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    Clinical Trial Results:
    A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with phenytoin in acute optic neuritis

    Summary
    EudraCT number
    		 2011-003475-11
    Trial protocol
    		 GB  
    Global end of trial date
    06 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Apr 2016
    First version publication date
    30 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCL/11/0083
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01451593
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom,
    Public contact
    CTIMPs , University College London (UCL), 0044 020 7679 6802, ctimps@ucl.ac.uk
    Scientific contact
    CTIMPs, University College London (UCL), 0044 020 7679 6802, ctimps@ucl.ac.uk
    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
    18 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In optic neuritis, there is inflammation of the optic nerve, which carries visual information from the eye into the brain. People with optic neuritis lose vision in the eye affected by the disorder, and vision may not recover fully. Current therapy for optic neuritis can lead to a faster recovery of vision, but does not improve the extent to which vision would recover eventually without treatment. Recent work suggests that loss of vision is due to damage to the nerve fibres in the optic nerve (which is accompanied by damage to the nerve fibres in the retina), that the damage is secondary to a buildup of sodium in these fibres, and that it can be prevented by blocking the entry of sodium into them. In this clinical trial, the principal objective is to assess whether immediate and sustained blockade of the entry of sodium into nerve fibres with the drug phenytoin protects nerve fibres in the retina and optic nerve from degeneration after an attack of optic neuritis.
    Protection of trial subjects
    Full blood count, urea, electrolytes, liver function tests were taken at the screening visit and each subsequent visit to ensure safety. Urine pregnancy test and ECG were also performed at the screening visit to ensure there was no contraindication to phenytoin. Aqua porin 4 antibodies were also taken at the the screening visit and patients found to be seropositive withdrawn from the trial. Participants were assessed clinically by a treating physician at 1, 3 and 6 months from baseline to assess safety
    Background therapy
    		 Concurrent treatment with glatiramer acetate or interferon beta was permitted and corticosteroids for acute optic neuritis could be given at the treating physician’s discretion (all participants were offered equivalent regimens of methylprednisolone, either 1 g intravenously daily for 3 days, or 500 mg orally daily for 5 days).
    Evidence for comparator
    		 Corticosteroids hasten recovery after optic neuritis without affecting the final prognosis for recovery. Also previous studies show that corticosteroids do not prevent atrophy of the RNFL or optic nerve, nor visual recovery after optic neuritis and immunomodulation has so far had limited effects on progressive disability. Currently there are no treatments that affect outcome after optic neuritis or other MS relapses. Hence, neuroprotection for both processes contributing to axonal loss and disability remains a key unmet need in optic neuritis and MS. The anterior visual system has many advantages for testing neuroprotection in MS: acute demyelinating optic neuritis (AON) is a common and often presenting manifes-tation of MS; the inflammatory optic nerve lesion is comparable to plaques found elsewhere in the central nervous system; and the visual system can be studied using clinical, electrophysiological and imaging techniques. In addition, the optic nerve le-sion leads to retrograde degeneration of the retinal nerve fibre layer (RNFL), a relatively pure compartment of unmyelinated axons whose thickness can be measured sensitively and non-invasively using optical coherence tomography (OCT). Therefore, the RNFL thickness provides a plausible biomarker of axonal loss. Reduction of RNFL thickness also corresponds with visual loss in AON and with changes of disability in MS, suggesting that it may provide information on treatment response that is also clinically relevant.
    Actual start date of recruitment
    03 Oct 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
    United Kingdom: 92
    Worldwide total number of subjects
    92
    EEA total number of subjects
    92
    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)
    92
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited between Feb 3, 2012, and May 22, 2014, and we performed the final assessments in December, 2014 Patients were recruited from one two trial centres in London and Sheffield, UK, or were referred there from a UK network of patient identification centres,

    Pre-assignment
    Screening details
    		 Patients were eligible if they were aged 18–60 years, had a clinical diagnosis of unilateral acute demyelinating optic neuritis with no alternative pathological abnormalities on OCT at presentation), visual acuity of 6/9 or worse, and an interval of 14 days or less between onset of vision loss and randomisation

    Pre-assignment period milestones
    Number of subjects started
    		 92
    Number of subjects completed
    		 86

