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    Clinical Trial Results:
    Optic neuritis and early treatment with methylprednisolone.

    Summary
    EudraCT number
    		 2012-002628-34
    Trial protocol
    		 DK  
    Global end of trial date
    30 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2020
    First version publication date
    18 Feb 2020
    Other versions
    Summary report(s)
    		 Time to steroid treatment in severe acute optic neuritis

    Trial information

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    Trial identification
    Sponsor protocol code
    thorp8617-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Neurology, Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus, Denmark,
    Public contact
    Sclerosis Clinic (Gro H. Dale), Department of Neurology, Aarhus University Hospital, grodale@gmail.com
    Scientific contact
    Sclerosis Clinic (Gro H. Dale), Department of Neurology, Aarhus University Hospital, grodale@gmail.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
    28 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To see if early treatment of acute optic neuritis with high-dosis intravenous Solu-medrol, has effect on visual function at follow-up 6 months and 12 months later.
    Protection of trial subjects
    To decrease the risk of side-effects, oral treatment with a proton pump inhibitor (Pantoprazol 20 mg × 1 daily) and a 400 mg calcium and 19 μg (760 E) vitamin D combination (1 tablet × 2 daily) was added to the steroid treatment for the 3–5 days. If the patient reported severe side-effects, the treatment would be terminated prematurely (n = 0).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 49
    Worldwide total number of subjects
    49
    EEA total number of subjects
    49
    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)
    49
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Ninety consecutive patients suspected of having ON that were referred to three neurological and two ophthalmological departments, and private ophthalmologists, in the Central Region of Denmark (population nearly 1.3 million citizens) between December 1st 2012 and May 31st 2014, were considered for inclusion in this study.

    Pre-assignment
    Screening details
    		 Inclusion criteria: Age above 18 years, duration of symptoms less than 30 days, confirmation of optic neuritis (ON) by an ophthalmologist, previous ON and/or demyelinating disease, new ON. Exclusion criteria: A refractive error >8 from emmetropia, known previous retinal disease, pregnancy, inability to give informed consent, etc.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Blinding was not used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Patients with severe optic neuritis
    Arm description
    		 Twenty-eight patients with severe ON, defined as BCVA ≤ 0.5 decimal (0.30 logMAR) or BCVA >0.5 but severe amblyopia in the nonaffected eye (only one patient), were offered treatment with high-dose intravenous methylprednisolone (Solu-Medrol), 1 gram per day for 3–5 days. 22 patients accepted treatment, 6 patients declined the offer.
    Arm type
    		 Intervention (steroid treatment)

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1 gram Methylprednisolone (Solu-Medrol) intravenously per day for 3-5 days.

    Arm title
    		 Patients with mild/moderate optic neuritis.
    Arm description
    		 Twenty-one patients with mild/moderate ON were not offered treatment since the risk of side-effects from the treatment was considered to be higher than the possible benefits.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Patients with severe optic neuritis Patients with mild/moderate optic neuritis.
    Started
    28
    21
    Completed
    25
    21
    Not completed
    3
    0
         Consent withdrawn by subject
    2
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 49 patients with acute ON enrolled in the study.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 49 49
    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 (full range (min-max))
    		 34.9 (18 to 60) -
    Gender categorical
    Units: Subjects
        Female
    		 32 32
        Male
    		 17 17
    Subject analysis sets

    Subject analysis set title
    Treated within 1 week
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with severe optic neuritis treated with steroids within 1 week after symptom presentation.

    Subject analysis set title
    Treated later than 1 week
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with severe optic neuritis treated with steroids later than 1 week after symptom presentation.

    Subject analysis set title
    Non-treated
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with severe optic neuritis who declined the offer of steroid treatment.

    Subject analysis sets values
    		 Treated within 1 week Treated later than 1 week Non-treated
    Number of subjects
    9
    13
    6
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    35.6 (25 to 48)
    35.5 (23 to 54)
    35.7 (18 to 45)
    Gender categorical
    Units: Subjects
        Female
    4
    9
    5
        Male
    5
    4
    1

    End points

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    End points reporting groups
    Reporting group title
    Patients with severe optic neuritis
    Reporting group description
    		 Twenty-eight patients with severe ON, defined as BCVA ≤ 0.5 decimal (0.30 logMAR) or BCVA >0.5 but severe amblyopia in the nonaffected eye (only one patient), were offered treatment with high-dose intravenous methylprednisolone (Solu-Medrol), 1 gram per day for 3–5 days. 22 patients accepted treatment, 6 patients declined the offer.

