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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Etanercept in Subjects with Rheumatoid Arthritis Who Have Had an Inadequate Response to Adalimumab or Infliximab Plus Methotrexate.

    Summary
    EudraCT number
    		 2012-003644-71
    Trial protocol
    		 ES   NL   BE  
    Global end of trial date
    22 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2016
    First version publication date
    16 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B1801355
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York,, United States, NY 10017
    Public contact
    ClinicalTrials.gov Call Center, Pfizer Inc., +1 800718 1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    ClinicalTrials.gov Call Center, Pfizer Inc., +1 800718 1021, ClinicalTrials.gov_Inquiries@pfizer.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
    08 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the efficacy of etanercept to placebo in inadequate responders to infliximab or adalimumab plus methotrexate (MTX) in all subjects and in subjects who are anti-drug antibody positive (ADA+) to one of these monoclonal antibodies (mAbs).
    Protection of trial subjects
    It was highly recommended that all participants take folic acid supplementation at a dose of 5 to 10 mg/week, either as a single dose on one day or as divided doses over several days to help minimize the side effects associated with Methotrexate (MTX, consistent with local label and guidelines).
    Background therapy
    		 The dose of oral MTX was to be ≥10 mg once daily and ≤25 mg once daily and stable for a minimum of 6 weeks before the baseline visit. From the baseline to the Week 12 visit, the dose of oral MTX was to remain stable (eg, no increase or decrease) unless there was an adverse event (AE) related to MTX. At the Week 12 and Week 16 visits, the dose of oral MTX could be increased by ≤5 mg once daily to a maximum dose of 25 mg once daily per investigator discretion. After Week 16 and through Week 24, the dose was to remain stable (eg, no increase or decrease) unless there was an AE related to MTX. If the subject experienced an AE possibly associated with MTX, dose reduction of MTX was permitted after consultation with the sponsor’s clinical team: The dose of MTX could be decreased or temporarily suspended for up to 2 weeks as needed and if possible, was to be re-titrated to the dose taken prior to the AE. If this was not possible, a minimum of 7.5 mg once daily was required to stay in the study; otherwise, the subject was withdrawn from the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Sep 2013
    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
    Australia: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Worldwide total number of subjects
    16
    EEA total number of subjects
    7
    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)
    11
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In this 24 week, multicenter, randomized, double-blind, placebo-controlled (Period 1), 2 period study, a total of 20 participants were screened, out of which 16 participants were randomized. Due to delayed enrollment and an insufficient number of participants, recruitment was terminated. Four participants were considered to be screen failures.

    Pre-assignment
    Screening details
    		 Eleven participants were randomly assigned to etanercept [ETN] and 5 participants to placebo in the blinded treatment period. A total of 11 participants (9 ETN treated and 2 placebo treated) completed the blinded treatment period and entered the open label treatment with ETN. One of the 2 placebo treated participants entered the Escape Arm.

    Pre-assignment period milestones
    Number of subjects started
    		 20 [1]
    Number of subjects completed
    		 16

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screening failures: 4
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Twenty participants had been screened, of which 16 participants were enrolled. Four participants did not meet the eligibility criteria.
    Period 1
    Period 1 title
    Period 1, Blinded Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Etanercept
    Arm description
    		 Participants received etanercept 50 mg subcutaneously with oral methotrexate tablets once-weekly.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Investigational product will be administered by the subject or a qualified designee. At the baseline visit, the initial dose of etanercept/placebo investigational product must be administered in the office by study personnel after all baseline evaluations have been completed, while the subject (or designee) observes.The etanercept or matching placebo was to be administered QW on the same day of the week throughout the study.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo injections with oral methotrexate tablets once-weekly.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The etanercept or matching placebo was administered QW on the same day of the week throughout the study.

