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    Clinical Trial Results:
    Double-blind extension of the study 27025 (REFLEX) to obtain long-term follow-up data in patients with clinically definite MS and patients with a first demyelinating event at high risk of converting to MS, treated with Rebif® New Formulation (REFLEXION)

    Summary
    EudraCT number
    2008-004954-34
    Trial protocol
    CZ   AT   FI   ES   PT   EE   DE   BE   LV   GR   IT   FR   BG   PL   SK  
    Global end of trial date
    30 Aug 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Apr 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    28981
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00813709
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250, Darmstadt, Germany, 64293
    Public contact
    Communication Centre merck KGaA, Merck Serono, a division of Merck KGaA, 49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre merck KGaA, Merck Serono, a division of 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
    30 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    REFLEXION is a double blind extension of the study 27025 (NCT00404352) (REFLEX). The purpose of the study is to obtain long-term follow-up data in subjects with clinically definite multiple sclerosis (MS) and subjects with a first demyelinating event at high risk of converting to MS, treated with fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of interferon [IFN]-beta-1a (RNF).
    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
    22 Dec 2008
    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
    Slovakia: 3
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 36
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Croatia: 53
    Country: Number of subjects enrolled
    Czech Republic: 64
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Lebanon: 18
    Country: Number of subjects enrolled
    Morocco: 4
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 34
    Country: Number of subjects enrolled
    Russian Federation: 72
    Country: Number of subjects enrolled
    Serbia: 17
    Worldwide total number of subjects
    402
    EEA total number of subjects
    273
    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)
    1
    Adults (18-64 years)
    401
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects who were randomized in Study 27025 (NCT00404352) were eligible to enroll into extension Study 28981 (NCT00813709) whether or not they completed main study on Investigational Medicinal Product (IMP), or no treatment or received other disease-modifying drugs (DMDs) during course of main study. No re-randomization was done for this study.

    Pre-assignment
    Screening details
    517 subjects randomized in Study 27025 used in this study as integrated intention to treat (ITT) population. Out of the 517, 402 subjects took part in study 28981: 300 comprised the double blind (DB) population and 122 comprised the open label (OL) population (some subjects (20) were included in both populations).

    Period 1
    Period 1 title
    Overall Study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/RNF 44 microgram (mcg) Thrice Weekly (ITT population)
    Arm description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of RNF injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 36 months. 84 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 49 subjects were initially assigned to OL RNF 44 mcg thrice weekly (9 subjects from DB converted to CDMS and switched to OL period over course of this study).
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Rebif
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    RNF was administered subcutaneously three times weekly at least 48 hours apart at a dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Arm title
    RNF 44 mcg Once Weekly (ITT population)
    Arm description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. 117 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 25 subjects were initially assigned to OL RNF 44 mcg thrice weekly (26 subjects from DB converted to CDMS and switched to OL period over course of this study).
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Rebif
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF will be administered subcutaneously once weekly at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Arm title
    RNF 44 mcg Thrice Weekly (ITT Population)
    Arm description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. 99 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 28 subjects were initially assigned to OL RNF 44 mcg thrice weekly (18 subjects from DB converted to CDMS and switched to OL period over course of this study).
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF was administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Number of subjects in period 1
    Placebo/RNF 44 microgram (mcg) Thrice Weekly (ITT population) RNF 44 mcg Once Weekly (ITT population) RNF 44 mcg Thrice Weekly (ITT Population)
    Started
    133
    142
    127
    Completed
    97
    118
    103
    Not completed
    36
    24
    24
         Unspecified
    7
    8
    5
         Premature treatment discontinuation
    24
    13
    16
         Lost to follow-up
    5
    3
    3
    Period 2
    Period 2 title
    Double blind period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/RNF 44 mcg Thrice Weekly (DB Population)
    Arm description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Rebif®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    RNF was administered subcutaneously three times weekly at least 48 hours apart at a dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Arm title
    RNF 44 mcg Once Weekly (DB Population)
    Arm description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Rebif
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF will be administered subcutaneously once weekly at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Arm title
    RNF 44 mcg Thrice Weekly (DB Population)
    Arm description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF was administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Number of subjects in period 2 [1]
    Placebo/RNF 44 mcg Thrice Weekly (DB Population) RNF 44 mcg Once Weekly (DB Population) RNF 44 mcg Thrice Weekly (DB Population)
    Started
    84
    117
    99
    Completed
    53
    76
    68
    Not completed
    31
    41
    31
         Randomized but not treated
    1
    3
    1
         Adverse event
    4
    1
    4
         Switched to open label phase
    9
    26
    18
         Unspecifed
    14
    -
    -
         Unspecified
    -
    9
    6
         Lost to follow-up
    3
    2
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 402 subjects took part in study 28981: 300 comprised the double blind (DB) population and 122 comprised the open label (OL) population (some subjects (20) were included in both populations).
    Period 3
    Period 3 title
    Open Label
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/RNF 44 mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
    Arm description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. 49 subjects in OL period initially + 9 subjects from DB converted to CDMS during the study were included in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF was administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Arm title
    RNF 44 mcg Once Weekly /OL RNF 44 mcg Thrice Weekly
    Arm description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. 25 subjects in OL period initially + 26 subjects from DB converted to CDMS during the study were included in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Rebif
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF will be administered subcutaneously once weekly at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF was administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Arm title
    RNF 44 mcg Thrice Weekly/OL RNF 44 mcg Thrice Weekly
    Arm description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. 28 subjects in OL period initially + 18 subjects from DB converted to CDMS during the study were included in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    RNF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single dose of RNF was administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Number of subjects in period 3 [2]
    Placebo/RNF 44 mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly RNF 44 mcg Once Weekly /OL RNF 44 mcg Thrice Weekly RNF 44 mcg Thrice Weekly/OL RNF 44 mcg Thrice Weekly
    Started
    58
    51
    46
    Completed
    38
    41
    35
    Not completed
    20
    10
    11
         Randomized but not treated
    1
    -
    1
         Adverse event
    -
    4
    3
         Lack of efficacy
    3
    1
    1
         Adverse events
    5
    -
    -
         Unspecified
    11
    5
    6
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 402subjects took part in study 28981: 300 comprised the double blind (DB) population and 122 comprised the open label (OL) population (some subjects (20) were included in both populations).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/RNF 44 microgram (mcg) Thrice Weekly (ITT population)
    Reporting group description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of RNF injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 36 months. 84 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 49 subjects were initially assigned to OL RNF 44 mcg thrice weekly (9 subjects from DB converted to CDMS and switched to OL period over course of this study).

