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    Clinical Trial Results:
    Randomized controlled 12 months trial with etanercept (enbrel ®) vs. sulfasalazine followed by an open-label extension with etanercept up to week 540 in early axial spondyloarthritis with focus on improvement of acute inflammatory lesions as detected by MRI (ESTHER)

    Summary
    EudraCT number
    		 2005-002320-34
    Trial protocol
    		 DE  
    Global end of trial date
    01 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Nov 2021
    First version publication date
    26 Nov 2021
    Other versions
    Summary report(s)
    		 FinalStudyReport

    Trial information

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    Trial identification
    Sponsor protocol code
    M01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00844142
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité
    Sponsor organisation address
    Hindenburgdamm 30, Berlin, Germany,
    Public contact
    Prof. Dr. Joachim Sieper, Charité, 0049 03084454547, joachim.sieper@charite.de
    Scientific contact
    Prof. Dr. Joachim Sieper, Charité, 0049 03084454547, joachim.sieper@charite.de
    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
    01 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy – to assess efficacy of etanercept vs. sulfasalazine when added to NSAIDs in patients with moderate to severe active early axial spondyloarthritis duration of ongoing axial symptoms of less than 5 years. Primary outcome is change of active inflammatory lesions in sacroiliac joints and spine as detected by MRI at 12 months and at week 216, sustained reduction of active inflammation up to week 540.
    Protection of trial subjects
    Adverse events, vital signs, physical examination results, and clinical laboratory values.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Dec 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety, Scientific research
    Long term follow-up duration
    		 8 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 76
    Worldwide total number of subjects
    76
    EEA total number of subjects
    76
    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)
    76
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 9 study centers in Germany, between 5th of December 2005 (first patient first visit) and recruitment was finished with the screening on 05 May 2008.

    Pre-assignment
    Screening details
    		 A total of 101 subjects entered the screening period (5th of May 2008), of whom 24 withdrew before randomization. The remaining 77 subjects were randomized and received at least one dose of study drug

    Period 1
    Period 1 title
    Week 48
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm1
    Arm description
    		 receive etanercept 2x25 mg weekly subcutaneous injection
    Arm type
    		 Treatment

    Investigational medicinal product name
    Enbrel
    Investigational medicinal product code
    WAY-143050
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    etanercept 2x25 mg weekly

    Arm title
    		 Arm2
    Arm description
    		 receive sulfasalazine up to 2 g/day (up to 3 g/ per day)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sulfasalazine
    Investigational medicinal product code
    59238.00.00
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500-0-0 mg/day in the first week; 500-0-500 mg/day in the second week; 500-0-1000mg/day in the third; 1000-0-1000 mg/day in the fourth week. In therapy refractory cases it is allowed to increase the dosage to 1000 – 1000 – 1000 mg/ day from week 12

    Number of subjects in period 1
    		Arm1 Arm2
    Started
    40
    36
    Completed
    35
    31
    Not completed
    5
    5
         Pregnancy
    2
    -
         Intolerance
    -
    1
         Lost to follow-up
    3
    2
         Lymphoma
    -
    1
         Lack of efficacy
    -
    1
    Period 2
    Period 2 title
    Long term follow-up tp year 10
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enbrel
    Investigational medicinal product code
    WAY-143050
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    etanercept 2x25 mg weekly

    Arm title
    		 Arm 2
    Arm description
    		 Switched to ETN from SSZ
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enbrel
    Investigational medicinal product code
    WAY-143050
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    etanercept 2x25 mg weekly

    Number of subjects in period 2
    		Arm1 Arm 2
    Started
    35
    31
    Completed
    19
    0
    Not completed
    47
    31
         deseases
    9
    -
         Consent withdrawn by subject
    4
    -
         live value increase
    1
    -
         Transferred to other arm/group
    -
    31
         Pregnancy
    10
    -
         Lost to follow-up
    8
    -
         non-compliance
    5
    -
         Lack of efficacy
    10
    -
    Joined
    31
    0
         Transferred in from other group/arm
    31
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm1
    Reporting group description
    		 receive etanercept 2x25 mg weekly subcutaneous injection

    Reporting group title
    Arm2
    Reporting group description
    		 receive sulfasalazine up to 2 g/day (up to 3 g/ per day)

    Reporting group values
    		 Arm1 Arm2 Total
    Number of subjects
    		 40 36 76
    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)
    		 40 36 76
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.6 ± 8.7 32.9 ± 8.4 -
    Gender categorical
    Units: Subjects
        Female
    		 17 15 32
        Male
    		 23 21 44

    End points

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    End points reporting groups
    Reporting group title
    Arm1
    Reporting group description
    		 receive etanercept 2x25 mg weekly subcutaneous injection

    Reporting group title
    Arm2
    Reporting group description
    		 receive sulfasalazine up to 2 g/day (up to 3 g/ per day)
    Reporting group title
    Arm1
    Reporting group description
    		 -

    Reporting group title
    Arm 2
    Reporting group description
    		 Switched to ETN from SSZ

    Subject analysis set title
    All Subject
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    as described in the manuscript (see attachement:FinalStudyReport/FinalStudyReport_ESTHER.pdf

    Primary: Pain

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    End point title
    		 Pain
    End point description
    FinalStudyReport/FinalStudyReport_ESTHER.pdf
    End point type
    Primary
    End point timeframe
    Weeks: 48, 108, 216, 264, 432, 540
    End point values
    		 Arm1 Arm2 Arm1 All Subject
    Number of subjects analysed
    35
    31
    66
    [1]
    Units: BASDAI
    3
    3
    3
    3
    Notes
    [1] - see manuskirpt
    Statistical analysis title
    		 Long-term efficacy of etanercept
    Statistical analysis description
    see manuscript: Final_Study_Report_ESTHER
    Comparison groups
    Arm1 v Arm2
    Number of subjects included in analysis
    66
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence [2]
    P-value
    		 ≤ 0.27 [3]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [2] - see manuscript: Final_Study_Report_ESTHER
    [3] - see manuscript: Final_Study_Report_ESTHER

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to Week 540 (year 10)
    Adverse event reporting additional description
    see manuscript: Final_Study_Report_ESTHER, table 19 page 63-64
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: we have not recorded any non- serious events in the trial.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jan 2006
    Amendment 1 Justification of the study duration, Modification of the safety assessment and specification of study related procedures
    02 Jan 2006
    Amendment 2 Modification/Specification of the ICF
    10 Apr 2006
    Amendment 3 Modification of the exclusion criterion regarding previous Sulfasalazine use to: only Sulfasalazine use within 6 months before screening is an exclusion criterion
    19 Dec 2006
    Amendment 4 Study extension for 12 months  up to 2 years and inclusion of x-rays
    10 Jul 2008
    Amendment 5 Study extension up to 4 years
    07 Jul 2010
    Amendment 6 Study extension up to 6 years
    24 Sep 2011
    Amendment 7 Inclusion of serum biomarkers
    05 Oct 2012
    Amendment 8 Study extension up to 8 years
    30 Sep 2014
    Amendment 9 Study extension up to 10 years

    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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