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    Clinical Trial Results:
    Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Apremilast (CC-10004) in the Treatment of Ankylosing Spondylitis (AS)

    Summary
    EudraCT number
    		 2008-004229-40
    Trial protocol
    		 GB  
    Global end of trial date
    18 Jan 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    112008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00944658
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensingston Campus, London, United Kingdom, SW7 2AZ
    Public contact
    Sonya Abraham, Imperial College London, +44 (0)20 3313 4114, s.abraham@imperial.ac.uk
    Scientific contact
    Sonya Abraham, Imperial College London, +44 (0)20 3313 4114, s.abraham@imperial.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
    31 Jan 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the effect of apremilast on magnetic resonance imaging lesions in ankylosing spondylitis. To explore the effect of apremilast on the signs and symptoms of ankylosing spondylitis.
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Aug 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Scientific research
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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)
    38
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a single-centre, randomised, double-blind, placebo controlled, Phase II, investigator-led, pilot study carried out at the Kennedy Clinical Trials Unit between Aug 2009 to Jan 2011.

    Pre-assignment
    Screening details
    		 55 patients were screened (6 failing to demonstrate bone oedema on MRI) and 38 were enrolled into this study. With the exception of 2 patients (both receiving apremilast), all others completed the study. The two withdrawals discontinued treatment within 1 week of commencing due to non-serious adverse events.

    Period 1
    Period 1 title
    Treatment (12 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    An unblinded pharmacist allocated patients to receive either placebo or active drug according to a randomisation code generated by Celgene. All other study person remained blinded to treatment until the end of the double-blind period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apremilast
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apremilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10mg twice daily and the dose was titrated by 20mg every 2days until the maximum dose of 30mg twice daily was achieved on day 5. Apremilast was then given daily until day 85 (week 12).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10mg twice daily and the dose was titrated by 20mg every 2days until the maximum dose of 30mg twice daily was achieved on day 5. Apremilast was then given daily until day 85 (week 12).

    Number of subjects in period 1
    		Apremilast Placebo
    Started
    19
    19
    Completed
    17
    19
    Not completed
    2
    0
         non serious adverse event
    2
    -
    Period 2
    Period 2 title
    Follow up
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apremilast
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    No intervention follow up
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No intervention, follow up

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    No intervention, follow up
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No intervention, follow up

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: 2 participants withdraw after 1 week of treatment due to non-serious adverse event, they were excluded from efficacy analysis
    Number of subjects in period 2 [2]
    		Apremilast Placebo
    Started
    17
    19
    Completed
    17
    19
    Notes
    [2] - 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: 2 participants withdraw after 1 week of treatment due to non-serious adverse event

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Apremilast
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Apremilast Placebo Total
    Number of subjects
    		 17 19 36
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 19 36
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 44.88 ± 11.1 39.21 ± 13.3 -
    Gender categorical
    Units: Subjects
        Female
    		 2 2 4
        Male
    		 15 17 32

    End points

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    End points reporting groups
    Reporting group title
    Apremilast
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    Apremilast
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Changes in BASDAI Score From Baseline

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    End point title
    		 Changes in BASDAI Score From Baseline
    End point description
    Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 0 – 10 score, higher reduction in the scores suggest better suboptimal control of disease.
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Apremilast Placebo
    Number of subjects analysed
    17
    19
    Units: unit on scale
        geometric mean (standard deviation)
    -1.59 ± 1.48
    -0.77 ± 1.47
    Statistical analysis title
    		 Bath Ankylosing Spondylitis Disease Activity Index
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.139
    Method
    		 ANCOVA
    Confidence interval

    Primary: Changes of Apremilast on the signs and symptoms of AS, night pain from baseline

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    End point title
    		 Changes of Apremilast on the signs and symptoms of AS, night pain from baseline
    End point description
    Changes of Apremilast on the signs and symptoms of AS, night pain from baseline This endpoint the night time pain score change was recorded by questionnaire to evaluate the Apremilast effect on symptom, higher reduction better improvement. scale is 0-10
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Apremilast Placebo
    Number of subjects analysed
    17
    19
    Units: score on a scale
        geometric mean (standard deviation)
    -0.81 ± 3.01
    -0.23 ± 2.75
    Statistical analysis title
    		 Changes in Night pain baseline to after treatment
    Comparison groups
    Placebo v Apremilast
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.587
    Method
    		 ANCOVA
    Confidence interval

    Primary: Changes in BASFI Score from baseline

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    End point title
    		 Changes in BASFI Score from baseline
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and 12 weeks
    End point values
    		 Apremilast Placebo
    Number of subjects analysed
    17
    19
    Units: score on a scale
        geometric mean (standard deviation)
    -1.74 ± 1.91
    -0.28 ± 1.61
    Statistical analysis title
    		 BASFI
    Comparison groups
    Apremilast v Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.108
    Method
    		 ANCOVA
    Confidence interval

    Secondary: The safety and tolerability of Apremilast in AS, Number of Participants with Adverse Events

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    End point title
    		 The safety and tolerability of Apremilast in AS, Number of Participants with Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    		 Apremilast Placebo
    Number of subjects analysed
    19
    19
    Units: Count of participants
    18
    17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Apremilast
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Apremilast Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Apremilast Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 19 (94.74%)
    17 / 19 (89.47%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 19 (42.11%)
    5 / 19 (26.32%)
         occurrences all number
    8
    5
    Blood and lymphatic system disorders
    Raised serum amylase
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Loose stools
         subjects affected / exposed
    5 / 19 (26.32%)
    2 / 19 (10.53%)
         occurrences all number
    5
    2
    Nausea
         subjects affected / exposed
    3 / 19 (15.79%)
    3 / 19 (15.79%)
         occurrences all number
    3
    3
    Flatulance
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    2 / 19 (10.53%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 19 (31.58%)
    6 / 19 (31.58%)
         occurrences all number
    6
    6

    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/22984171
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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
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