    Reporting group title
    RNF 44 mcg Once Weekly (ITT population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. 117 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 25 subjects were initially assigned to OL RNF 44 mcg thrice weekly (26 subjects from DB converted to CDMS and switched to OL period over course of this study).

    Reporting group title
    RNF 44 mcg Thrice Weekly (ITT Population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. 99 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 28 subjects were initially assigned to OL RNF 44 mcg thrice weekly (18 subjects from DB converted to CDMS and switched to OL period over course of this study).

    Reporting group values
    Placebo/RNF 44 microgram (mcg) Thrice Weekly (ITT population) RNF 44 mcg Once Weekly (ITT population) RNF 44 mcg Thrice Weekly (ITT Population) Total
    Number of subjects
    133 142 127 402
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31 ± 8.2 31.4 ± 8.2 31.8 ± 8.6 -
    Gender categorical
    Units: Subjects
        Female
    82 88 78 248
        Male
    51 54 49 154

    End points

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    End points reporting groups
    Reporting group title
    Placebo/RNF 44 microgram (mcg) Thrice Weekly (ITT population)
    Reporting group description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of RNF injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 36 months. 84 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 49 subjects were initially assigned to OL RNF 44 mcg thrice weekly (9 subjects from DB converted to CDMS and switched to OL period over course of this study).

    Reporting group title
    RNF 44 mcg Once Weekly (ITT population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. 117 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 25 subjects were initially assigned to OL RNF 44 mcg thrice weekly (26 subjects from DB converted to CDMS and switched to OL period over course of this study).

    Reporting group title
    RNF 44 mcg Thrice Weekly (ITT Population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. 99 subjects were initially assigned to DB RNF 44 mcg thrice weekly and 28 subjects were initially assigned to OL RNF 44 mcg thrice weekly (18 subjects from DB converted to CDMS and switched to OL period over course of this study).
    Reporting group title
    Placebo/RNF 44 mcg Thrice Weekly (DB Population)
    Reporting group description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.

    Reporting group title
    RNF 44 mcg Once Weekly (DB Population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.

    Reporting group title
    RNF 44 mcg Thrice Weekly (DB Population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.
    Reporting group title
    Placebo/RNF 44 mcg Thrice Weekly/OL RNF 44 Mcg Thrice Weekly
    Reporting group description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. 49 subjects in OL period initially + 9 subjects from DB converted to CDMS during the study were included in this arm.

    Reporting group title
    RNF 44 mcg Once Weekly /OL RNF 44 mcg Thrice Weekly
    Reporting group description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. 25 subjects in OL period initially + 26 subjects from DB converted to CDMS during the study were included in this arm.

    Reporting group title
    RNF 44 mcg Thrice Weekly/OL RNF 44 mcg Thrice Weekly
    Reporting group description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months. 28 subjects in OL period initially + 18 subjects from DB converted to CDMS during the study were included in this arm.

    Subject analysis set title
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 36 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first. After having converted to CDMS, subjects received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Subject analysis set title
    RNF 44 Mcg thrice Weekly (integrated ITT population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Subject analysis set title
    RNF 44 Mcg Once Weekly (integrated ITT population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first. After having converted to CDMS, subjects received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months.

    Subject analysis set title
    Placebo/RNF 44 Mcg thrice Weekly (integrated DB population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.

    Subject analysis set title
    RNF 44 Mcg Once Weekly (integrated DB population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.

    Subject analysis set title
    RNF 44 Mcg thrice Weekly (integrated DB population)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 36 months or until conversion to CDMS whichever occurs first.

    Subject analysis set title
    Placebo/RNF 44 Mcg thrice Weekly (DB safety population)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.

    Subject analysis set title
    RNF 44 Mcg Once Weekly (DB safety population)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.

    Subject analysis set title
    RNF 44 Mcg thrice Weekly (DB safety population)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.