    Number of subjects in period 1
    		Etanercept Placebo
    Started
    11
    5
    Completed
    9
    2
    Not completed
    2
    3
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    -
    1
         Protocol violation
    -
    1
         Study terminated by sponsor
    2
    -
    Period 2
    Period 2 title
    Period 2 - Open Label
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Period 2 - Open Label Etanercept
    Arm description
    		 Participants received etanercept 50 mg subcutaneously with oral methotrexate 10 to 25 mg once weekly.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Open-label MTX will be administered QW as a single oral dose or in divided doses on the same day.

    Number of subjects in period 2
    		Period 2 - Open Label Etanercept
    Started
    11
    Completed
    5
    Not completed
    6
         Study terminated by sponsor
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period 1, Blinded Treatment
    Reporting group description
    		 Participants received etanercept 50 mg subcutaneously with oral methotrexate tablets once-weekly.

    Reporting group values
    		 Period 1, Blinded Treatment Total
    Number of subjects
    		 16 16
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 11 11
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.5 ( 13.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 4 4
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analyses set will include all randomized participants who have taken at least one dose of test article.

    Subject analysis set title
    Period I - Blinded Treatment - Etanercept
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received etanercept 50 mg subcutaneously with oral methotrexate tablets once-weekly.

    Subject analysis set title
    Period I - Blinded Treatment - Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo injections with oral methotrexate tablets once-weekly.

    Subject analysis sets values
    		 Safety Population Period I - Blinded Treatment - Etanercept Period I - Blinded Treatment - Placebo
    Number of subjects
    16
    11
    5
    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)
    11
        From 65-84 years
    5
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.6 ( 14.91 )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    12
        Male
    4

    End points

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    End points reporting groups
    Reporting group title
    Etanercept
    Reporting group description
    		 Participants received etanercept 50 mg subcutaneously with oral methotrexate tablets once-weekly.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo injections with oral methotrexate tablets once-weekly.
    Reporting group title
    Period 2 - Open Label Etanercept
    Reporting group description
    		 Participants received etanercept 50 mg subcutaneously with oral methotrexate 10 to 25 mg once weekly.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analyses set will include all randomized participants who have taken at least one dose of test article.

    Subject analysis set title
    Period I - Blinded Treatment - Etanercept
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received etanercept 50 mg subcutaneously with oral methotrexate tablets once-weekly.

    Subject analysis set title
    Period I - Blinded Treatment - Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo injections with oral methotrexate tablets once-weekly.

    Primary: Change from baseline in the disease activity score based on a 28 joint count (DAS28-C-reactive protein [CRP]) at week 12.

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    End point title
    		 Change from baseline in the disease activity score based on a 28 joint count (DAS28-C-reactive protein [CRP]) at week 12. [1]
    End point description
    DAS28 calculated from the number of swollen joints (SJC) and painful joints (PJC) using the 28 joints count, the c-reactive protein (CRP) and Subject General Health Visual Analogue Scale (VAS) assessment (participant rated health assessment with scores ranging 0 to 100; higher scores indicate worse health status).
    End point type
    Primary
    End point timeframe
    Baseline, 12 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study was prematurely terminated on 25 June 2014 due to significant and continuing delays in achieving study enrollment. The decision to stop the study was not driven by any safety concerns. At the time of study termination, 20 subjects had been screened, of which 16 subjects were enrolled. No analyses were done due to small numbers of subjects and insufficient data for meaningful statistical analysis available at study termination.
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: participants
    Notes
    [2] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [3] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [4] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the DAS28 at Week 24

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    End point title
    		 Change from Baseline in the DAS28 at Week 24
    End point description
    DAS28 calculated from the number of SJC and PJC using the 28 joints count, the CRP and Subject General Health VAS assessment (participant rated health assessment with scores ranging 0 to 100; higher scores indicate worse health status).
    End point type
    Secondary
    End point timeframe
    Baseline, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    Units: participants
    Notes
    [5] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [6] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [7] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants with DAS28 <3.2

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    End point title
    		 Number of Participants with DAS28 <3.2
    End point description
    Number of participants with DAS28 <3.2. A score of < 3.2 implied low disease activity.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: participants
    Notes
    [8] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [9] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [10] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants with DAS28 <2.6

