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    Clinical Trial Results:
    Multicenter, open-label, 12 weeks, phase IV pRospectivE randomized study aimed at evaLuating whether sc IFN beta 1a (Rebif®) administered In the morning may affEct the severity of Flu-like syndrome and patient perceived invisible symptoms in subjects with relapsing multiple sclerosis (RELIEF)

    Summary
    EudraCT number
    		 2013-004450-21
    Trial protocol
    		 IT  
    Global end of trial date
    11 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Apr 2018
    First version publication date
    06 Apr 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EMR200136-570
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02064816
    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 Healthcare, a business of Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Scientific contact
    Merck KGaA Communication Center, Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany, +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
    13 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective was to assess the severity of flu like symptoms (FLS), as measured by Items 13 to 16 of the Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ), in subjects injecting Rebif 44 mcg in the morning versus the evening.
    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
    12 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 200
    Worldwide total number of subjects
    200
    EEA total number of subjects
    200
    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)
    200
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 29 clinical trial sites in Italy.

    Pre-assignment
    Screening details
    		 A total of 200 subjects were enrolled in the study, of which 104 were randomized to Rebif morning treatment group, and 96 were randomized to Rebif evening treatment group. A subgroup of subjects also took part in a sub study assessing cytokines and other immunological biomarkers.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rebif Morning Administration
    Arm description
    		 Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rebif
    Investigational medicinal product code
    Other name
    Interferon (IFN) beta 1a
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.

    Arm title
    		 Rebif Evening Administration
    Arm description
    		 Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rebif
    Investigational medicinal product code
    Other name
    Interferon (IFN) beta 1a
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks

    Number of subjects in period 1
    		Rebif Morning Administration Rebif Evening Administration
    Started
    104
    96
    Completed
    96
    88
    Not completed
    8
    8
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    3
    2
         Therapeutic failure
    -
    1
         Unspecified
    1
    3
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rebif Morning Administration
    Reporting group description
    		 Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.

    Reporting group title
    Rebif Evening Administration
    Reporting group description
    		 Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.

    Reporting group values
    		 Rebif Morning Administration Rebif Evening Administration Total
    Number of subjects
    		 104 96 200
    Age Categorical
    Units: Subjects
        <18 years
    		 0 0 0
        >=18 years to 64 years
    		 104 96 200
        >64 years
    		 0 0 0
    Gender, Male/Female
    Units: Subjects
        Female
    		 76 62 138
        Male
    		 28 34 62

    End points

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    End points reporting groups
    Reporting group title
    Rebif Morning Administration
    Reporting group description
    		 Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.

    Reporting group title
    Rebif Evening Administration
    Reporting group description
    		 Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.

    Primary: Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 12

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    End point title
    		 Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 12
    End point description
    The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 12 is presented in statistical analysis section. The Intention to Treat Analysis Set (ITT) included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Missing data on FLS were imputed using the last observation carried forward (LOCF) method.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    99
    88
    Units: units on scale
        arithmetic mean (standard deviation)
    12.3 ( 3.87 )
    11.8 ( 3.02 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.277763
    Method
    		 Mann-Whitney Non Parameteric test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 1.56
    Variability estimate
    Standard deviation
    Dispersion value
    3.5

    Secondary: Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4 and 8

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    End point title
    		 Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Flu Like Symptom (FLS) Score Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4 and 8
    End point description
    The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to multiple sclerosis (MS) medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. Difference between Rebif Morning Administration and Rebif Evening Administration groups at Week 4 and 8 is presented in statistical analysis section. The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Week 4 and 8
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    99
    88
    Units: units on scale
    least squares mean (confidence interval 95%)
        Week 4 (n= 81, 81)
    12.4368 (11.7402 to 13.1333)
    11.0876 (10.3705 to 11.8046)
        Week 8 (n= 97, 88)
    13.0039 (12.3244 to 13.6834)
    11.6672 (10.9565 to 12.3779)
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Week 4
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0083
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 Least Square (LS) Mean difference
    Point estimate
    1.3492
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3495
         upper limit
    		 2.3489
    Notes
    [1] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Week 8
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.0079
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    1.3367
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3534
         upper limit
    		 2.32
    Notes
    [2] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.