    Primary: Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to 36 months

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    End point title
    Time to Conversion to Clinically Definite Multiple Sclerosis (CDMS) Defined by Either a Second Attack or a Sustained Increase (Greater Than or Equal to 1.5 Points) in the Expanded Disability Status Scale (EDSS) Score up to 36 months
    End point description
    CDMS was defined by the occurrence of a second attack or relapse over 36 months in subjects who presented with clinically isolated syndrome (CIS) accompanied by an abnormal magnetic resonance imaging (MRI) scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]) was calculated. Time to conversion to CDMS was represented by Kaplan-Meier estimates of the cumulative percentage (%) of subjects with CDMS. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Primary
    End point timeframe
    Baseline (Day 1 of Study 27025) up to 36 Months
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: Cumulative % of subjects with CDMS
        number (confidence interval 95%)
    41.3 (33.5 to 49.1)
    27.6 (20.6 to 34.6)
    27.1 (19.9 to 34.3)
    Statistical analysis title
    Statistical analysis 1 for TIme to CDMS
    Comparison groups
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) v RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.555
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.378
         upper limit
    0.816
    Statistical analysis title
    Statistical analysis 2 for TIme to CDMS
    Comparison groups
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) v RNF 44 Mcg Once Weekly (integrated ITT population)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.006
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.573
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.391
         upper limit
    0.839
    Statistical analysis title
    Statistical analysis 3 for TIme to CDMS
    Comparison groups
    RNF 44 Mcg Once Weekly (integrated ITT population) v RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.941
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.993
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.654
         upper limit
    1.51

    Secondary: Time to confirmed Expanded Disability Status Scale (EDSS) progression up to 36 months

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    End point title
    Time to confirmed Expanded Disability Status Scale (EDSS) progression up to 36 months
    End point description
    EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A confirmed EDSS progression was defined EDSS greater than or equal to 1.0 point confirmed during a visit performed 6 months later. Time to confirmed EDSS progression was represented by Kaplan-Meier estimates of the cumulative percentage (%) of subjects with confirmed EDSS progression. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025) up to 36 Months
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: % of subjects with EDSS progression
        number (not applicable)
    7.5
    11.8
    13.2
    Statistical analysis title
    Statistical Analysis 1 for EDSS progression
    Comparison groups
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) v RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects included in analysis
    342
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.205
    Method
    Logrank
    Confidence interval
         level
    95%
    Statistical analysis title
    Statistical Analysis 2 for EDSS progression
    Comparison groups
    RNF 44 Mcg Once Weekly (integrated ITT population) v RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.629
    Method
    Logrank
    Confidence interval
         level
    95%
    Statistical analysis title
    Statistical Analysis 3 for EDSS progression
    Comparison groups
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) v RNF 44 Mcg Once Weekly (integrated ITT population)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.263
    Method
    Logrank
    Confidence interval
         level
    95%

    Secondary: Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, new Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Lesions Per Subjects Per Scan at Month 36

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    End point title
    Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, new Gadolinium Enhanced (Gd+) Lesions and New Time Constant 1 (T1) Lesions Per Subjects Per Scan at Month 36
    End point description
    Number of CUA lesions, new T2 lesions, new Gd+ lesions and new T1 lesions were measured by using MRI scans. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352) and who were evaluable for this measure at this time point.
    End point type
    Secondary
    End point timeframe
    Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    124
    133
    114
    Units: lesions
    arithmetic mean (standard deviation)
        CUA Lesions
    1.02 ± 1.85
    1.83 ± 3.317
    1.63 ± 5.947
        New T2 Lesions
    0.83 ± 1.545
    1.39 ± 2.573
    1.19 ± 4.217
        New Gd+ Lesions
    0.17 ± 0.506
    0.4 ± 1.354
    0.41 ± 1.754
        New T1 Lesions
    0.69 ± 1.721
    1.09 ± 2.482
    0.91 ± 4.143
    No statistical analyses for this end point

    Secondary: Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36

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    End point title
    Change From Baseline in Time Constant 1 (T1) Hypointense Lesion Volume and Time Constant 2 (T2) Lesion Volume at Month 36
    End point description
    Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions at Month 36. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352). “n” signifies those subjects who were evaluated for this measure at the specified time point for each arm group respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: cubic millimeter (mm^3)
    arithmetic mean (standard deviation)
        T1 lesion volume at Baseline (n=171,175,171)
    670.3 ± 1054.1
    774.8 ± 1288
    675 ± 1049.9
        Change in T1 lesion volume Month 36(n=124,133,114)
    303.2 ± 1034.6
    272 ± 921.4
    133.3 ± 763.5
        T2 lesion volume at Baseline (n=171,175,171)
    3334.9 ± 3990.4
    3853.1 ± 4716.7
    3110.5 ± 3410.7
        Change in T2 lesion volume Month 36(n=124,133,114)
    -3.8 ± 2101.8
    -56.9 ± 2436.3
    -398.1 ± 1415.4
    No statistical analyses for this end point

    Secondary: Percent change From Baseline in Brain Volume at Month 36

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    End point title
    Percent change From Baseline in Brain Volume at Month 36
    End point description
    Percent change in brain volume was measured by using MRI scans. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352) and who were evaluable for this measure at this time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    120
    132
    112
    Units: percent change
        arithmetic mean (standard deviation)
    -1.02 ± 1.248
    -0.86 ± 1.073
    -1.14 ± 1.321
    No statistical analyses for this end point

    Secondary: Percentage of subjects with conversion to McDonald multiple sclerosis (MS) up to 36 Months