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    End point title
    		 Number of Participants with DAS28 <2.6
    End point description
    Number of Participants with DAS28 <2.6. A DAS28 < 2.6 implies remission.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: participants
    Notes
    [11] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [12] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [13] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving American College of Rheumatology 20% (ACR20) Response

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    End point title
    		 Number of Participants Achieving American College of Rheumatology 20% (ACR20) Response
    End point description
    ACR20 response: greater than or equal to (≥) 20 percent (%) improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of 5 remaining ACR core measures: participant's assessment of pain; Subject Global Assessment (SGA) of disease activity; Physician Global Assessment (PGA) of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and CRP.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    Units: participants
    Notes
    [14] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [15] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [16] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response

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    End point title
    		 Number of Participants Achieving American College of Rheumatology 50% (ACR50) Response
    End point description
    ACR50 response: greater than or equal to (≥) 50 percent (%) improvement in tender or swollen joint counts and ≥ 50% improvement in 3 of the 5 remaining ACR core measures: participant's assessment of pain; SGA of disease activity; PGA of disease activity; subject's assessment of functional disability via a HAQ; and CRP.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: participants
    Notes
    [17] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [18] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [19] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response

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    End point title
    		 Number of Participants Achieving American College of Rheumatology 70% (ACR70) Response
    End point description
    ACR70 response: greater than or equal to (≥) 70 percent (%) improvement in tender or swollen joint counts and ≥ 70% improvement in 3 of the 5 remaining ACR core measures: participant's assessment of pain; SGA of disease activity; PGA of disease activity; subject's assessment of functional disability via a HAQ; and CRP.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    Units: participants
    Notes
    [20] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [21] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [22] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response

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    End point title
    		 Number of Participants Achieving American College of Rheumatology 90% (ACR90) Response
    End point description
    ACR90 response: greater than or equal to (≥) 90 percent (%) improvement in tender or swollen joint counts and ≥ 90% improvement in 3 of the 5 remaining ACR core measures: participant's assessment of pain; SGA of disease activity; PGA of disease activity; subject's assessment of functional disability via a HAQ; and CRP.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [23]
    0 [24]
    0 [25]
    Units: participants
    Notes
    [23] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [24] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [25] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving European League against Rheumatism (EULAR) Good and/or Moderate Response.

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    End point title
    		 Number of Participants Achieving European League against Rheumatism (EULAR) Good and/or Moderate Response.
    End point description
    The Disease Activity Score Based on 28-joints Count based (DAS28-based) EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 =< 3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to =<5.1 or change from baseline >0.6 to =<1.2 with DAS28 =<5.1; non-responders: change from baseline =< 0.6 or change from baseline >0.6 and =<1.2 with DAS28 >5.1.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [26]
    0 [27]
    0 [28]
    Units: participants
    Notes
    [26] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [27] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [28] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving Low Disease Activity or Remission Based on Clinical Disease Activity Index (CDAI)

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    End point title
    		 Number of Participants Achieving Low Disease Activity or Remission Based on Clinical Disease Activity Index (CDAI)
    End point description
    The CDAI is the numerical sum of 4 outcome parameters: tender joint count (TJC) and SJC based on a 28-joint assessment, SGA and PGA assessed on 0-10 point scale; higher scores=greater affliction due to disease activity. CDAI total score = 0-76. CDAI <= 2.8 indicates disease remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, and >22 = high disease activity.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [29]
    0 [30]
    0 [31]
    Units: participants
    Notes
    [29] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [30] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [31] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants Achieving Low Disease Activity or Remission Based on Simplified Disease Activity Index (SDAI)

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    End point title
    		 Number of Participants Achieving Low Disease Activity or Remission Based on Simplified Disease Activity Index (SDAI)
    End point description
    The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, SGA and PGA assessed on 0-10 point scale; and CRP (mg/dL). SDAI total score= 0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high disease activity.
    End point type
    Secondary
    End point timeframe
    12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [32]
    0 [33]
    0 [34]
    Units: participants
    Notes
    [32] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [33] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [34] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in CDAI