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 6
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Participants were randomly assigned (1:1) to phenytoin or placebo via an online randomisation service. Participants were allocated a randomisation code by the treating physician, which was matched to a confidential treatment list by the study pharmacist to assign participants either to phenytoin or placebo (which were identical in appearance). Only the pharmacist was aware of treatment allocation. Treating and assessing physicians and participants were masked to treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active
    Arm description
    		 Participants were loaded orally with a total dose of 15 mg per kg of bodyweight divided into three equal doses (each rounded up to the nearest 50 mg) for a period of 3 days. A daily maintenance dose of 4 mg per kg of bodyweight (rounded up to the nearest 50 mg, to a maximum of 350 mg) was given for 3 months, and was increased to 6 mg per kg of bodyweight from July 17, 2013, at the recommendation of the data monitoring and ethics committee to achieve higher serum drug concentrations, because concentrations with the lower dose were thought to be sub therapeutic.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Phenytoin
    Investigational medicinal product code
    Other name
    Epanuitin
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    articipants were loaded orally with a total dose of 15 mg per kg of bodyweight divided into three equal doses (each rounded up to the nearest 50 mg) for a period of 3 days A daily maintenance dose of 4 mg per kg of bodyweight (rounded up to the nearest 50 mg, to a maximum of 350 mg) was given for 3 months, and was increased to 6 mg per kg of bodyweight from July 17, 2013, at the recommendation of the data monitoring and ethics committee to achieve higher serum drug concentrations, because concentrations with the lower dose were thought to be sub therapeutic.

    Arm title
    		 Placebo
    Arm description
    		 Capsules were over-encapsulated with matching active and placebo capsules to maintain blinding. The placebo capsules contained no active ingredient
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules were over-encapsulated with matching active and placebo capsules to maintain blinding. The placebo capsules contained no active ingredient

    Number of subjects in period 1 [1]
    		Active Placebo
    Started
    42
    44
    Completed
    39
    42
    Not completed
    3
    2
         Lost to follow-up
    3
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 92 patients were initially enrolled into the trial but 6 patients were subsequently withdrawn after entry into the trial due to alternative diagnoses - this is the reason for this discrepancy

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Participants were loaded orally with a total dose of 15 mg per kg of bodyweight divided into three equal doses (each rounded up to the nearest 50 mg) for a period of 3 days. A daily maintenance dose of 4 mg per kg of bodyweight (rounded up to the nearest 50 mg, to a maximum of 350 mg) was given for 3 months, and was increased to 6 mg per kg of bodyweight from July 17, 2013, at the recommendation of the data monitoring and ethics committee to achieve higher serum drug concentrations, because concentrations with the lower dose were thought to be sub therapeutic.

    Reporting group title
    Placebo
    Reporting group description
    		 Capsules were over-encapsulated with matching active and placebo capsules to maintain blinding. The placebo capsules contained no active ingredient

    Reporting group values
    		 Active Placebo Total
    Number of subjects
    		 42 44 86
    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)
    		 33 ± 8.2 35 ± 9.1 -
    Gender categorical
    Units: Subjects
        Female
    		 31 32 63
        Male
    		 11 12 23

    End points

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    End points reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Participants were loaded orally with a total dose of 15 mg per kg of bodyweight divided into three equal doses (each rounded up to the nearest 50 mg) for a period of 3 days. A daily maintenance dose of 4 mg per kg of bodyweight (rounded up to the nearest 50 mg, to a maximum of 350 mg) was given for 3 months, and was increased to 6 mg per kg of bodyweight from July 17, 2013, at the recommendation of the data monitoring and ethics committee to achieve higher serum drug concentrations, because concentrations with the lower dose were thought to be sub therapeutic.

