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    Clinical Trial Results:
    Can simvastatin significantly reduce the amount of immunosuppressive medication required by patients with sight threatening uveitis? A phase IIb, single site, randomized, placebo controlled, double blinded trial.

    Summary
    EudraCT number
    2014-003119-13
    Trial protocol
    GB  
    Global end of trial date
    20 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Apr 2019
    First version publication date
    11 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14/0172
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02252328
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCL
    Sponsor organisation address
    Joint Research Office, Gower Street , London , United Kingdom, WC1E 6BT
    Public contact
    Sue Lightman, UCL, +44 20 7566-2266, s.lightman@ucl.ac.uk
    Scientific contact
    Sue Lightman, UCL, +44 20 7566-2266, s.lightman@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
    15 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine whether the mean reduction in prednisolone dosage achieved at 12 months is greater in the simvastatin group compared to the placebo treated group?
    Protection of trial subjects
    Repeat clinical assessments and assessment of any adverse event. Monitoring of complete blood tests and blood chemistry including lipid and creatinine kinase levels.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Sep 2015
    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
    United Kingdom: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    33
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The patient’s recruitment process started in Sep 2015.Trial candidates were selected from the pool of patients under the care of one consultant (SL) at Moorfields Eye Hospital. Eligibility for the trial was assessed and patients were offered the trial Participant's information sheet was given before subject's enrolment as per study protocol.

    Pre-assignment
    Screening details
    A detailed medical history including current medications was performed. The information obtained were checked against the study inclusion and exclusion criteria. Finally, a consent form was obtained before subjects enrolment.

    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
    Blinding implementation details
    We used an online software application (Sealed envelope) for randomising patients into the trial. A random code was generated after confirming that the patient does meet all the inclusion criteria and dose not meet any exclusion criteria. During the trial subjects received double encapsulated IMPs.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo drug
    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
    Placebo

    Arm title
    Simvastatin
    Arm description
    Simvastatin 80mg
    Arm type
    Active comparator

    Investigational medicinal product name
    Simvastatin 80mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Simvastatin 80mg

    Number of subjects in period 1
    Placebo Simvastatin
    Started
    17
    16
    Completed
    16
    16
    Not completed
    1
    0
         Adverse event, serious fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo drug

    Reporting group title
    Simvastatin
    Reporting group description
    Simvastatin 80mg

    Reporting group values
    Placebo Simvastatin Total
    Number of subjects
    17 16 33
    Age categorical
    Units: Subjects
        Adults between 18 and 80 years old
    17 16 33
    Gender categorical
    Units: Subjects
        Female
    11 10 21
        Male
    6 6 12
    Subject analysis sets

    Subject analysis set title
    Analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The primary outcome is prednisolone dose measured at 12 months. The main statistical analyses will estimate the difference in mean prednisolone dose between patients randomised to simvastatin and placebo by intention to treat at 12 months. Group difference estimates and corresponding confidence intervals will be reported.Initially, prednisolone dose at 12 months will be described for each treatment group using means and standard deviations. In addition, plots will be produced that show dosing over time (every 3 months) for each group and the percentage of patients whose dose is under 10mg (safe dose). The outcome will be formally compared between treatment groups using a linear regression model (below) that adjusts for baseline dose. All modelling assumptions will be checked.

    Subject analysis sets values
    Analysis
    Number of subjects
    32
    Age categorical
    Units: Subjects
        Adults between 18 and 80 years old
    32
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    20
        Male
    12

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo drug

    Reporting group title
    Simvastatin
    Reporting group description
    Simvastatin 80mg

    Subject analysis set title
    Analysis
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The primary outcome is prednisolone dose measured at 12 months. The main statistical analyses will estimate the difference in mean prednisolone dose between patients randomised to simvastatin and placebo by intention to treat at 12 months. Group difference estimates and corresponding confidence intervals will be reported.Initially, prednisolone dose at 12 months will be described for each treatment group using means and standard deviations. In addition, plots will be produced that show dosing over time (every 3 months) for each group and the percentage of patients whose dose is under 10mg (safe dose). The outcome will be formally compared between treatment groups using a linear regression model (below) that adjusts for baseline dose. All modelling assumptions will be checked.

    Primary: Prednisolone dose at 1-year

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    End point title
    Prednisolone dose at 1-year
    End point description
    The primary outcome is prednisolone dose measured at 12 months. The main statistical analyses will estimate the difference in mean prednisolone dose between patients randomised to simvastatin and placebo by intention to treat at 12 months. Group difference estimates and corresponding confidence intervals will be reported. Initially, prednisolone dose at 12 months will be described for each treatment group using means and standard deviations. In addition, plots will be produced that show dosing over time (every 3 months) for each group and the percentage of patients whose dose is under 10mg (safe dose). The outcome will be formally compared between treatment groups using a linear regression model that adjusts for baseline dose.
    End point type
    Primary
    End point timeframe
    One year
    End point values
    Placebo Simvastatin Analysis
    Number of subjects analysed
    16 [1]
    16
    32
    Units: mg
        number (not applicable)
    16
    16
    32
    Attachments
    Mean reduction in prednisolone dose at 52 weeks
    Notes
    [1] - One subject did not complete primary endpoint due to fatal adverse event.
    Statistical analysis title
    Prednisolone dose at 1 year
    Comparison groups
    Placebo v Simvastatin v Analysis
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.54 [2]
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    3.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.15
         upper limit
    15.38
    Variability estimate
    Standard deviation
    Notes
    [2] - The regression analysis adjusted for baseline dose suggests no significant difference at 12 months, i.e. patients in simvastatin group have higher prednisolone dose, and the mean difference is 3.62mg (95% CI: -8.15 to 15.38) with a p-value of 0.54