    Secondary: Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Subscale Scores Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4, 8 and 12

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    End point title
    		 Difference in Multiple Sclerosis Treatment Concern Questionnaire (MSTCQ) Subscale Scores Between Rebif Morning Administration and Rebif Evening Administration Groups at Week 4, 8 and 12
    End point description
    MSTCQ: a tool to measure treatment satisfaction, focusing on attributes specific to MS medications. Following sub-scales were assessed: Injection site reactions (ISRs), Global side-effects, Benefits, Pain, Visual Analog Scale (VAS), and Rating of Pain. ISR subscale: defined as sum of scores for questions 17 to 20 (minimum score 4 and maximum score of 20). Global side-effects subscale: defined as sum of scores for questions 21 to 23 (minimum score 3 and maximum score 15). Benefits (question 35); description of pain (question 36); VAS (question 37); rating of pain (question 38) subscales ranged from 1 to 5, with minimum score of 1 and maximum score of 5. For each of subscales, lower scores indicated better satisfaction. ITT population was used. "Number of Subjects Analyzed" = subjects who were evaluable for this outcome measure and "n" = subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Week 4, 8 and 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    103
    93
    Units: units on scale
    least squares mean (confidence interval 95%)
        ISRs subscale Week 4 (n= 75; 66)
    10.8459 (10.1609 to 11.5309)
    10.4456 (9.7177 to 11.1735)
        ISRs subscale Week 8 (n= 80; 77)
    11.5363 (10.8625 to 12.2101)
    11.4515 (10.7540 to 12.1490)
        ISRs subscale Week 12 (n= 83; 75)
    11.6380 (10.9720 to 12.3041)
    11.9625 (11.2598 to 12.6652)
        Global side-effect subscale: Week 4 (n= 96; 91)
    10.2144 (9.6771 to 10.7518)
    10.2852 (9.7276 to 10.8429)
        Global side-effect subscale: Week 8 (n= 94; 87)
    10.4111 (9.8698 to 10.9525)
    10.2214 (9.6567 to 10.7862)
        Global side-effect subscale: Week 12 (n= 93; 87)
    10.5879 (10.0456 to 11.1302)
    10.1782 (9.6132 to 10.7432)
        Benefits: Week 4 (n= 76; 75)
    3.1325 (2.7856 to 3.4794)
    3.5408 (3.1912 to 3.8905)
        Benefits: Week 8 (n= 71; 74)
    3.5779 (3.2207 to 3.9351)
    3.7137 (3.3622 to 4.0652)
        Benefits: Week 12 (n= 70; 71)
    3.6059 (3.2467 to 3.9652)
    3.6640 (3.3062 to 4.0218)
        Description of pain: Week 4 (n= 89; 86)
    4.3755 (3.2024 to 5.5485)
    3.7846 (2.5846 to 4.9847)
        Description of pain: Week 8 (n= 85; 84)
    5.3132 (4.1262 to 6.5003)
    6.0821 (4.8767 to 7.2875)
        Description of pain: Week 12 (n= 88; 80)
    5.7853 (4.6089 to 6.9617)
    5.6431 (4.4239 to 6.8624)
        VAS: Week 4 (n= 96; 89)
    11.8837 (7.6691 to 16.0983)
    11.2293 (6.8280 to 15.6305)
        VAS: Week 8 (n= 91; 87)
    17.2316 (12.9597 to 21.5035)
    19.4610 (15.0359 to 23.8860)
        VAS: Week 12 (n= 91; 84)
    16.1757 (11.9054 to 20.4460)
    21.5953 (17.1359 to 26.0547)
        Rating of pain: Week 4 (n= 98; 90)
    1.3073 (1.1008 to 1.5138)
    1.3004 (1.0846 to 1.5162)
        Rating of pain: Week 8 (n= 93; 89)
    1.5653 (1.3553 to 1.7753)
    1.6522 (1.4356 to 1.8688)
        Rating of pain: Week 12 (n= 93; 86)
    1.4994 (1.2895 to 1.7094)
    1.7218 (1.5029 to 1.9407)
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    ISRs subscale Week 4
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.4311
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.4003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5992
         upper limit
    		 1.3998
    Notes
    [3] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    ISRs subscale Week 8
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.8635
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.08479
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.885
         upper limit
    		 1.0546
    Notes
    [4] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    ISRs subscale Week 12
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.5099
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.3245
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2927
         upper limit
    		 0.6437
    Notes
    [5] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Global side-effect subscale: Week 4
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.8574
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.07079
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8452
         upper limit
    		 0.7036
    Notes
    [6] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Global side-effect subscale: Week 8
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.6338
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.1897
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5926
         upper limit
    		 0.972
    Notes
    [7] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Global side-effect subscale: Week 12
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.3042
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.4097
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3734
         upper limit
    		 1.1929
    Notes
    [8] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Benefits: Week 4
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.1038
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.4083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9008
         upper limit
    		 0.08419
    Notes
    [9] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Benefits: Week 8
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.594
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.1358
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.637
         upper limit
    		 0.3653
    Notes
    [10] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Benefits: Week 12
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.8217
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.05809
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5651
         upper limit
    		 0.4489
    Notes
    [11] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Description of pain: Week 4
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.489
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.5909
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.0873
         upper limit
    		 2.269
    Notes
    [12] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Description of pain: Week 8
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.3719
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.7689
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4607
         upper limit
    		 0.9229
    Notes
    [13] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Description of pain: Week 12
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.869
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.1422
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5521
         upper limit
    		 1.8364
    Notes
    [14] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    VAS: Week 4
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.8328
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.6544
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4393
         upper limit
    		 6.7482
    Notes
    [15] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    VAS: Week 8
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    P-value
    		 = 0.4764
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.2294
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.38
         upper limit
    		 3.9212
    Notes
    [16] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    VAS: Week 12
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 = 0.0852
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -5.4196
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.5939
         upper limit
    		 0.7547
    Notes
    [17] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Rating of pain: Week 4
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [18]
    P-value
    		 = 0.9639
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.006873
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2918
         upper limit
    		 0.3055
    Notes
    [18] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Rating of pain: Week 8
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [19]
    P-value
    		 = 0.5715
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.08689
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3886
         upper limit
    		 0.2148
    Notes
    [19] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Rating of pain: Week 12
    Comparison groups
    Rebif Morning Administration v Rebif Evening Administration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    P-value
    		 = 0.1502
    Method
    		 linear mixed model for repeated measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.2224
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5256
         upper limit
    		 0.0809
    Notes
    [20] - "Subjects in this analysis" are the total of maximum number of subjects analyzed in both the arms.

