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    Clinical Trial Results:
    A 3-year, multi-center study to evaluate optical coherence tomography as an outcome measure in patients with multiple sclerosis

    Summary
    EudraCT number
    		 2011-001437-16
    Trial protocol
    		 DE  
    Global end of trial date
    07 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jan 2021
    First version publication date
    28 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CFTY720D2319
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02907281
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    24 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate optical coherence tomography (OCT) as a technique to detect and longitudinally follow the degeneration of retinal axons by measuring change in retinal nerve fiber layer (RNFL) thickness and overall average macular ganglion cell layer (mGCL) thickness in patients with relapsing-remitting multiple sclerosis (RRMS) followed for up to 36 months compared to a group of reference subjects (without neurologic or ophthalmic disease).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2012
    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
    Australia: 38
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Czechia: 32
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Germany: 56
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Spain: 77
    Country: Number of subjects enrolled
    Switzerland: 30
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    United States: 79
    Worldwide total number of subjects
    422
    EEA total number of subjects
    236
    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)
    422
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 28 investigative sites in 12 countries.

    Pre-assignment
    Screening details
    		 The trial had an screening period of up to one month.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MS patients
    Arm description
    		 Patients with a diagnosis of multiple sclerosis
    Arm type
    		 Test

    Investigational medicinal product name
    Multiple sclerosis disease-modifying therapies
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients with MS could have been untreated or treated with a commercially available MS disease-modifying therapies (DMTs). The most common prior DMTs were interferon and glatiramer and the most common route of administration was subcutaneous injection. The purpose of the trial was not to evaluate the efficacy or security of these therapies.

    Arm title
    		 Reference subjects
    Arm description
    		 Volunteer subjects without neurological or ophthalmic disease
    Arm type
    		 Reference

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		MS patients Reference subjects
    Started
    353
    69
    Completed
    302
    57
    Not completed
    51
    12
         Consent withdrawn by subject
    23
    6
         Adverse event, non-fatal
    2
    -
         Protocol deviation
    2
    -
         Administrative problems
    3
    1
         Unknown
    1
    -
         Lost to follow-up
    19
    5
         Abnormal test procedure result(s)
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MS patients
    Reporting group description
    		 Patients with a diagnosis of multiple sclerosis

    Reporting group title
    Reference subjects
    Reporting group description
    		 Volunteer subjects without neurological or ophthalmic disease

    Reporting group values
    		 MS patients Reference subjects Total
    Number of subjects
    		 353 69 422
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 353 69 422
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.1 ± 8.57 35.3 ± 9.66 -
    Gender Categorical
    Units: Subjects
        Female
    		 248 47 295
        Male
    		 105 22 127
    Race
    Units: Subjects
        Caucasian
    		 332 66 398
        Black
    		 6 0 6
        Asian
    		 5 2 7
        Other
    		 10 1 11

    End points

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    End points reporting groups
    Reporting group title
    MS patients
    Reporting group description
    		 Patients with a diagnosis of multiple sclerosis

    Reporting group title
    Reference subjects
    Reporting group description
    		 Volunteer subjects without neurological or ophthalmic disease

    Subject analysis set title
    MS patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All MS subjects who gave written informed consent to participate in the study, satisfied all eligibility criteria at screening, and provided a valid baseline and at least one post-baseline RNFL measurement in at least one eye.

    Subject analysis set title
    MS patients – Left eye
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MS patients with valid measurements in the left eye for a given endpoint.

    Subject analysis set title
    MS patients – Right eye
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MS patients with valid measurements in the right eye for a given endpoint.

    Subject analysis set title
    MS patients – All eyes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    MS patients with valid measurements in the left and/or right eye for a given endpoint.

    Subject analysis set title
    Reference subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All reference subjects who gave written informed consent to participate in the study, satisfied all eligibility criteria at screening, and provided a valid baseline and at least one post-baseline RNFL measurement in at least one eye.

    Subject analysis set title
    Reference subjects – Left eye
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Reference subjects with valid measurements in the left eye for a given endpoint.

    Subject analysis set title
    Reference subjects – Right eye
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Reference subjects with valid measurements in the right eye for a given endpoint.