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    End point title
    		 Change from Baseline in CDAI
    End point description
    Change from Baseline in CDAI scores was to be calculated. The CDAI is the numerical sum of 4 outcome parameters: TJC and SJC based on a 28-joint assessment, SGA and PGA assessed on 0-10 point scale; higher scores=greater affliction due to disease activity. CDAI total score = 0-76. CDAI <= 2.8 indicates disease remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, and >22 = high disease activity.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [35]
    0 [36]
    0 [37]
    Units: units on a scale
    Notes
    [35] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [36] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [37] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in SDAI

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    End point title
    		 Change from Baseline in SDAI
    End point description
    Change from Baseline in SDAI scores were to be calculated. The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, SGA and PGA assessed on 0-10 point scale; higher scores=greater affliction due to disease activity, and CRP (mg/dL). SDAI total score= 0-86. SDAI <=3.3 indicates disease remission, >3.4 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high disease activity.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [38]
    0 [39]
    0 [40]
    Units: units on a scale
    Notes
    [38] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [39] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [40] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Number of Tender/Painful Joints

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    End point title
    		 Change from Baseline in Number of Tender/Painful Joints
    End point description
    Change from Baseline in the number of tender/painful joints using the 28 joint count including shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints, and knees was to be calculated.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [41]
    0 [42]
    0 [43]
    Units: number of joints
    Notes
    [41] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [42] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [43] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Number of Swollen Joints

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    End point title
    		 Change from Baseline in Number of Swollen Joints
    End point description
    Change from Baseline in the number of swollen joints including shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints, and knees was to be calculated.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [44]
    0 [45]
    0 [46]
    Units: number of swollen joints
    Notes
    [44] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [45] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [46] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Physician Global Assessment of Disease Activity

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    End point title
    		 Change from Baseline in Physician Global Assessment of Disease Activity
    End point description
    Change from Baseline in the PGA scores was to be estimated. The Study Physician estimated the participant's overall disease activity over the last 2 to 3 days using a scale between 0 (no disease activity) and 10 (extreme disease activity).
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [47]
    0 [48]
    0 [49]
    Units: units on a scale
    Notes
    [47] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [48] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [49] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Subject Global Assessment of Disease Activity

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    End point title
    		 Change from Baseline in Subject Global Assessment of Disease Activity
    End point description
    Change from Baseline in Subject Global Assessment of Disease Activity was to be estimated. Participants were to assess their overall disease activity over the last 2 to 3 days using a scale between 0 (no disease activity) and 10 (extreme disease activity).
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [50]
    0 [51]
    0 [52]
    Units: units on a scale
    Notes
    [50] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [51] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [52] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Subject Pain

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    End point title
    		 Change from Baseline in Subject Pain
    End point description
    Subject Pain was to be measured on a 0 to 100 mm Visual Analog Scale (VAS), with 0 mm = no pain and 100 mm = most severe pain.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [53]
    0 [54]
    0 [55]
    Units: units on a scale
    Notes
    [53] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [54] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [55] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in CRP

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    End point title
    		 Change from Baseline in CRP
    End point description
    The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation through the use of an ultrasensitive assay. A decrease in the level of CRP indicates reduction in inflammation and therefore improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [56]
    0 [57]
    0 [58]
    Units: mg/dL
        number (not applicable)
    Notes
    [56] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [57] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [58] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Health Assessment Questionnaire Disability and Discomfort Scales (HAQ-DI)

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    End point title
    		 Change from Baseline in Health Assessment Questionnaire Disability and Discomfort Scales (HAQ-DI)
    End point description
    Health Assessment Questionnaire-Disability Index (HAQ-DI): participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [59]
    0 [60]
    0 [61]
    Units: units on a scale
    Notes
    [59] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [60] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [61] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Euro Quality of Life (Qol) EQ-5 Dimensions Questionnaire (EQ-5D)