    Secondary: Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score at Week 4, 8 and 12

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    End point title
    		 Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score at Week 4, 8 and 12
    End point description
    HADS was used to measure depression and anxiety in subjects. The scale was limited to 14 questions. Seven of the items related to anxiety and 7 related to depression. Each item on the questionnaire was scored from 0-3 giving a total score between 0 and 21 for either anxiety or depression where higher score indicates more anxiety/depression. The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8 and 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    101
    93
    Units: units on scale
    least squares mean (confidence interval 95%)
        Anxiety score: Change at Week 4 (n= 95; 90)
    -0.6625 (-1.1976 to -0.1273)
    -0.4604 (-1.0106 to 0.08968)
        Anxiety score: Change at Week 8 (n= 89; 88)
    -0.7222 (-1.2688 to -0.1755)
    -0.3763 (-0.9308 to 0.1782)
        Anxiety score: Change at Week 12 (n= 90; 86)
    -0.6435 (-1.1879 to -0.09918)
    0.05023 (-0.5081 to 0.6085)
        Depression score: Change at Week 4 (n= 97; 89)
    -0.1539 (-0.8083 to 0.5005)
    0.2211 (-0.4617 to 0.9038)
        Depression score: Change at Week 8 (n= 92; 89)
    -0.2397 (-0.9062 to 0.4267)
    0.1999 (-0.4835 to 0.8833)
        Depression score: Change at Week 12 (n= 91; 86)
    0.1906 (-0.4778 to 0.8590)
    0.1162 (-0.5741 to 0.8066)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Score at Week 4, 8 and 12