    Subject analysis set title
    Reference Subjects – All eyes
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Reference subjects with valid measurements in the left and/or right eye for a given endpoint.

    Primary: Change from baseline in the RNFL thickness at Month 36 measured by OCT

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    End point title
    		 Change from baseline in the RNFL thickness at Month 36 measured by OCT
    End point description
    Change from baseline in retinal nerve fiber layer (RNFL) thickness, measured by optical coherence tomography (OCT), was investigated using the global score for RNFL thickness, which was calculated as the mean of the measurements of fields 1 to 8 from the circular scan of the optic nerve head (ONH). If at least one result from fields 1 to 8 was missing then the global score for RNFL thickness was not calculated. The change from baseline was derived as “measurement at post-baseline visit – measurement at baseline”.
    End point type
    Primary
    End point timeframe
    Baseline, Month 36
    End point values
    		 MS patients – Left eye MS patients – Right eye MS patients – All eyes Reference subjects – Left eye Reference subjects – Right eye Reference Subjects – All eyes
    Number of subjects analysed
    283
    277
    284 [1]
    55
    55
    56 [2]
    Units: microns
        arithmetic mean (standard deviation)
    -1.90 ± 3.490
    -1.32 ± 5.499
    -1.61 ± 4.600
    -0.17 ± 3.002
    -0.02 ± 2.988
    -0.09 ± 2.982
    Notes
    [1] - A total of 560 eyes were assessed.
    [2] - A total of 110 eyes were assessed.
    Statistical analysis title
    		 Change from baseline to Month 36 in RNFL thickness
    Comparison groups
    Reference Subjects – All eyes v MS patients – All eyes
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Mixed-model repeated measures (MMRM)
    Parameter type
    		 Least Squares (LS) mean difference
    Point estimate
    -1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 -1.17

    Secondary: Correlation of change from baseline in global score for RNFL thickness (microns) for the most affected eye at baseline with percentage change from baseline in brain volume (%)

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    End point title
    		 Correlation of change from baseline in global score for RNFL thickness (microns) for the most affected eye at baseline with percentage change from baseline in brain volume (%)
    End point description
    The RNFL thickness was measured by OCT and the brain volume was measured by magnetic resonance imaging (MRI). The relationship between change from baseline in global score for RNFL thickness (microns) for the most affected eye at baseline and percentage change from baseline in brain volume (%) was assessed graphically. Scatter plots at Month 36 were produced for MS patients and reference subjects separately, showing change in RNFL thickness on the x-axis and change in brain volume on the y-axis. To aid interpretation of these relationships, the Pearson product-moment correlation coefficient (r) was calculated and it is reported in this record for each group of participants.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 36
    End point values
    		 MS patients Reference subjects
    Number of subjects analysed
    284 [3]
    56 [4]
    Units: no units
        number (not applicable)
    0.020235
    0.026099
    Notes
    [3] - approximate number of participants analyzed.
    [4] - approximate number of participants analyzed.
    No statistical analyses for this end point

    Secondary: Correlation of change from baseline in mGCL thickness (microns) for the most affected eye at baseline with percentage change from baseline in brain volume (%)

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    End point title
    		 Correlation of change from baseline in mGCL thickness (microns) for the most affected eye at baseline with percentage change from baseline in brain volume (%)
    End point description
    The macular ganglion cell layer (mGCL) thickness was measured by OCT and the brain volume was measured by magnetic resonance imaging (MRI). The relationship between change from baseline in mGCL thickness (microns) for the most affected eye at baseline and percentage change from baseline in brain volume (%) was assessed graphically. Scatter plots at Month 36 were produced for MS patients and reference subjects separately, showing change in RNFL thickness on the x-axis and change in brain volume on the y-axis. To aid interpretation of these relationships, the Pearson product-moment correlation coefficient (r) was calculated and it is reported in this record for each group of participants.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 36
    End point values
    		 MS patients Reference subjects
    Number of subjects analysed
    285 [5]
    55 [6]
    Units: no units
        number (not applicable)
    0.111615
    -0.09672
    Notes
    [5] - approximate number of participants analyzed.
    [6] - approximate number of participants analyzed.
    No statistical analyses for this end point