    Reporting group title
    Placebo
    Reporting group description
    		 Capsules were over-encapsulated with matching active and placebo capsules to maintain blinding. The placebo capsules contained no active ingredient

    Primary: Active-placebo difference in mean 6 month RNFL thickness adjusted for the baseline RNFL thickness of the unaffected eye

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    End point title
    		 Active-placebo difference in mean 6 month RNFL thickness adjusted for the baseline RNFL thickness of the unaffected eye
    End point description
    High resolution spectral domain OCT images (Spectralis, software version 5.4B, Heidelberg Engineering, Heidelberg, Germany) were acquired at baseline and 6 months using identical protocols at both sites. RNFL measurements used a 3·45 mm diameter circle scan.
    End point type
    Primary
    End point timeframe
    Mean RNFL thickness was measured at baseline and at 6 months
    End point values
    		 Active Placebo
    Number of subjects analysed
    39
    42
    Units: microns
        arithmetic mean (standard deviation)
    81.46 ± 16.27
    74.29 ± 15.14
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    We used an ANCOVA analysis method, using multiple linear regression of the 6-month RNFL of the affected eye on a trial arm indicator with the following prespecified covariates: baseline RNFL thickness in the fellow eye, centre (binary), days between onset and baseline assessment, and whether the participant was prescribed corticosteroids at the time of baseline assessment (no vs 1–5 days before assessment vs 6–30 days before assessment).
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 ≤ 0.05 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [1] - The trial was powered to detect a treatment effect of 50% at a 5% significance level at 80% power while allowing for a 20% combined rate of loss to follow-up and non-adherence.
    [2] - Statistical significance, where referred to, indicates a p value of less than 0·05, and all p values refer to two-tailed tests. When regression residuals showed signs of non- normality or heteroscedasticity, we checked p values using a permutation te

    Secondary: Active-placebo difference in mean 6 month logMAR visual acuity adjusted for the baseline measurement in the unaffected eye

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    End point title
    		 Active-placebo difference in mean 6 month logMAR visual acuity adjusted for the baseline measurement in the unaffected eye
    End point description
    Best corrected high-contrast logMAR visual acuity was measured using retro-illuminated Early Treatment Diabetic Retinopathy Study charts at 4 m. When no letters could be correctly identified, a score of 1·7 was assigned by the masked researcher.
    End point type
    Secondary
    End point timeframe
    Best corrected logMAR visual acuity was measured at baseline and 6 months
    End point values
    		 Active Placebo
    Number of subjects analysed
    39
    42
    Units: logMAR
        arithmetic mean (standard deviation)
    0.09 ± 0.4
    0.04 ± 0.18
    Statistical analysis title
    		 Secondary endpoints
    Statistical analysis description
    We analysed secondary outcomes in the same way as the primary outcome measure using the corresponding baseline fellow-eye value of the outcome and the same prespecified covariates.
    Comparison groups
    Placebo v Active
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 ≤ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [3] - The trial was powered to detect a treatment effect of 50% at a 5% significance level at 80% power for the primary outcome measure while allowing for a 20% combined rate of loss to follow-up and non-adherence. The trial was not powered to detect treatment effects in the secondary outcome measures

    Secondary: Active-placebo difference in mean 6 month low contrast letter score (2.5%) adjusted for the baseline measurement in the unaffected eye

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    End point title
    		 Active-placebo difference in mean 6 month low contrast letter score (2.5%) adjusted for the baseline measurement in the unaffected eye
    End point description
    low-contrast letter scores were measured at baseline and 6 months using retro- illuminated 1·25% and 2·5% Sloan charts (Precision Vision, La Salle, IL, USA) using best refractive correction for each eye at 2 m.
    End point type
    Secondary
    End point timeframe
    Low contrast letters scores at both 1.25% and 2.5% were measured at baseline and 6 months
    End point values
    		 Active Placebo
    Number of subjects analysed
    39
    42
    Units: low contrast letter score
        arithmetic mean (standard deviation)
    19.69 ± 13.8
    17.55 ± 14.19
    Statistical analysis title
    		 Secondary endpoints
    Statistical analysis description
    We analysed secondary outcomes in the same way as the primary outcome measure using the corresponding baseline fellow-eye value of the outcome and the same prespecified covariates.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Active-placebo difference in mean 6 month FM-Hue 100 error score adjusted for the baseline measurement in the unaffected eye