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    End point title
    		 Change from Baseline in Euro Quality of Life (Qol) EQ-5 Dimensions Questionnaire (EQ-5D)
    End point description
    The EuroQol-5 Dimensions (EQ-5D) is a participant-completed questionnaire designed to assess health related quality of life involving 2 components: a Health State Profile and a VAS. For the Health State Profile, participants recorded their level of current health for 5 domains comprising a health profile: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Scores from the 5 domains may be used to calculate a single index value, also known as a utility score. On the VAS participants were asked to rate their current health on a scale from 0 to 100 mm, where 0 represented the “worst imaginable health state” and 100 represented the “best imaginable health state.”
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [62]
    0 [63]
    0 [64]
    Units: units on a scale
    Notes
    [62] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [63] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [64] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Short Form-36 Health Survey (SF-36)

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    End point title
    		 Change from Baseline in Short Form-36 Health Survey (SF-36)
    End point description
    The 36-Item Short Form Health Survey (SF-36) is widely used 36-item questionnaire that measures general health-related quality of life in the following 8 domains: physical function, role limitations due to physical health, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health. Scores for the 8 domains range from 0 to 100 where higher scores are better.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [65]
    0 [66]
    0 [67]
    Units: units on a scale
    Notes
    [65] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [66] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [67] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Vectra disease activity levels

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    End point title
    		 Change from Baseline in Vectra disease activity levels
    End point description
    The change from Baseline in Vectra disease activity levels was to be estimated. The assessment measures serum protein biomarkers associated with RA. It has a range from 1-100 with lower scores indicating the better outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [68]
    0 [69]
    0 [70]
    Units: units on a scale
    Notes
    [68] - Vectra disease activity analysis of laboratory samples was not conducted due to study termination.
    [69] - Vectra disease activity analysis of laboratory samples was not conducted due to study termination.
    [70] - Vectra disease activity analysis of laboratory samples was not conducted due to study termination.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Patient Acceptable Symptom State (PASS)

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    End point title
    		 Change from Baseline in Patient Acceptable Symptom State (PASS)
    End point description
    The Patient Acceptable Symptom State (PASS) was a participant-completed form in which participants were asked to “Think about all the ways your rheumatoid arthritis (RA) has affected you during the last 48 hours. If you were to remain in the next few months as you were during the last 48 hours, would this be acceptable or unacceptable to you?” The participant indicated a response of either “acceptable” or “unacceptable”.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [71]
    0 [72]
    0 [73]
    Units: units on a scale
    Notes
    [71] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [72] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [73] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants with Positive Etanercept Anti-drug Antibody Status

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    End point title
    		 Number of Participants with Positive Etanercept Anti-drug Antibody Status
    End point description
    Blood samples (6 mL) were collected at the baseline, Week 12, and Week 24 visits, or upon early withdrawal, to provide a minimum of 1 mL serum each for ETN ADA and ETN neutralizing antibody analyses. Samples which were positive for ETN antidrug antibodies were then also tested for ETN neutralizing antibodies.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [74]
    0 [75]
    0 [76]
    Units: participants
    Notes
    [74] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [75] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [76] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Number of Participants with Positive Etanercept Neutralizing Anti-drug Antibody Status

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    End point title
    		 Number of Participants with Positive Etanercept Neutralizing Anti-drug Antibody Status
    End point description
    Blood samples (6 mL) were collected at the baseline, Week 12, and Week 24 visits, or upon early withdrawal, to provide a minimum of 1 mL serum each for ETN ADA and ETN neutralizing antibody analyses. Samples which were positive for ETN antidrug antibodies were then also tested for ETN neutralizing antibodies.
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [77]
    0 [78]
    0 [79]
    Units: participants
    Notes
    [77] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [78] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [79] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Subject General Health VAS.