    Secondary: Correlation of change from baseline in global score for RNFL thickness (microns) for the most affected eye at baseline with change from baseline in Expanded Disability Status Scale (EDSS) score

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    End point title
    		 Correlation of change from baseline in global score for RNFL thickness (microns) for the most affected eye at baseline with change from baseline in Expanded Disability Status Scale (EDSS) score
    End point description
    The RNFL thickness was measured by OCT and the disability was measured for MS patients only by the EDSS score, ranging from 0 (normal) to 10 (death due to multiple sclerosis). The relationship between change from baseline in global score for RNFL thickness (microns) for the most affected eye at baseline and change from baseline in EDSS score was assessed graphically. Scatter plots at Month 36 were produced for MS patients only, showing change in RNFL thickness on the x-axis and change in EDSS score on the y-axis. To aid interpretation of these relationships, the Pearson product-moment correlation coefficient (r) was calculated and it is reported in this record for MS patients.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 36
    End point values
    		 MS patients
    Number of subjects analysed
    284 [7]
    Units: no units
        number (not applicable)
    0.005841
    Notes
    [7] - approximate number of participants analyzed.
    No statistical analyses for this end point

    Secondary: Correlation of change from baseline in mGCL thickness (microns) for the most affected eye at baseline with change from baseline in Expanded Disability Status Scale (EDSS)

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    End point title
    		 Correlation of change from baseline in mGCL thickness (microns) for the most affected eye at baseline with change from baseline in Expanded Disability Status Scale (EDSS)
    End point description
    The mGCL thickness was measured by OCT and the disability was measured for MS patients only by the EDSS score, ranging from 0 (normal) to 10 (death due to multiple sclerosis). The relationship between change from baseline in mGCL thickness (microns) for the most affected eye at baseline and change from baseline in EDSS score was assessed graphically. Scatter plots at Month 36 were produced for MS patients only, showing change in RNFL thickness on the x-axis and change in EDSS score on the y-axis. To aid interpretation of these relationships, the Pearson product-moment correlation coefficient (r) was calculated and it is reported in this record for MS patients.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 36
    End point values
    		 MS patients
    Number of subjects analysed
    285 [8]
    Units: no units
        number (not applicable)
    -0.00425
    Notes
    [8] - approximate number of participants analyzed.
    No statistical analyses for this end point

    Secondary: Correlation of change from baseline in global score for RNFL thickness (microns) with change from baseline in visual acuity (total number of letters correct)

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    End point title
    		 Correlation of change from baseline in global score for RNFL thickness (microns) with change from baseline in visual acuity (total number of letters correct)
    End point description
    The RNFL thickness was measured by OCT and visual acuity was evaluated by the total number of letters correct from high-contrast and low-contrast tests. The relationship between change from baseline in global score for RNFL thickness (microns) and change from baseline in visual acuity (total number of letters correct) from high-contrast and low-contrast tests was assessed graphically. Scatter plots at Month 36 were produced for MS patients and reference subjects separately, showing change in RNFL thickness on the x-axis and change in visual acuity on the y-axis for both eyes separately. To aid interpretation of these relationships, the Pearson product-moment correlation coefficient (r) was calculated and it is reported in this record for each group of participants.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 36
    End point values
    		 MS patients – Left eye MS patients – Right eye Reference subjects – Left eye Reference subjects – Right eye
    Number of subjects analysed
    283 [9]
    277 [10]
    55 [11]
    55 [12]
    Units: no units
    number (not applicable)
        High-contrast visual test
    0.039801
    -0.00911
    -0.12477
    0.125906
        Low-contrast visual test
    -0.04888
    -0.00212
    -0.13731
    0.11323
    Notes
    [9] - approximate number of participants analyzed.
    [10] - approximate number of participants analyzed.
    [11] - approximate number of participants analyzed.
    [12] - approximate number of participants analyzed.
    No statistical analyses for this end point

    Secondary: Short-term reproducibility (ICC) of the mGCL thickness measure based on within-subject measures obtained between baseline and Month 1