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    End point title
    		 Change From Baseline in Fatigue Severity Scale (FSS) Score at Week 4, 8 and 12
    End point description
    FSS is a method designed to assess disabling fatigue in all the individuals. The Fatigue Severity Scale is a 9-item questionnaire developed to assess the level of fatigue due to neurological disease, were each item assessed on a 1-7 scale (1= no fatigue and 7= severe fatigue). The total score was calculated as the average of individual 9-items and ranged from 1 to 7 with a higher value indicating greater impairment due to fatigue. The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8 and 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    98
    94
    Units: units on scale
    least squares mean (confidence interval 95%)
        Change at Week 4 (n= 93; 92)
    0.2089 (-0.05810 to 0.4759)
    0.06901 (-0.2010 to 0.3391)
        Change at Week 8 (n= 92; 90)
    0.2062 (-0.06211 to 0.4746)
    0.1366 (-0.1354 to 0.4085)
        Change at Week 12 (n= 88; 87)
    0.1464 (-0.1253 to 0.4182)
    0.1942 (-0.08036 to 0.4688)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Score at Week 4, 8 and 12

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    End point title
    		 Change From Baseline in Pittsburgh Sleep Quality Index (PSQI) Score at Week 4, 8 and 12
    End point description
    PSQI is a self-rated questionnaire which assess sleep quality and disturbances over a 1-month interval using seven clinically derived components of sleep difficulties: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. PSQI is a summary of 7 components. Each component is scored from 0 to 3, therefore PSQI has a range of 0 (better) to 21 (worse). Interpretation of the PSQI is that a score less than 5 is associated with good sleep quality and a score of 5 or greater is associated with poor sleep quality. The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8 and 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    69
    55
    Units: units on scale
    least squares mean (confidence interval 95%)
        Change at Week 4 (n= 58; 50)
    -0.08889 (-0.7690 to 0.5912)
    0.5747 (-0.1653 to 1.3147)
        Change at Week 8 (n= 62; 53)
    -0.4513 (-1.1161 to 0.2136)
    0.7092 (-0.01588 to 1.4343)
        Change at Week 12 (n= 53; 47)
    0.07841 (-0.6265 to 0.7833)
    0.4293 (-0.3270 to 1.1855)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Multiple Sclerosis International Quality of Life (MusiQOL) Score at Week 4, 8 and 12

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    End point title
    		 Change From Baseline in Multiple Sclerosis International Quality of Life (MusiQOL) Score at Week 4, 8 and 12
    End point description
    MusiQoL: validated 31-item questionnaire describing 9 dimensions: activities of daily living; psychological well-being; symptoms; relationships with friends; relationships with family; relationship with healthcare system; sentimental and sexual life; coping; and rejection. Each of questions was answered using a 6-point Likert scale ranging from 1 (never/not at all) to 6 (always/very much). Scores of each dimension were obtained by computing mean of item scores of dimension with negatively worded item scores reversed so that higher scores indicated higher health-related quality of life (QoL). All 9 dimension scores were linearly transformed to 0 to 100 scale and average of 9 dimensions was used to give a Global Score ranging from 0 to 100 (higher scores indicated higher health-related QoL. ITT population was used. "Number of Subjects Analyzed" = subjects who were evaluable for this outcome measure and "n" = subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8 and 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    89
    85
    Units: units on scale
    least squares mean (confidence interval 95%)
        Global Score: Change at Week 4 (n= 83; 81)
    1.6283 (-0.3761 to 3.6326)
    0.1174 (-1.9196 to 2.1544)
        Global Score: Change at Week 8 (n= 81; 78)
    1.1439 (-0.8780 to 3.1658)
    -2.2945 (-4.3568 to -0.2321)
        Global Score: Change at Week 12 (n= 78; 75)
    0.9670 (-1.0753 to 3.0094)
    -1.3948 (-3.4796 to 0.6900)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment Adherence at Week 4, 8 and 12