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    End point title
    Percentage of subjects with conversion to McDonald multiple sclerosis (MS) up to 36 Months
    End point description
    The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025) up to CDMS conversion and/or up to 36 Months
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: percentage of subjects
        number (not applicable)
    84.2
    76
    66.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36

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    End point title
    Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 36
    End point description
    The Paced Auditory Serial Addition Test (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Score ranges from ‘0-60’. Higher scores reflect better neurological function and a positive change from baseline indicates improvement. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352). “n” signifies those subjects who were evaluated for this measure at the specified time point for each arm group respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day of Study 27025), Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=171,175,171)
    0.0358 ± 0.8787
    -0.0909 ± 1.1223
    0.0031 ± 1.1387
        Change at Month 36 (n=123,135,118)
    0.3483 ± 0.6949
    0.5044 ± 0.7588
    0.4515 ± 0.9164
    No statistical analyses for this end point

    Secondary: Percentage of Relapse-Free Subjects at Month 36

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    End point title
    Percentage of Relapse-Free Subjects at Month 36
    End point description
    A relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Secondary
    End point timeframe
    Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: Percentage of subjects
        number (not applicable)
    42.7
    58.3
    51.5
    No statistical analyses for this end point

    Secondary: Change from baseline in expanded disability status scale (EDSS) score at month 36

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    End point title
    Change from baseline in expanded disability status scale (EDSS) score at month 36
    End point description
    EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS score at Month 36 was calculated as EDSS score at Month 36 minus EDSS score at baseline. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352). “n” signifies those subjects who were evaluated for this measure at the specified time point for each arm group respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day of Study 27025), Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=171,175,171)
    1.53 ± 0.77
    1.5 ± 0.72
    1.51 ± 0.83
        Change at Month 36 (n=120,136,116)
    -0.21 ± 0.93
    -0.11 ± 0.96
    -0.09 ± 0.9
    No statistical analyses for this end point

    Secondary: Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36

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    End point title
    Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 36
    End point description
    The MSFC is a multidimensional clinical outcome measure of three sub-tests; Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Test-3(PASAT-3). The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The 9-Hole Peg Test is a quantitative measure of upper extremity function. The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Standardized results (Z-scores) of these sub-tests and the overall MSFC Z-score as an average of these 3 Z-scores was calculated. Higher Z-scores reflect better neurological function and a positive change from baseline indicates improvement. An increase in score indicates an improvement (range -3 to +3). Data was presented for integrated ITT population of 27025 (NCT00404352) study. “n”signifies those subjects who were evaluated for this measure at the specified time point for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: Z-score
    arithmetic mean (standard deviation)
        MFSC score at Baseline (n=171,175,171)
    0.0352 ± 0.5844
    0.0071 ± 0.6653
    -0.0575 ± 0.6226
        Change at Month 36 (n=123,135,118)
    0.1993 ± 0.4863
    0.2529 ± 0.5794
    0.3074 ± 0.6071
    No statistical analyses for this end point

    Secondary: Numbers of Subjects With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36

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    End point title
    Numbers of Subjects With Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 36
    End point description
    BAbs are all antibodies which are capable of binding to the investigational drug molecule (RNF) irrespective of their binding site. NAbs are defined as a subgroup of BAbs which bind to the active sites of the RNF and therefore neutralize its potency. NAbs were detected using a viral cytopathic assay. BAbs were measured by using an ELISA (Enzyme-linked immunosorbent assay). Data has been presented as per planned analysis for integrated DB population which included all subjects who received at least one dose of DB treatment in REFLEX study 27025 (NCT00404352) and who were evaluable for this measure at this time point.
    End point type
    Secondary
    End point timeframe
    Month 36
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated DB population) RNF 44 Mcg Once Weekly (integrated DB population) RNF 44 Mcg thrice Weekly (integrated DB population)
    Number of subjects analysed
    118
    131
    118
    Units: Subjects
    number (not applicable)
        BAb-
    77
    97
    88
        BAb+
    41
    34
    30
        NAb-
    100
    109
    99
        NAb+
    18
    22
    19
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to treatment discontinuation

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    End point title
    Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to treatment discontinuation
    End point description
    An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition. DB Safety Population 28981 (REFLEXION) included all the subjects who discontinued DB treatment in REFLEX study 27025 (NCT00404352) and were enrolled in 28981 (REFLEXION) study and received at least one dose of DB treatment in this study and who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Month 24 up to Month 36 (DB treatment period for study 28981 (REFLEXION)
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (DB safety population) RNF 44 Mcg Once Weekly (DB safety population) RNF 44 Mcg thrice Weekly (DB safety population)
    Number of subjects analysed
    84
    117
    99
    Units: Subjects
    number (not applicable)
        AEs
    79
    67
    45
        SAEs
    3
    2
    4
        AEs leading to discontinuation
    2
    0
    2
    No statistical analyses for this end point

    Secondary: Time to conversion to Clinically Definite Multiple Sclerosis (CDMS) defined by either a second attack or a sustained increase (greater than or equal to 1.5 points) in the Expanded Disability Status Scale (EDSS) score up to Month 60