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    End point title
    		 Short-term reproducibility (ICC) of the mGCL thickness measure based on within-subject measures obtained between baseline and Month 1
    End point description
    The intraclass correlation coefficient (ICC) can range from 0 to 1 with a value closer to 1 indicating better reproducibility. ICC was determined by fitting a 1-way ANOVA model with mGCL thickness as the response and subject as a random effect. ICC was then calculated by dividing (MSB–MSW) by (MSB+MSW), where MSB = between-subject mean square and MSW = within-subject mean square.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 1
    End point values
    		 MS patients – Left eye MS patients – Right eye Reference subjects – Left eye Reference subjects – Right eye
    Number of subjects analysed
    296
    288
    61
    60
    Units: no units
        number (confidence interval 95%)
    0.974 (0.967 to 0.979)
    0.971 (0.963 to 0.977)
    0.835 (0.741 to 0.897)
    0.904 (0.845 to 0.941)
    No statistical analyses for this end point

    Secondary: Change from baseline in the mGCL thickness at Month 36 measured by OCT

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    End point title
    		 Change from baseline in the mGCL thickness at Month 36 measured by OCT
    End point description
    Change from baseline in the mGCL thickness was investigated using the overall average mGCL thickness, which was calculated as the average of the 16 individual subfield areas measured using OCT. If at least one result was missing from any of the 16 individual subfields then the average was not calculated. The change from baseline was derived as “measurement at post-baseline visit – measurement at baseline”.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 36
    End point values
    		 MS patients – Left eye MS patients – Right eye MS patients – All eyes Reference subjects – Left eye Reference subjects – Right eye Reference Subjects – All eyes
    Number of subjects analysed
    283
    284
    285 [13]
    55
    54
    55 [14]
    Units: microns
        arithmetic mean (standard deviation)
    -0.30 ± 3.832
    -0.42 ± 3.990
    -0.36 ± 3.909
    -0.50 ± 3.823
    -1.20 ± 4.004
    -0.85 ± 3.911
    Notes
    [13] - A total of 567 eyes were assessed.
    [14] - A total of 109 eyes were assessed.
    Statistical analysis title
    		 Change from baseline to Month 36 in mGCL thickness
    Comparison groups
    MS patients – All eyes v Reference Subjects – All eyes
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3829
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 1.15

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from signature of informed consent until 30 days after the patient/subject had stopped study participation.
    Adverse event reporting additional description
    Any sign or symptom that occurs from signature of informed consent until 30 days after the patient/subject had stopped study participation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    MS patients
    Reporting group description
    		 MS patients

    Reporting group title
    Reference subjects
    Reporting group description
    		 Reference subjects

    Serious adverse events
    		 MS patients Reference subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 353 (7.08%)
    1 / 69 (1.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral venous disease
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    6 / 353 (1.70%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervix disorder
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranoia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypoparathyroidism
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MS patients Reference subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 353 (20.11%)
    15 / 69 (21.74%)
    Nervous system disorders
    Migraine
         subjects affected / exposed
    3 / 353 (0.85%)
    4 / 69 (5.80%)
         occurrences all number
    3
    4
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    17 / 353 (4.82%)
    6 / 69 (8.70%)
         occurrences all number
    18
    6
    Eye disorders
    Optic atrophy
         subjects affected / exposed
    24 / 353 (6.80%)
    1 / 69 (1.45%)
         occurrences all number
    26
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    21 / 353 (5.95%)
    2 / 69 (2.90%)
         occurrences all number
    32
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    18 / 353 (5.10%)
    6 / 69 (8.70%)
         occurrences all number
    31
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Aug 2011
    The main changes incorporated in this protocol amendment were the changes in Section 7 (Safety monitoring) of the protocol, which was modified to require all AEs, SAEs, and pregnancies to be reported and not just those reported in connection to a Novartis licensed pharmaceutical product.
    17 Jun 2013
    The primary objective was modified to remove reference to assessing RNFL thickness “to be useful as a monitoring tool”. In some countries, this monitoring with OCT devices was already part of medical practice for monitoring patients with MS. The investigational plan and study population were modified to clarify that healthy volunteers (control) group were to be enrolled in selected countries only, in addition to selected sites.
    07 Aug 2017
    The statistical methodology sections of the protocol were updated to align with the planned statistical analysis following input from advisors and steering committee members overseeing the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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