    Reporting group title
    Patients with mild/moderate optic neuritis.
    Reporting group description
    		 Twenty-one patients with mild/moderate ON were not offered treatment since the risk of side-effects from the treatment was considered to be higher than the possible benefits.

    Subject analysis set title
    Treated within 1 week
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with severe optic neuritis treated with steroids within 1 week after symptom presentation.

    Subject analysis set title
    Treated later than 1 week
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with severe optic neuritis treated with steroids later than 1 week after symptom presentation.

    Subject analysis set title
    Non-treated
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with severe optic neuritis who declined the offer of steroid treatment.

    Primary: BCVA

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    End point title
    		 BCVA
    End point description
    End point type
    Primary
    End point timeframe
    Best corrected visual acuity (BCVA) was measured at baseline, 6 months and 12 months.
    End point values
    		 Patients with severe optic neuritis Patients with mild/moderate optic neuritis. Treated within 1 week Treated later than 1 week Non-treated
    Number of subjects analysed
    28
    21
    9
    13
    6
    Units: logMAR
        number (not applicable)
    28
    21
    9
    13
    6
    Statistical analysis title
    		 Repeated measurements of continuous data
    Statistical analysis description
    Continuous data were analyzed in a mixed model with nested effects and an unstructured covariance matrix for repeated measurement analysis of variance (ANOVA). An inspection of residuals and fitted values supported the validity of the model. Post hoc overall likelihood ratio tests and marginal Wald tests were calculated.
    Comparison groups
    Treated within 1 week v Treated later than 1 week v Non-treated
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Primary: Inter-eye thickness difference in GCIP layer

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    End point title
    		 Inter-eye thickness difference in GCIP layer
    End point description
    End point type
    Primary
    End point timeframe
    The inter-eye thickness difference (i.e. affected eye - fellow eye) of the ganglion cell + inner plexiform (GCIP) layer was measured at baseline, 6 months and 12 months.
    End point values
    		 Patients with severe optic neuritis Patients with mild/moderate optic neuritis. Treated within 1 week Treated later than 1 week Non-treated
    Number of subjects analysed
    28
    21
    9
    13
    6
    Units: µm
        number (not applicable)
    28
    21
    9
    13
    6
    Statistical analysis title
    		 Repeated measurements of continuous data
    Statistical analysis description
    Continuous data were analyzed in a mixed model with nested effects and an unstructured covariance matrix for repeated measurement analysis of variance (ANOVA). An inspection of residuals and fitted values supported the validity of the model. Post hoc overall likelihood ratio tests and marginal Wald tests were calculated.
    Comparison groups
    Treated within 1 week v Treated later than 1 week v Non-treated
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first day of treatment and for up to four days after terminated treatment.
    Adverse event reporting additional description
    The SAR/SAE are registered in the CRF, and an initial reporting at CIOSM-I form to the sponsor. A final reporting will be done when the patient has recovered or is not expected to recover any further. SAR/SAE will be noted on a list, which is sent yearly to the Danish Health Authorities and the Committees on Health Research Ethics.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Treated patients
    Reporting group description
    		 Patients with severe optic neuritis who were treated with iv. steroids.

    Serious adverse events
    		 Treated patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treated patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 22 (90.91%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Nervous system disorders
    Sleep disorder
         subjects affected / exposed
    10 / 22 (45.45%)
         occurrences all number
    10
    General disorders and administration site conditions
    General discomfort
         subjects affected / exposed
    6 / 22 (27.27%)
         occurrences all number
    6
    Tiredness
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Metallic taste in the mouth
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Skin rash
         subjects affected / exposed
    5 / 22 (22.73%)
         occurrences all number
    5
    Psychiatric disorders
    Euphoric mood
         subjects affected / exposed
    4 / 22 (18.18%)
         occurrences all number
    4
    Infections and infestations
    Infections
         subjects affected / exposed
    3 / 22 (13.64%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29931830
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