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    End point title
    Time to conversion to Clinically Definite Multiple Sclerosis (CDMS) defined by either a second attack or a sustained increase (greater than or equal to 1.5 points) in the Expanded Disability Status Scale (EDSS) score up to Month 60
    End point description
    CDMS was defined by the occurrence of a second attack or relapse over 60 months in subjects who presented with clinically isolated syndrome (CIS) accompanied by an abnormal magnetic resonance imaging (MRI) scan. EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]) was calculated. Time to conversion to CDMS was represented by Kaplan-Meier estimates of the cumulative percentage (%) of subjects with CDMS. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025) up to 60 Months
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: Cumulative % of subjects with CDMS
        number (confidence interval 95%)
    44.6 (36.6 to 52.6)
    40.7 (32.8 to 48.6)
    39.2 (30.8 to 47.6)
    No statistical analyses for this end point

    Secondary: Time to confirmed Expanded Disability Status Scale (EDSS) progression up to 60 months

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    End point title
    Time to confirmed Expanded Disability Status Scale (EDSS) progression up to 60 months
    End point description
    EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A confirmed EDSS progression was defined EDSS greater than or equal to 1.0 point confirmed during a visit performed 6 months later. Time to confirmed EDSS progression was represented by Kaplan-Meier estimates of the cumulative percentage (%) of subjects with confirmed EDSS progression. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025) up to 60 Months
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: % of subjects with EDSS progression
        number (not applicable)
    11
    18.7
    18.4
    No statistical analyses for this end point

    Secondary: Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, New Gadolinium Enhanced (Gd+) Lesions and New T1 Lesions Per Subject Per Scan at Month 60

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    End point title
    Number of Combined Unique Active (CUA) Lesions, New Time Constant 2 (T2) Lesions, New Gadolinium Enhanced (Gd+) Lesions and New T1 Lesions Per Subject Per Scan at Month 60
    End point description
    Number of CUA lesions, new T2 lesions, new Gd+ Lesions and new T1 lesions were measured by using MRI scans. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352). “n” signifies those subjects who were evaluated for this measure at the specified time point for each arm group respectively.
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: lesions
    arithmetic mean (standard deviation)
        CUA Lesions (n=102, 121, 110)
    1.46 ± 3.394
    1.6 ± 3.542
    1.94 ± 4.803
        New T2 Lesions (n=102, 121, 110)
    1.17 ± 2.576
    1.17 ± 2.628
    1.35 ± 3.284
        New Gd+ Lesions (n=102, 121, 110)
    0.24 ± 0.823
    0.36 ± 1.225
    0.48 ± 1.618
        New T1 Lesions (n=102, 120, 110)
    0.57 ± 1.656
    0.69 ± 1.659
    0.71 ± 1.917
    No statistical analyses for this end point

    Secondary: Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60

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    End point title
    Change From Baseline in Time Constant 1 (T1) Hypointense Volume, and Time Constant 2 (T2) Lesion Volume at Month 60
    End point description
    Change from baseline in lesion volume was measured by using MRI scans for T1 hypointense lesions and T2 lesions. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352). “n” signifies those subjects who were evaluated for this measure at the specified time point for each arm group respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: mm^3
    arithmetic mean (standard deviation)
        T1 lesion volume at Baseline (n=171,175,171)
    670.3 ± 1054.1
    774.8 ± 1288
    675 ± 1049.9
        Change at Month 60 (n=102,120,110)
    415 ± 1080.3
    412.3 ± 1020.8
    261.8 ± 1006.1
        T2 lesion volume at Baseline (n=171,175,171)
    3334.9 ± 3990.4
    3853.1 ± 4716.7
    3110.5 ± 3410.7
        Change at Month 60 (n=102,121,110)
    119.4 ± 2225.2
    25 ± 2827.1
    -188.5 ± 2576.1
    No statistical analyses for this end point

    Secondary: Percent change from baseline in Brain Volume at month 60

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    End point title
    Percent change from baseline in Brain Volume at month 60
    End point description
    Percent Change in brain volume was measured by using MRI scans. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352) and who were evaluable for this measure at this time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    98
    120
    110
    Units: percent change
        arithmetic mean (standard deviation)
    -1.82 ± 1.494
    -1.54 ± 1.378
    -2.03 ± 1.644
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Conversion to McDonald Multiple Sclerosis (MS) at Month 60

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    End point title
    Percentage of Subjects With Conversion to McDonald Multiple Sclerosis (MS) at Month 60
    End point description
    The McDonald criteria use dissemination in time and space established by MRI findings to provide a clinical diagnosis for MS. Dissemination in time is established by a new T2 or Gd+ lesion found on a repeat MRI. Dissemination in space is established by the presence of any 3 of the following: 1 Gd+ lesion or 9 T2 bright lesions if there is no enhancement; greater than or equal to 1 infratentorial lesion; greater than or equal to 1 juxtacortical lesion; greater than or equal to 3 periventricular lesions. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: percentage of subjects
        number (not applicable)
    84.2
    82.9
    72.5
    No statistical analyses for this end point

    Secondary: Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60

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    End point title
    Change From Baseline in Paced Auditory Serial Addition Test 3 (PASAT-3) Score at Month 60
    End point description
    The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Score ranges from ‘0-60’. Higher scores reflect better neurological function and a positive change from baseline indicates improvement. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352). “n” signifies those subjects who were evaluated for this measure at the specified time point for each arm group respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=171, 175, 171)
    0.0358 ± 0.8787
    -0.0909 ± 1.1223
    0.0031 ± 1.1387
        Change at Month 60 (n=112, 132, 118)
    0.4109 ± 0.6844
    0.4785 ± 0.9886
    0.4608 ± 0.863
    No statistical analyses for this end point

