizing the Health Resource Utilization Questionnaire (HRUQ), a subject self-report tool designed to evaluate the economic impact of MS. Healthcare resource utilization was collected in the following areas: admissions and stays in the hospital, emergency room, consultations with specialists, general practitioners, or other healthcare professionals, work productivity, health care financial impact. Amount of work done by subjects in spite of multiple sclerosis was presented under different percentages (0-100%). Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment. Here “Number of Subjects Analyzed” signifies number of subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    7
    1
    Units: Subjects
        0% Work Completed
    0
    0
        10% Work Completed
    1
    0
        20% Work Completed
    0
    0
        30% Work Completed
    1
    0
        40% Work Completed
    0
    0
        50% Work Completed
    0
    0
        60% Work Completed
    0
    0
        70% Work Completed
    0
    0
        80% Work Completed
    3
    1
        90% Work Completed
    2
    0
        100% Work Completed
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with Medication Adherence based on Morisky Medication Adherence Score

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    End point title
    Number of subjects with Medication Adherence based on Morisky Medication Adherence Score
    End point description
    The Morisky Medication Adherence Scale (MMAS) is a valid and reliable instrument that consists of 8 items that measure medication adherence. The scores of the MMAS-8 range from 0 to 8. This self-report scale consists of 7 items answered with a yes or no and 1 item with a 5-point Likert scale. A score below 6 indicates low adherence, a score between 6 to < 8 indicates medium adherence and a score of 8 indicates high adherence. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    89
    17
    Units: subjects
        Low Adherence
    23
    3
        Medium Adherence
    45
    6
        High Adherence
    21
    8
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Event or Adverse Drug Reaction (AE/ADR), Serious AE/ADR, AE/ADR Leading to Death and AE/ADR Leading to Early Termination

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    End point title
    Number of Subjects With Adverse Event or Adverse Drug Reaction (AE/ADR), Serious AE/ADR, AE/ADR Leading to Death and AE/ADR Leading to Early Termination
    End point description
    An AE was any untoward medical occurrence in a subject or clinical investigation in a subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An ADR was any unfavourable or unintended response (adverse event) that could possibly be related to the drug treatment. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. AE/ADR was planned to be reported for both the arms together. Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 12 months
    End point values
    Rebif in RMS and CIS Subjects
    Number of subjects analysed
    106
    Units: subjects
        AE/ADR
    30
        Serious AE/ADR
    1
        AE/ADR Leading to Death
    0
        AE/ADR Leading to Early Termination
    4
    No statistical analyses for this end point

    Secondary: Expanded Disability Status Scale (EDSS) Score

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    End point title
    Expanded Disability Status Scale (EDSS) Score
    End point description
    EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    Rebif In RMS Subjects Rebif in CIS Subjects
    Number of subjects analysed
    89
    17
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.87 ± 0.991
    1.24 ± 0.615
        Month 12
    1.8 ± 0.981
    1.13 ± 0.581
    No statistical analyses for this end point

    Secondary: Body Mass Index (BMI)

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    End point title
    Body Mass Index (BMI)
    End point description
    BMI was defined as weight in kilogram (kg) divided by height in square meter (m^2). Full analysis set included all subjects enrolled into the study and who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    Rebif in RMS and CIS Subjects
    Number of subjects analysed
    106
    Units: Kg/m^2
    arithmetic mean (standard deviation)
        Baseline
    23.57 ± 3.347
        Month 12
    23.51 ± 3.582
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 12 months
    Adverse event reporting additional description
    AE/ADR was planned to be reported for both the arms together.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Rebif in RMS and CIS Subjects
    Reporting group description
    Rebif was administered in RMS and CIS subjects at a dose of 44 mcg subcutaneously using RebiSmart auto-injector three times a week for a total duration up to 12 months.

    Serious adverse events
    Rebif in RMS and CIS Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 106 (0.94%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Rebif in RMS and CIS Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 106 (14.15%)
    Investigations
    Hepatic Enzyme Increased
         subjects affected / exposed
    7 / 106 (6.60%)
         occurrences all number
    7
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    9 / 106 (8.49%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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