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    End point title
    		 Active-placebo difference in mean 6 month FM-Hue 100 error score adjusted for the baseline measurement in the unaffected eye
    End point description
    Colour vision was assessed by masked researchers using the Farnsworth-Munsell 100 hue test and recorded as the total error score. This test was assessed under standard daylight conditions using daylight linear full-spectrum bulbs with a colour temperature of 6500 K in participants with a logMAR visual acuity better than 1·0.
    End point type
    Secondary
    End point timeframe
    FM-Huee 100 error score was measured at baseline and 6 months
    End point values
    		 Active Placebo
    Number of subjects analysed
    39
    42
    Units: FM-Hue 100 error score
        arithmetic mean (standard deviation)
    181.28 ± 223.79
    195.24 ± 212.61
    Statistical analysis title
    		 Secondary outcome analysis
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: active-placebo difference in mean total macular volume adjusted for the baseline measurement in the unaffected eye

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    End point title
    		 active-placebo difference in mean total macular volume adjusted for the baseline measurement in the unaffected eye
    End point description
    A fast macular volume scan (20 x20° field, 25 horizontal B scans, ART 9) was performed using a Heidelberg Spectralis machine. Scans were excluded if they had a signal strength of <25 or violated international consensus quality control criteria.
    End point type
    Secondary
    End point timeframe
    Macular volume was measured at baseline and 6 months
    End point values
    		 Active Placebo
    Number of subjects analysed
    39
    42
    Units: mm3
        arithmetic mean (standard deviation)
    8.25 ± 0.45
    8.07 ± 0.42
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Secondary outcomes were analysed in a similar way to the primary outcome measure, with the corresponding baseline fellow-eye value and the same pre-specified covariates.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 ≤ 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         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
    Adverse events were recorded for the 6 month follow up period
    Adverse event reporting additional description
    Adverse events were analysed in all randomised patients including those lost to follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Participants were loaded orally with a total dose of 15 mg per kg of bodyweight divided into three equal doses (each rounded up to the nearest 50 mg) for a period of 3 days. A daily maintenance dose of 4 mg per kg of bodyweight (rounded up to the nearest 50 mg, to a maximum of 350 mg) was given for 3 months, and was increased to 6 mg per kg of bodyweight from July 17, 2013, at the recommendation of the data monitoring and ethics committee to achieve higher serum drug concentrations, because concentrations with the lower dose were thought to be sub therapeutic.

    Reporting group title
    Placebo
    Reporting group description
    		 Capsules were over-encapsulated with matching active and placebo capsules to maintain blinding. The placebo capsules contained no active ingredient

    Serious adverse events
    		 Active Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 42 (11.90%)
    2 / 44 (4.55%)
         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)
    Breast cancer female
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Incidental finding of dilated superior opthalmic vein seen on MRI
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital malformation
    Additional description: Microtia following unplanned conception after randomisation
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Appendicitis
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cellulitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe rash
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 44 (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: 1%
    Non-serious adverse events
    		 Active Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 42 (80.95%)
    40 / 44 (90.91%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 42 (42.86%)
    15 / 44 (34.09%)
         occurrences all number
    18
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 42 (7.14%)
    17 / 44 (38.64%)
         occurrences all number
    3
    17
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 42 (11.90%)
    7 / 44 (15.91%)
         occurrences all number
    5
    7
    Skin and subcutaneous tissue disorders
    rash
         subjects affected / exposed
    8 / 42 (19.05%)
    1 / 44 (2.27%)
         occurrences all number
    8
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2011
    This amendment was sent as a part of the changes MHRA mentioned in the grounds of Non acceptance. New version of the protocol was submitted to the MHRA.
    24 Oct 2011
    This amendment was done as part of the changes required as per the provisional opinion from the ethics committee. Main study and sub study patient information sheets were modified and sent to the Ethics committee for approvals.
    02 Jul 2012
    Changes were done to Protocol and Patient Information Sheet. Protocol changes include minor changes to the inclusion criteria, schematic diagram of overall trial design, and minor treatment procedures.
    09 Nov 2012
    This amendment was done to reflect the change in the IMP supplier used in the Trial. The license was transferred from Pfizer to Flynn Pharma. This is administrative change and hence the protocol and IMPD were updated and notified to the MHRA
    05 Jun 2013
    The maintenance dose of the study drug was increased from 4mg/kg to 6mg/kg. The protocol has been updated to reflect the change and was notified to the regulatory bodies in the UK.

    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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