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    Clinical Trial Results:
    Multi-centre, randomized, double-blind, placebo-controlled, parallel-group, 9 month, equivalence trial comparing the efficacy and safety and tolerability of GTR (Synthon BV) to Copaxone® (Teva) in subjects with relapsing remitting multiple sclerosis followed by an open-label 15 month GTR treatment part evaluating the long-term GTR treatment effects

    Summary
    EudraCT number
    		 2011-000888-27
    Trial protocol
    		 CZ   BG   GB   DE   EE   GR   IT   RO  
    Global end of trial date
    16 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jul 2016
    First version publication date
    10 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GTR001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01489254
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Synthon BV
    Sponsor organisation address
    Microweg 22, Nijmegen, Netherlands, 6545 CM
    Public contact
    Clinical Development, Synthon BV, +31 24 3727700, clinicaltrials@synthon.com
    Scientific contact
    Clinical Development, Synthon BV, +31 24 3727700, clinicaltrials@synthon.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
    16 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the efficacy of Synthon’s glatiramer acetate (GTR) is equivalent to Copaxone® (TEVA) in subjects with relapsing remitting multiple sclerosis (RRMS) as measured by the number of gadolinium-enhancing lesions on T1-weighted MRIs during the months 7-9.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice according to the regulations and procedures described in the protocol. Written informed consent was obtained from each participant in the study. Approval from the independent Ethics Committees/Institutional Review Board was obtained before starting the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belarus: 65
    Country: Number of subjects enrolled
    Croatia: 16
    Country: Number of subjects enrolled
    Serbia: 62
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 24
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Russian Federation: 188
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Ukraine: 195
    Country: Number of subjects enrolled
    Moldova, Republic of: 26
    Country: Number of subjects enrolled
    Georgia: 32
    Country: Number of subjects enrolled
    South Africa: 15
    Country: Number of subjects enrolled
    Poland: 72
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Bulgaria: 31
    Country: Number of subjects enrolled
    Czech Republic: 20
    Country: Number of subjects enrolled
    Estonia: 3
    Worldwide total number of subjects
    796
    EEA total number of subjects
    175
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    796
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 1549 patients were assessed for eligibility of whom 796 subjects were randomized in a 4.3:4.3:1 ratio to receive generic glatiramer acetate (GTR), brand glatiramer acetate (Copaxone) or matching placebo.

    Pre-assignment
    Screening details
    		 Overall 1549 subjects were screened of whom 796 subjects were randomized into the study, two subjects were randomized to the generic glatiramer acetate group but did not start treatment

    Period 1
    Period 1 title
    Double-blind Part
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Glatiramer 20 mg
    Arm description
    		 Glatiramer Acetate (GTR) 20 mg daily for 9 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glatiramer Acetate 20 mg
    Investigational medicinal product code
    GTR
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20 mg/mL, 1 mL syringe, daily injections

    Arm title
    		 Copaxone 20 mg
    Arm description
    		 Glatiramer Acetate (Copaxone) 20 mg daily for 9 months
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Copaxone 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20 mg/mL, 1 mL syringe, daily injections

    Arm title
    		 Placebo
    Arm description
    		 Placebo daily for 9 months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mL syringe, daily injections

    Number of subjects in period 1
    		Glatiramer 20 mg Copaxone 20 mg Placebo
    Started
    355
    357
    84
    Completed
    330
    324
    81
    Not completed
    25
    33
    3
         Consent withdrawn by subject
    12
    20
    1
         Adverse event, non-fatal
    7
    2
    2
         Other
    4
    6
    -
         Pregnancy
    1
    3
    -
         Lost to follow-up
    1
    2
    -
    Period 2
    Period 2 title
    Open-label Extension Part
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Extension glatiramer 20 mg
    Arm description
    		 Glatiramer Acetate (GTR) 20 mg daily for 15 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glatiramer Acetate 20 mg
    Investigational medicinal product code
    GTR
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20 mg/mL, 1 mL syringe, daily injections