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    End point title
    		 Percentage of Subjects With Treatment Adherence at Week 4, 8 and 12
    End point description
    Adherence to treatment was calculated as 100 x the number of completed injections the subject administered divided by the expected number of injections. Treatment adherence was divided in two categories: percentage of subjects with less than (<) 80 percent adherence and percentage of subjects with more than and equal to (>=) 80 percent adherence. The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Week 4, 8 and 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    92
    85
    Units: Percentage of subjects
    number (not applicable)
        < 80 percent adherence at Week 4 (n= 92; 85)
    3.3
    5.9
        >= 80 percent adherence at Week 4 (n= 92; 85)
    96.7
    94.1
        < 80 percent adherence at Week 8 (n= 69; 67)
    2.9
    1.5
        >= 80 percent adherence at Week 8 (n= 69; 67)
    97.1
    98.5
        < 80 percent adherence at Week 12 (n= 84; 79)
    4.8
    6.3
        >= 80 percent adherence at Week 12 (n= 84; 79)
    95.2
    93.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Circulating Levels of Cytokines at Week 12

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    End point title
    		 Change From Baseline in Circulating Levels of Cytokines at Week 12
    End point description
    Results are presented for three cytokines: leptin, resistin and adiponectin. The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    89
    77
    Units: microgram per liter (mcg/L)
    arithmetic mean (standard deviation)
        Leptin: Change at Week 12
    -2.6 ( 3.42 )
    -2.6 ( 3.90 )
        Resistin: Change at Week 12
    -3.1 ( 3.31 )
    -3.0 ( 3.77 )
        Adiponectin: Change at Week 12
    2.8 ( 6.38 )
    2.8 ( 5.51 )
    No statistical analyses for this end point

    Secondary: Correlation Between Change From Baseline in Circulating Levels of Cytokines and in Flu Like Symptom (FLS) Score at Week 12

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    End point title
    		 Correlation Between Change From Baseline in Circulating Levels of Cytokines and in Flu Like Symptom (FLS) Score at Week 12
    End point description
    Correlation was assessed by using Pearson correlation coefficient. The MSTCQ was used as a tool to measure treatment satisfaction, focusing on the attributes specific to MS medications. The FLS subscale of MSTCQ was defined as the sum of the scores for questions 13 to 16 with a minimum possible total FLS score = 1 and a maximum possible total FLS score = 20. Lower score indicates lower flu like symptoms and better satisfaction. The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    77
    70
    Units: Correlation coefficient
    number (not applicable)
        Leptin: Change at Week 12
    0.08822
    0.03944
        Resistin: Change at Week 12
    -0.20200
    -0.01069
        Adiponectin: Change at Week 12
    0.04616
    -0.13571
    No statistical analyses for this end point

    Secondary: Correlation Between Change From Baseline in Circulating Levels of Cytokines and in Other MSTCQ Items, HADS, FSS, PSQI and MusiQOL Scores at Week 12