    Secondary: Percentage of Relapse-Free Subjects at Month 60

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    End point title
    Percentage of Relapse-Free Subjects at Month 60
    End point description
    A relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352).
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: Percentage of subjects
        number (not applicable)
    34.5
    45.1
    40.9
    No statistical analyses for this end point

    Secondary: Change From Baseline in Expanded Disability Status scale (EDSS) score at Month 60

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    End point title
    Change From Baseline in Expanded Disability Status scale (EDSS) score at Month 60
    End point description
    EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. The change in EDSS score at Month 60 was calculated as EDSS score at Month 60 minus EDSS score at baseline. Data has been presented as per planned analysis for integrated ITT population which included all subjects who were randomized in REFLEX study 27025 (NCT00404352). “n” signifies those subjects who were evaluated for this measure at the specified time point for each arm group respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=171,175,171)
    1.53 ± 0.77
    1.5 ± 0.72
    1.51 ± 0.83
        Change at Month 60 (n=111,133,117)
    -0.11 ± 0.94
    -0.01 ± 1.01
    0.04 ± 1.02
    No statistical analyses for this end point

    Secondary: Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60

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    End point title
    Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Month 60
    End point description
    The MSFC is a multidimensional clinical outcome measure of three sub-tests; Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Test-3(PASAT-3). The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The 9-Hole Peg Test is a quantitative measure of upper extremity function. The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Standardized results (Z-scores) of these sub-tests and the overall MSFC Z-score as an average of these 3 Z-scores was calculated. Higher Z-scores reflect better neurological function and a positive change from baseline indicates improvement. An increase in score indicates an improvement (range -3 to +3). Data was presented for integrated ITT population of 27025 (NCT00404352) study. “n”signifies those subjects who were evaluated for this measure at the specified time point for each arm respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 27025), Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated ITT population) RNF 44 Mcg Once Weekly (integrated ITT population) RNF 44 Mcg thrice Weekly (integrated ITT population)
    Number of subjects analysed
    171
    175
    171
    Units: Z-score
    arithmetic mean (standard deviation)
        MFSC score at Baseline (n=171,175,171)
    -0.0575 ± 0.6226
    0.0071 ± 0.6653
    0.0352 ± 0.5844
        Change at Month 60 (n=112,132,132)
    0.2192 ± 0.6229
    0.2213 ± 0.5602
    0.229 ± 0.4824
    No statistical analyses for this end point

    Secondary: Numbers of Subjects with Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60

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    End point title
    Numbers of Subjects with Binding Antibodies (BAb) and Neutralizing Antibody (NAb) at Month 60
    End point description
    BAbs are all antibodies which are capable of binding to the RNF irrespective of their binding site. NAbs are defined as a subgroup of BAbs which bind to the active sites of the RNF and therefore neutralize its potency. NAbs were detected using a viral cytopathic assay. BAbs were measured by using an ELISA. Data has been presented as per planned analysis for integrated DB population which included all subjects who received at least one dose of DB treatment in REFLEX study 27025 (NCT00404352) and who were evaluable for this measure at this time point.
    End point type
    Secondary
    End point timeframe
    Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (integrated DB population) RNF 44 Mcg Once Weekly (integrated DB population) RNF 44 Mcg thrice Weekly (integrated DB population)
    Number of subjects analysed
    115
    130
    115
    Units: Subjects
    number (not applicable)
        BAb-
    89
    99
    100
        BAb+
    25
    30
    15
        BAb (Missing)
    1
    1
    0
        Nab-
    97
    110
    102
        Nab+
    18
    20
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to treatment discontinuation

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    End point title
    Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs leading to treatment discontinuation
    End point description
    An AE was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition.
    End point type
    Secondary
    End point timeframe
    Month 24 up to Month 60
    End point values
    Placebo/RNF 44 Mcg thrice Weekly (DB safety population) RNF 44 Mcg Once Weekly (DB safety population) RNF 44 Mcg thrice Weekly (DB safety population)
    Number of subjects analysed
    84
    117
    99
    Units: Subjects
    number (not applicable)
        AEs
    70
    96
    84
        SAEs
    7
    7
    9
        AEs leading to discontinuation
    3
    0
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Month 24 to 60 for both DB safety population and OL safety population
    Adverse event reporting additional description
    An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with IMP, regardless of causal relationship and even if no IMP has been administered.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo/RNF 44 Mcg thrice Weekly (DB population)
    Reporting group description
    Subjects who were initially randomized in study 27025 (REFLEX) to the placebo treatment group were switched to single dose of fetal bovine serum [FBS]-free/human serum albumin [HSA]-free formulation of Interferon [IFN]-beta-1a (RNF) injection administered subcutaneously 3 times weekly at least 48 hours apart at a starting dose of 8.8 microgram (mcg) for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months or until conversion to clinically definite multiple sclerosis (CDMS) whichever occurs first.

    Reporting group title
    RNF 44 Mcg Once Weekly (DB population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously once weekly plus 2 matching placebo doses at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.

    Reporting group title
    RNF 44 Mcg Once Weekly /OL RNF 44 Mcg thrice Weekly
    Reporting group description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months.

    Reporting group title
    RNF 44 Mcg thrice Weekly (DB population)
    Reporting group description
    Single dose of RNF injection administered subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and then 44 mcg until 60 months or until conversion to CDMS whichever occurs first.