    Number of subjects in period 2 [1]
    		Extension glatiramer 20 mg
    Started
    728
    Completed
    670
    Not completed
    58
         Consent withdrawn by subject
    30
         Adverse event, non-fatal
    10
         Other
    5
         Pregnancy
    3
         Lost to follow-up
    9
         Protocol deviation
    1
    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: 735 completed the DB part, 729 were eligible to continue in the OL part, 1 opted not to continue

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Glatiramer 20 mg
    Reporting group description
    		 Glatiramer Acetate (GTR) 20 mg daily for 9 months

    Reporting group title
    Copaxone 20 mg
    Reporting group description
    		 Glatiramer Acetate (Copaxone) 20 mg daily for 9 months

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo daily for 9 months

    Reporting group values
    		 Glatiramer 20 mg Copaxone 20 mg Placebo Total
    Number of subjects
    		 355 357 84 796
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.6 ( 8.6 ) 33.8 ( 9 ) 32.6 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 234 238 57 529
        Male
    		 121 119 27 267
    Time from onset of symptoms to randomization (y)
    Units: Years
        arithmetic mean (standard deviation)
    		 5.5 ( 5.3 ) 6.4 ( 6 ) 5.7 ( 6 ) -
    No. of relapses in prior 2 y
    Units: Relapses
        arithmetic mean (standard deviation)
    		 1.9 ( 0.9 ) 1.8 ( 0.9 ) 1.9 ( 0.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Glatiramer 20 mg
    Reporting group description
    		 Glatiramer Acetate (GTR) 20 mg daily for 9 months

    Reporting group title
    Copaxone 20 mg
    Reporting group description
    		 Glatiramer Acetate (Copaxone) 20 mg daily for 9 months

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo daily for 9 months
    Reporting group title
    Extension glatiramer 20 mg
    Reporting group description
    		 Glatiramer Acetate (GTR) 20 mg daily for 15 months

    Primary: The number of T1-Gadolinium enhancing lesions during months 7-9

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    End point title
    		 The number of T1-Gadolinium enhancing lesions during months 7-9
    End point description
    End point type
    Primary
    End point timeframe
    9 months
    End point values
    		 Glatiramer 20 mg Copaxone 20 mg Placebo
    Number of subjects analysed
    353
    357
    84
    Units: Number of Gd lesions
    arithmetic mean (confidence interval 95%)
        Number of Gd lesions (study sensitivity)
    0.42 (0.31 to 0.57)
    0.38 (0.28 to 0.52)
    0.82 (0.57 to 1.2)
        Number of Gd lesions (equivalence)
    0.45 (0.34 to 0.59)
    0.41 (0.31 to 0.54)
    0 (0 to 0)
    Statistical analysis title
    		 Study sensitivity
    Statistical analysis description
    Estimates represent the mean total lesions during months 7 through 9 and were estimated from the fitted random effect generalized linear model (longitudinal model) with a negative binomial distribution and logaritmic link function. To assess study sensitivity, data of the active treatment groups and placebo were included in the model, resulting in the ratios and 95% CIs for the combined Glatiramer 20 mg and Copaxone 20 mg treatment group and the individual treatments over placebo.
    Comparison groups
    Copaxone 20 mg v Placebo v Glatiramer 20 mg
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 Ratio (or Ratio of estimated means)
    Point estimate
    0.488
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.365
         upper limit
    		 0.651
    Notes
    [1] - To conclude study sensitivity the combined active treatment groups Glatiramer 20 mg and Copaxone 20 mg needed to be superior to placebo.
    Statistical analysis title
    		 Equivalence
    Statistical analysis description
    Estimates represent the mean total lesions during months 7 through 9 and were estimated from the fitted random effect generalized linear model (longitudinal model) with a negative binomial distribution and logaritmic link function including Glatiramer 20 mg and Copaxone 20 mg treatment groups to assess study equivalence.
    Comparison groups
    Glatiramer 20 mg v Copaxone 20 mg
    Number of subjects included in analysis
    710
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Ratio (or Ratio of estimated means)
    Point estimate
    1.095
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.883
         upper limit
    		 1.36
    Notes
    [2] - To conclude equivalence between Glatiramer 20 mg and Copaxone 20 mg, efficacy in the combined active treatment groups needed to be superior to placebo (confirming study sensitivity) and the 2-sided 95% CI for the estimated ratio of Glatiramer 20 mg to Copaxone 20 mg needed to be fully enclosed in the prespecified equivalence margin (0.727 - 1.375). Study sensitivity was already concluded in statistical analysis "Study sensitivity".