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    End point title
    		 Correlation Between Change From Baseline in Circulating Levels of Cytokines and in Other MSTCQ Items, HADS, FSS, PSQI and MusiQOL Scores at Week 12
    End point description
    Correlation was assessed by using Pearson correlation coefficient. MSTCQ, HADS, FSS, PSQI and MusiQOL are described in the above endpoints. Following abbreviations used in the categories: Global side-effects (GLOBSE); description of pain (PAINDESCR). The ITT included all subjects enrolled into the study and assigned to the RebiSmart device. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    85
    77
    Units: Correlation Coefficient
    number (not applicable)
        Leptin and MSTCQ-ISR: Week 12(n= 76; 65)
    0.00595
    -0.10214
        Resistin and MSTCQ-ISR: Week 12(n= 76; 65)
    -0.22380
    0.04855
        Adiponectin and MSTCQ-ISR: Week 12 (n= 76; 65)
    -0.13365
    -0.14865
        Leptin and MSTCQ-GLOBSE: Week 12 (n= 85; 76)
    0.03121
    0.21425
        Resistin and MSTCQ-GLOBSE: Week 12 (n= 85; 76)
    0.20285
    -0.12730
        Adiponectin and MSTCQ-GLOBSE: Week 12 (n= 85; 76)
    0.00169
    -0.06398
        Leptin and MSTCQ-benefits: Week 12 (n= 63; 61)
    0.13023
    -0.10915
        Resistin and MSTCQ-benefits: Week 12 (n= 63; 61)
    -0.13544
    -0.15636
        Adiponectin and MSTCQ-benefits: Week 12(n= 63; 61)
    0.10726
    0.04081
        Leptin and MSTCQ-PAINDESCR: Week 12 (n= 82; 69)
    0.09118
    0.01165
        Resistin and MSTCQ-PAINDESCR: Week 12 (n= 82; 69)
    -0.13918
    0.04150
        Adiponectin and MSTCQ-PAINDESCR: Week12(n= 82;69)
    0.07093
    0.01535
        Leptin and MSTCQ-VAS: Week 12 (n= 84; 73)
    0.34840
    -0.01433
        Resistin and MSTCQ-VAS: Week 12 (n= 84; 73)
    -0.15231
    0.16220
        Adiponectin and MSTCQ-VAS: Week 12 (n= 84; 73)
    -0.07840
    0.02109
        Leptin and MSTCQ-pain rating: Week 12 (n= 85; 75)
    0.16675
    -0.14381
        Resistin and MSTCQ-pain rating: Week 12(n= 85;75)
    -0.23531
    0.12355
        Adiponectin and MSTCQ-pain rating: Week12(n=85;75)
    -0.08060
    -0.08718
        Leptin and HADS-anxiety: Week 12 (n= 83; 76)
    0.00754
    -0.06360
        Resistin and HADS-anxiety: Week 12 (n= 83; 76)
    0.02447
    0.07986
        Adiponectin and HADS-anxiety: Week 12 (n= 83; 76)
    0.06295
    0.08818
        Leptin and HADS-depression: Week 12 (n= 83; 76)
    0.05226
    -0.14953
        Resistin and HADS-depression: Week 12 (n= 83; 76)
    0.01970
    -0.04154
        Adiponectin and HADS-depression: Week 12(n= 83;76)
    0.03228
    0.19209
        Leptin and FSS: Week 12 (n= 81; 77)
    0.04256
    0.14284
        Resistin and FSS: Week 12 (n= 81; 77)
    -0.23755
    -0.10961
        Adiponectin and FSS: Week 12 (n= 81; 77)
    -0.00326
    0.03090
        Leptin and PSQI: Week 12 (n= 52; 43)
    0.00873
    0.00099
        Resistin and PSQI: Week 12 (n= 52; 43)
    -0.03765
    0.12085
        Adiponectin and PSQI: Week 12 (n= 52; 43)
    0.25795
    0.24406
        Leptin and MusiQoL- Global: Week 12 (n= 74; 64)
    -0.25650
    0.17917
        Resistin and MusiQoL-Global: Week 12 (n= 74; 64)
    0.12190
    0.21936
        Adiponectin and MusiQoL-Global: Week 12(n=74; 64)
    0.07152
    -0.05924
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cytokines (Leptin and Resistin) Levels at Week 12

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    End point title
    		 Change From Baseline in Cytokines (Leptin and Resistin) Levels at Week 12
    End point description
    Results are presented for cytokines: leptin and resistin. The Substudy Analysis Set (SSAS) included all subjects in the ITT who were enrolled in the substudy. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    8
    7
    Units: Nanogram/milliliter (ng/mL)
    least squares mean (confidence interval 95%)
        Leptin: Change at Week 12
    -2.7826 (-6.1880 to 0.6227)
    -0.7936 (-4.4371 to 2.8499)
        Resistin: Change at Week 12
    -3.6628 (-5.3424 to -1.9831)
    -5.8360 (-7.6339 to -4.0381)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cytokine (Adiponectin) Level at Week 12