    Reporting group title
    Placebo/RNF 44 Mcg thrice Weekly/OL RNF 44 Mcg thrice weekly
    Reporting group description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received open-label (OL) study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months.

    Reporting group title
    RNF 44 Mcg thrice Weekly/OL RNF 44 Mcg thrice Weekly
    Reporting group description
    Subjects after having converted to CDMS during study 28981 (REFLEXION), received OL study treatment with RNF. Single dose of RNF injection administrated subcutaneously three times weekly at least 48 hours apart at a starting dose of 8.8 mcg for first 2 weeks followed by 22 mcg for next 2 weeks and finally 44 mcg until 60 months. The subjects who were converted to CDMS in study 27025 (REFLEX) and were enrolled in this study continued receiving RNF 44 mcg three times weekly until 60 months.

    Serious adverse events
    Placebo/RNF 44 Mcg thrice Weekly (DB population) RNF 44 Mcg Once Weekly (DB population) RNF 44 Mcg Once Weekly /OL RNF 44 Mcg thrice Weekly RNF 44 Mcg thrice Weekly (DB population) Placebo/RNF 44 Mcg thrice Weekly/OL RNF 44 Mcg thrice weekly RNF 44 Mcg thrice Weekly/OL RNF 44 Mcg thrice Weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 84 (8.33%)
    7 / 117 (5.98%)
    3 / 51 (5.88%)
    9 / 99 (9.09%)
    2 / 58 (3.45%)
    4 / 46 (8.70%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Venous insufficiency
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    1 / 51 (1.96%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Appendicectomy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma stage 0
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal distress syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fibula fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural fistula
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina stable
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    1 / 58 (1.72%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Foetal chromosome abnormality
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Lumbar radiculopathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    1 / 51 (1.96%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterovesical fistula
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    1 / 51 (1.96%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    1 / 58 (1.72%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess intestinal
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo/RNF 44 Mcg thrice Weekly (DB population) RNF 44 Mcg Once Weekly (DB population) RNF 44 Mcg Once Weekly /OL RNF 44 Mcg thrice Weekly RNF 44 Mcg thrice Weekly (DB population) Placebo/RNF 44 Mcg thrice Weekly/OL RNF 44 Mcg thrice weekly RNF 44 Mcg thrice Weekly/OL RNF 44 Mcg thrice Weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 84 (82.14%)
    97 / 117 (82.91%)
    37 / 51 (72.55%)
    84 / 99 (84.85%)
    46 / 58 (79.31%)
    36 / 46 (78.26%)
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 84 (5.95%)
    7 / 117 (5.98%)
    3 / 51 (5.88%)
    1 / 99 (1.01%)
    0 / 58 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    5
    7
    3
    1
    0
    1
    Injury, poisoning and procedural complications
    Overdose
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    8 / 51 (15.69%)
    0 / 99 (0.00%)
    2 / 58 (3.45%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    8
    0
    2
    1
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    2 / 51 (3.92%)
    0 / 99 (0.00%)
    1 / 58 (1.72%)
    3 / 46 (6.52%)
         occurrences all number
    0
    0
    2
    0
    1
    3
    Aspartate aminotransferase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    2 / 51 (3.92%)
    0 / 99 (0.00%)
    1 / 58 (1.72%)
    3 / 46 (6.52%)
         occurrences all number
    0
    0
    2
    0
    1
    3
    Blood creatine phosphokinase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    1 / 51 (1.96%)
    0 / 99 (0.00%)
    4 / 58 (6.90%)
    0 / 46 (0.00%)
         occurrences all number
    0
    0
    1
    0
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    2 / 51 (3.92%)
    0 / 99 (0.00%)
    3 / 58 (5.17%)
    2 / 46 (4.35%)
         occurrences all number
    0
    0
    2
    0
    3
    2
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    9 / 84 (10.71%)
    2 / 117 (1.71%)
    4 / 51 (7.84%)
    2 / 99 (2.02%)
    0 / 58 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    9
    2
    4
    2
    0
    1
    Lymphopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 84 (4.76%)
    1 / 117 (0.85%)
    0 / 51 (0.00%)
    5 / 99 (5.05%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    4
    1
    0
    5
    0
    0
    Neutropenia
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 84 (9.52%)
    3 / 117 (2.56%)
    4 / 51 (7.84%)
    5 / 99 (5.05%)
    0 / 58 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    8
    3
    4
    5
    0
    1
    Nervous system disorders
    Headache
    alternative assessment type: Systematic
         subjects affected / exposed
    11 / 84 (13.10%)
    19 / 117 (16.24%)
    6 / 51 (11.76%)
    16 / 99 (16.16%)
    4 / 58 (6.90%)
    9 / 46 (19.57%)
         occurrences all number
    11
    19
    6
    16
    4
    9
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    1 / 51 (1.96%)
    0 / 99 (0.00%)
    1 / 58 (1.72%)
    3 / 46 (6.52%)
         occurrences all number
    0
    0
    1
    0
    1
    3
    Migraine
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    3 / 51 (5.88%)
    0 / 99 (0.00%)
    1 / 58 (1.72%)
    0 / 46 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    Insomnia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    7 / 117 (5.98%)