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Total trial period
    Adverse event reporting additional description
    The safety population consisted of all subjects who received at least 1 injection with study treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Glatiramer Acetate 20 mg
    Reporting group description
    		 -

    Reporting group title
    Copaxone 20 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Extension Glatiramer 20 mg
    Reporting group description
    		 -

    Serious adverse events
    		 Glatiramer Acetate 20 mg Copaxone 20 mg Placebo Extension Glatiramer 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 353 (3.40%)
    17 / 357 (4.76%)
    2 / 84 (2.38%)
    22 / 728 (3.02%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous sytem
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    2 / 728 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioblastoma multiforme
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign hydatidiform mole
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Immediate post-injection reaction
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactoid reaction
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    1 / 84 (1.19%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    2 / 728 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 353 (0.57%)
    4 / 357 (1.12%)
    0 / 84 (0.00%)
    5 / 728 (0.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculitis cervical
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Secondary progressive multiple sclerosis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 357 (0.56%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    1 / 84 (1.19%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 357 (0.28%)
    0 / 84 (0.00%)
    0 / 728 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    0 / 84 (0.00%)
    1 / 728 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Glatiramer Acetate 20 mg Copaxone 20 mg Placebo Extension Glatiramer 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    175 / 353 (49.58%)
    190 / 357 (53.22%)
    47 / 84 (55.95%)
    252 / 728 (34.62%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 353 (4.53%)
    12 / 357 (3.36%)
    7 / 84 (8.33%)
    16 / 728 (2.20%)
         occurrences all number
    21
    12
    11
    19
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    58 / 353 (16.43%)
    62 / 357 (17.37%)
    6 / 84 (7.14%)
    15 / 728 (2.06%)
         occurrences all number
    79
    86
    8
    18
    Immediate post-injection reaction
         subjects affected / exposed
    24 / 353 (6.80%)
    17 / 357 (4.76%)
    0 / 84 (0.00%)
    11 / 728 (1.51%)
         occurrences all number
    48
    23
    0
    16
    Injection site swelling
         subjects affected / exposed
    14 / 353 (3.97%)
    12 / 357 (3.36%)
    3 / 84 (3.57%)
    4 / 728 (0.55%)
         occurrences all number
    26
    15
    4
    6
    Injection site pain
         subjects affected / exposed
    11 / 353 (3.12%)
    13 / 357 (3.64%)
    1 / 84 (1.19%)
    7 / 728 (0.96%)
         occurrences all number
    17
    21
    1
    12
    Injection site haematoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 357 (0.00%)
    3 / 84 (3.57%)
    0 / 728 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Injection site bruising
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 357 (0.00%)
    3 / 84 (3.57%)
    1 / 728 (0.14%)
         occurrences all number
    0
    0
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 353 (3.68%)
    23 / 357 (6.44%)
    6 / 84 (7.14%)
    39 / 728 (5.36%)
         occurrences all number
    20
    28
    9
    52
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 353 (1.70%)
    6 / 357 (1.68%)
    3 / 84 (3.57%)
    5 / 728 (0.69%)
         occurrences all number
    7
    6
    3
    6
    Respiratory tract infection
         subjects affected / exposed
    2 / 353 (0.57%)
    4 / 357 (1.12%)
    4 / 84 (4.76%)
    4 / 728 (0.55%)
         occurrences all number
    2
    4
    7
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2012
    As per Protocol Amendment 1 (i) a local tolerance assessment was added at the start of the open label phase (month 9), (ii) subjects with active disease who experienced a relapse after being found eligible were allowed to be randomized and, (iii) subjects who could not start day 1 assessments due to logistical reasons beyond their control were allowed an extended screening window of maximally 90 days.
    31 May 2013
    As per Protocol Amendment 2 additional requirements were formulated in the protocol related to the inclusion criteria and characteristics for patients or volunteers undergoing an MRI test scan to qualify each imaging site prior to the start of screening trial participants.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26458034
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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