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    End point title
    		 Change From Baseline in Cytokine (Adiponectin) Level at Week 12
    End point description
    The SSAS included all subjects in the ITT who were enrolled in the substudy. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    8
    7
    Units: microgram per milliliter (mcg/mL)
        least squares mean (confidence interval 95%)
    2.7093 (-1.0663 to 6.4848)
    4.3574 (0.3174 to 8.3975)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hormone-Like Cytokine (Interleukin-6, 10 and 12) Levels at Week 12

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    End point title
    		 Change From Baseline in Hormone-Like Cytokine (Interleukin-6, 10 and 12) Levels at Week 12
    End point description
    The SSAS included all subjects in the ITT who were enrolled in the substudy. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    8
    7
    Units: Picogram/milliliter (pg/mL)
    least squares mean (confidence interval 95%)
        Interleukin-6: Change at Week 12 (n= 8, 7)
    -0.5173 (-1.7940 to 0.7593)
    -0.6970 (-2.0624 to 0.6683)
        Interleukin-10: Change at Week 12 (n= 5, 3)
    -0.05819 (-0.5453 to 0.4290)
    -0.6660 (-1.2999 to -0.03210)
        Interleukin-12: Change at Week 12 (n= 7, 7)
    -0.3490 (-0.9115 to 0.2135)
    -0.4384 (-0.9973 to 0.1204)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Sleep Time (TST) and Rapid Eye Movement (REM) Sleep Time at Week 12

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    End point title
    		 Change From Baseline in Total Sleep Time (TST) and Rapid Eye Movement (REM) Sleep Time at Week 12
    End point description
    Polysomnography (PSG) was performed for subjects who participated in the substudy. PSG is a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine. Total sleep time is the total of all REM and non-REM sleep in a sleep episode. The SSAS included all subjects in the ITT who were enrolled in the substudy. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    7
    6
    Units: minutes
    median (full range (min-max))
        Total Sleep Time: Change at Week 12 (n= 7; 6)
    10.0 (-73.0 to 117.0)
    33.0 (-227.0 to 165.0)
        REM sleep: Change at Week 12 (n= 4; 5)
    -3.0 (-207.0 to 9.0)
    6.0 (-67.0 to 288.0)
    No statistical analyses for this end point

    Secondary: Correlation Between Change From Baseline in Cytokines (Leptin, Resistin and Adiponectin) and Hormone-like Cytokine Levels (Interleukin-6, 10 and 12), and TST and REM Sleep Time at Week 12

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    End point title
    		 Correlation Between Change From Baseline in Cytokines (Leptin, Resistin and Adiponectin) and Hormone-like Cytokine Levels (Interleukin-6, 10 and 12), and TST and REM Sleep Time at Week 12
    End point description
    Correlations between change from baseline at Week 12 in TST or REM sleep and the area under the curve (AUC) calculated using the trapezoidal method for cytokine levels (ie, leptin, resistin, adiponectin, Interleukin (IL)-12, IL 10, and IL 6) were analyzed using Pearson’s correlation coefficient. Polysomnography (PSG) was performed for subjects who participated in the substudy. The SSAS included all subjects in the ITT who were enrolled in the substudy. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this outcome measure. Here "n" signifies those subjects who were evaluable for this outcome measure for specified category. Here 99999 signifies that Correlation Coefficient could not be estimated as there was only 1 subject analysed for this arm at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    7
    6
    Units: Correlation Coefficients
    number (not applicable)
        AUC Leptin and TST: Week 12 (n= 7; 6)
    0.10816
    0.46984
        AUC Resistin and TST: Week 12 (n= 7; 6)
    -0.56278
    -0.05056
        AUC Adiponectin and TST: Week 12 (n= 7; 5)
    0.17402
    0.58181
        AUC IL-12 and TST: Week 12 (n= 5; 5)
    -0.44328
    0.24717
        AUC IL-10 and TST: Week 12 (n= 2; 1)
    1.00000
    99999
        AUC IL-6 and TST: Week 12 (n= 7; 6)
    0.18626
    -0.51662
        AUC Leptin and REM: Week 12 (n= 4; 5)
    0.99732
    0.63155
        AUC Resistin and REM: Week 12 (n= 4; 5)
    0.22684
    -0.38234
        AUC Adiponectin and REM: Week 12 (n= 4; 4)
    0.98335
    -0.05732
        AUC IL-12 and REM: Week 12 (n= 2; 4)
    1.00000
    -0.76606
        AUC IL-10 and REM: Week 12 (n= 2; 1)
    -1.00000
    99999
        AUC IL-6 and REM: Week 12 (n= 4; 5)
    0.06269
    -0.34860
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Discontinuation
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. The Safety Analysis Set (SAF) included all subjects in the ITT who received at least 1 dose of the planned study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Rebif Morning Administration Rebif Evening Administration
    Number of subjects analysed
    104
    96
    Units: Subjects
        TEAEs
    82
    77
        Serious TEAEs
    1
    2
        TEAEs Leading to Death
    0
    0
        TEAE leading to Discontinuation
    6
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 12
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Rebif Morning Administration
    Reporting group description
    		 Subjects self-injected Rebif at a dose of 44 microgram (mcg) subcutaneously three times a week by using RebiSmart autoinjector device in the morning for 12 weeks.