    1 / 51 (1.96%)
    4 / 99 (4.04%)
    2 / 58 (3.45%)
    4 / 46 (8.70%)
         occurrences all number
    1
    7
    1
    4
    2
    4
    General disorders and administration site conditions
    Influenza like illness
    alternative assessment type: Systematic
         subjects affected / exposed
    45 / 84 (53.57%)
    39 / 117 (33.33%)
    12 / 51 (23.53%)
    17 / 99 (17.17%)
    11 / 58 (18.97%)
    10 / 46 (21.74%)
         occurrences all number
    45
    39
    12
    17
    11
    10
    Injection site erythema
    alternative assessment type: Systematic
         subjects affected / exposed
    17 / 84 (20.24%)
    6 / 117 (5.13%)
    8 / 51 (15.69%)
    8 / 99 (8.08%)
    4 / 58 (6.90%)
    2 / 46 (4.35%)
         occurrences all number
    17
    6
    8
    8
    4
    2
    Chills
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    3 / 51 (5.88%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    2 / 51 (3.92%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    0
    2
    0
    0
    3
    Ear and labyrinth disorders
    Vertigo
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 117 (0.85%)
    3 / 51 (5.88%)
    5 / 99 (5.05%)
    2 / 58 (3.45%)
    0 / 46 (0.00%)
         occurrences all number
    5
    1
    3
    5
    2
    0
    Psychiatric disorders
    Anxiety
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 84 (3.57%)
    7 / 117 (5.98%)
    0 / 51 (0.00%)
    4 / 99 (4.04%)
    2 / 58 (3.45%)
    3 / 46 (6.52%)
         occurrences all number
    3
    7
    0
    4
    2
    3
    Depression
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    6 / 117 (5.13%)
    0 / 51 (0.00%)
    2 / 99 (2.02%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    1
    6
    0
    2
    0
    0
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 84 (3.57%)
    8 / 117 (6.84%)
    0 / 51 (0.00%)
    3 / 99 (3.03%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    3
    8
    0
    3
    0
    0
    Toothache
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 117 (3.42%)
    0 / 51 (0.00%)
    4 / 99 (4.04%)
    0 / 58 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    5
    4
    0
    4
    0
    0
    Dyspepsia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    3 / 46 (6.52%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    3 / 51 (5.88%)
    0 / 99 (0.00%)
    0 / 58 (0.00%)
    2 / 46 (4.35%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    3 / 51 (5.88%)
    0 / 99 (0.00%)
    2 / 58 (3.45%)
    0 / 46 (0.00%)
         occurrences all number
    0
    0
    3
    0
    2
    0
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 84 (5.95%)
    7 / 117 (5.98%)
    2 / 51 (3.92%)
    6 / 99 (6.06%)
    5 / 58 (8.62%)
    5 / 46 (10.87%)
         occurrences all number
    5
    7
    2
    6
    5
    5
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    1 / 51 (1.96%)
    0 / 99 (0.00%)
    4 / 58 (6.90%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    1
    0
    4
    1
    Infections and infestations
    Bronchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 84 (3.57%)
    5 / 117 (4.27%)
    1 / 51 (1.96%)
    6 / 99 (6.06%)
    4 / 58 (6.90%)
    2 / 46 (4.35%)
         occurrences all number
    3
    5
    1
    6
    4
    2
    Cystitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    3 / 58 (5.17%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    Influenza
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 84 (3.57%)
    8 / 117 (6.84%)
    2 / 51 (3.92%)
    7 / 99 (7.07%)
    4 / 58 (6.90%)
    3 / 46 (6.52%)
         occurrences all number
    3
    8
    2
    7
    4
    3
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    12 / 84 (14.29%)
    14 / 117 (11.97%)
    7 / 51 (13.73%)
    9 / 99 (9.09%)
    6 / 58 (10.34%)
    4 / 46 (8.70%)
         occurrences all number
    12
    14
    7
    9
    6
    4
    Pharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 84 (0.00%)
    0 / 117 (0.00%)
    0 / 51 (0.00%)
    0 / 99 (0.00%)
    2 / 58 (3.45%)
    4 / 46 (8.70%)
         occurrences all number
    0
    0
    0
    0
    2
    4
    Upper respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 84 (11.90%)
    11 / 117 (9.40%)
    5 / 51 (9.80%)
    10 / 99 (10.10%)
    6 / 58 (10.34%)
    5 / 46 (10.87%)
         occurrences all number
    10
    11
    5
    10
    6
    5
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 84 (1.19%)
    8 / 117 (6.84%)
    3 / 51 (5.88%)
    3 / 99 (3.03%)
    2 / 58 (3.45%)
    4 / 46 (8.70%)
         occurrences all number
    1
    8
    3
    3
    2
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2009
    The purpose of this amendment was: - To ensure that AEs, concomitant medications and procedures that occurred prior to the baseline of Trial 28981 (i.e. within the 24 month period of Trial 27025) were collected only once -- i.e., in Trial 27025 rather than in Trial 28981. - Change of the visit window from ±21 days to ±7 days - Reduction of the number of visits required by subjects (i.e., visits at Months 25, 27, 33, 39, 45, 51 and 57 could be eliminated for some subjects)
    11 Jul 2011
    This amendment was substantial, global except in France. The purpose of this amendment was: - Introduction of new assessments (years of education and vocational status) at Month 60 - Clarification of operational aspects of the trial related to blood sampling - To include a provision for a possible switch of subjects from ow dosing to tiw dosing upon availability of the Month 36 results

    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
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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