    Secondary: Reduction in immunosuppressive agents at 24 months

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    End point title
    Reduction in immunosuppressive agents at 24 months
    End point description
    This will be analysed using a chi-squared test
    End point type
    Secondary
    End point timeframe
    Two years
    End point values
    Placebo Simvastatin Analysis
    Number of subjects analysed
    3
    2
    21
    Units: numbers
        Reduction in second-line immunosuppressive agent
    3
    2
    5
    Statistical analysis title
    Reduction in second-line immunosuppressive agent
    Statistical analysis description
    The total number of patients included in the analysis is 12, with 6 from each of the treatment arms. chi-square test suggests a test statistic of 0.34 with a p-value of 0.56.
    Comparison groups
    Simvastatin v Placebo v Analysis
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.56 [3]
    Method
    Chi-squared
    Parameter type
    NA
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Notes
    [3] - The reduction in second-line immunosuppressive agent does not differ significantly between the two groups at 5% level.

    Secondary: Number of patients with disease relapses at 24 months

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    End point title
    Number of patients with disease relapses at 24 months
    End point description
    Disease relapses at 24 months The number of patients who had disease relapses at 24 months is shown below. The number of patients included in the analysis are 10 and 11 for placebo and simvastatin group, respectively. The proportion of patients who had disease relapses at 24 months is higher (45.5%) compared to that in the placebo group (10%). will be analysed using a chi-squared test.
    End point type
    Secondary
    End point timeframe
    Two years
    End point values
    Placebo Simvastatin Analysis
    Number of subjects analysed
    1
    5
    21
    Units: numbers
        Number of disease relapse
    1
    5
    6
    Statistical analysis title
    Number of patients with disease relapse at 2 years
    Statistical analysis description
    e proportion of patients who had disease relapse by 24 months was higher in the simvastatin group (45.5%) compared to that in the placebo group (10%).
    Comparison groups
    Placebo v Simvastatin
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [4]
    P-value
    = 0.072 [5]
    Method
    Chi-squared
    Parameter type
    Na
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Notes
    [4] - The chi-square test suggests that there is weak evidence of a difference between the two groups in disease relapses
    [5] - The chi-square test suggests a test statistics of 3.23 with a P-value of 0.072, therefore, the disease relapse rate does not differ significantly at 5% level.

    Secondary: Mean reduction in prednisolone dose at two years

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    End point title
    Mean reduction in prednisolone dose at two years
    End point description
    Prednisolone dose at 24 months The number of patients included in the secondary analysis is 11 and 10 for simvastatin and placebo group, respectively. The results from the regression analysis suggest that there is little difference in mean prednisolone dose between the groups at 24 months (difference: -0.3 (Simvastatin.-Placebo.) 95% CI: -4.7 to 4.0, P = 0.87).
    End point type
    Secondary
    End point timeframe
    Two years
    End point values
    Placebo Simvastatin Analysis
    Number of subjects analysed
    17
    16
    21 [6]
    Units: mg
        arithmetic mean (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    -0.34 (-4.71 to 4.03)
    Notes
    [6] - 10 in placebo and 11 in simvastatin
    Statistical analysis title
    Prednisolone dose at 2 years
    Statistical analysis description
    Prednisolone dose at 24 months The number of patients included in the secondary analysis is 11 and 10 for simvastatin and placebo group, respectively. The results from the regression analysis suggest that there is little difference in mean prednisolone dose between the groups at 24 months (difference: -0.3 (Simvastatin.-Placebo.) 95% CI: -4.7 to 4.0, P = 0.87).
    Comparison groups
    Simvastatin v Placebo v Analysis
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.87
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.71
         upper limit
    4.03
    Variability estimate
    Standard deviation
    Dispersion value
    0

    Secondary: Cholesterol at 24 months

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    End point title
    Cholesterol at 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    Two years
    End point values
    Placebo Simvastatin
    Number of subjects analysed
    10
    11
    Units: mmol/L
        arithmetic mean (standard deviation)
    9.92 ± 13.17
    4.56 ± 1.48
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Jan 2016 to July 2018
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Simvastatin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 17 (17.65%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Surgical and medical procedures
    Surgical procedures
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Death
    Additional description: Severe Sickle cell crises led to respiratory and renal failure which ended in death of that patient
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Simvastatin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    17 / 17 (100.00%)
    General disorders and administration site conditions
    General symptom
         subjects affected / exposed
    16 / 16 (100.00%)
    17 / 17 (100.00%)
         occurrences all number
    16
    17

    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
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