    Reporting group title
    Rebif Evening Administration
    Reporting group description
    		 Subjects self-injected Rebif at a dose of 44 mcg subcutaneously three times a week by using RebiSmart autoinjector device in the evening for 12 weeks.

    Serious adverse events
    		 Rebif Morning Administration Rebif Evening Administration
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 104 (0.96%)
    2 / 96 (2.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 104 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Rebif Morning Administration Rebif Evening Administration
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 104 (74.04%)
    70 / 96 (72.92%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    4 / 104 (3.85%)
    7 / 96 (7.29%)
         occurrences all number
    4
    7
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    4 / 104 (3.85%)
    5 / 96 (5.21%)
         occurrences all number
    4
    5
    Transaminases Increased
         subjects affected / exposed
    4 / 104 (3.85%)
    6 / 96 (6.25%)
         occurrences all number
    4
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 104 (22.12%)
    16 / 96 (16.67%)
         occurrences all number
    23
    16
    Multiple Sclerosis Relapse
         subjects affected / exposed
    3 / 104 (2.88%)
    7 / 96 (7.29%)
         occurrences all number
    3
    7
    General disorders and administration site conditions
    Influenza Like Illness
         subjects affected / exposed
    52 / 104 (50.00%)
    42 / 96 (43.75%)
         occurrences all number
    52
    42
    Pyrexia
         subjects affected / exposed
    15 / 104 (14.42%)
    11 / 96 (11.46%)
         occurrences all number
    15
    11
    Injection Site Erythema
         subjects affected / exposed
    14 / 104 (13.46%)
    8 / 96 (8.33%)
         occurrences all number
    14
    8
    Fatigue
         subjects affected / exposed
    9 / 104 (8.65%)
    2 / 96 (2.08%)
         occurrences all number
    9
    2
    Asthenia
         subjects affected / exposed
    7 / 104 (6.73%)
    4 / 96 (4.17%)
         occurrences all number
    7
    4
    Injection Site Pain
         subjects affected / exposed
    5 / 104 (4.81%)
    5 / 96 (5.21%)
         occurrences all number
    5
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    10 / 104 (9.62%)
    2 / 96 (2.08%)
         occurrences all number
    10
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 104 (1.92%)
    9 / 96 (9.38%)
         occurrences all number
    2
    9
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    10 / 104 (9.62%)
    6 / 96 (6.25%)
         occurrences all number
    10
    6
    Arthralgia
         subjects affected / exposed
    5 / 104 (4.81%)
    7 / 96 (7.29%)
         occurrences all number
    5
    7
    Pain In Extremity
         subjects affected / exposed
    4 / 104 (3.85%)
    6 / 96 (6.25%)
         occurrences all number
    4
    6

    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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