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    End point title
    		 Change from Baseline in Subject General Health VAS.
    End point description
    Subject General Health VAS assessment (participant rated health assessment with scores ranging 0 to 100; higher scores indicate worse health status).
    End point type
    Secondary
    End point timeframe
    Baseline, 12 weeks, 24 weeks
    End point values
    		 Etanercept Placebo Period 2 - Open Label Etanercept
    Number of subjects analysed
    0 [80]
    0 [81]
    0 [82]
    Units: units on a scale
    Notes
    [80] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [81] - No analyses were done due to insufficient data for meaningful statistical analysis.
    [82] - No analyses were done due to insufficient data for meaningful statistical analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the day the first dose of the investigational product was administered up to 28 days after last dose was administered
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Period I - Blinded Treatment - Etanercept
    Reporting group description
    		 Participants received etanercept 50 mg subcutaneously with oral methotrexate tablets once-weekly.

    Reporting group title
    Period I - Blinded Treatment - Placebo
    Reporting group description
    		 Participants received placebo injections with oral methotrexate tablets once-weekly.

    Reporting group title
    Period 2 - Open-Label - Etanercept
    Reporting group description
    		 Participants received etanercept 50 mg subcutaneously with oral methotrexate 10 to 25 mg once weekly.

    Serious adverse events
    		 Period I - Blinded Treatment - Etanercept Period I - Blinded Treatment - Placebo Period 2 - Open-Label - Etanercept
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Period I - Blinded Treatment - Etanercept Period I - Blinded Treatment - Placebo Period 2 - Open-Label - Etanercept
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 11 (45.45%)
    3 / 5 (60.00%)
    4 / 11 (36.36%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    Injection site reaction
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Tendonitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 5 (20.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    Tooth infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 5 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2013
    Key substantial amendments: 2. STUDY OBJECTIVES AND ENDPOINTS: added ETN ADA status and neutralizing antibody (NA) status as secondary endpoints. 3. STUDY DESIGN: reduced sample size; add an interim analysis after 30 mAb ADA+ subjects have either withdrawn prior to or completed Period 1; added that sample size may be increased based on the results of interim analysis; clarify that enrollment into study will not be stopped while interim analysis is prepared. 4.2. EXCLUSION CRITERIA: revised latent tuberculosis (TB) criteria and added criteria for testing of ALT and AST in subjects receiving TB chemoprophylaxis between screening and baseline visits. 5. STUDY TREATMENTS: revised planned number of subjects. 5.5.3. OTHER PERMITTED TREATMENTS: allowed chemoprophylaxis for latent TB to be started between screening and baseline visits. 6.1. SCREENING: added details on PPD test; clarifed that high-sensitivity CRP will be used . 6.2. BASELINE VISIT, 6.3. TREATMENT PERIOD – WEEK 4 TO WEEK 24 VISITS and 6.4. EARLY WITHDRAWAL VISIT: added testing for ETN ADA status, NA, and drug levels. 7.5.2. SERUM FOR PHARMACOKINETIC ANALYSIS OF ETN: added section to describe collection and analysis of samples for ETN concentrations. 7.5.4. SERUM FOR ANALYSIS OF ETN ADA AND ETN NEUTRALIZING ANTIBODIES: added section to describe collection and analysis of samples for ETN ADAs and NA. 7.5.6. PHARMACOKINETIC/PHARMACODYNAMICS (PK/PD): revisions made to the ETN concentrations; an analysis plan for infliximab, adalimumab, and ETN drug concentrations. 8.2. REPORTING PERIOD; 8.3. DEFINITION OF AN ADVERSE EVENT: modify safety monitoring procedures 9.1. SAMPLE SIZE DETERMINATION: use simulation approach for sample size calculation, revise power and number of subjects. 9.2.1. ANALYSIS OF PRIMARY ENDPOINT; 9.2.2 ANALYSIS OF SECONDARY ENDPOINT: changes to the statistical methods. 9.6.2. SAMPLE SIZE REESTIMATION: added information regarding interim analysis.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    25 Jun 2014
    This study was prematurely terminated on 25 June 2014 due to significant and continuing delays in achieving study enrollment. The decision to stop the study was not driven by any safety concerns.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    No analyses were done due to small numbers of subjects and insufficient data for meaningful statistical analysis available at study termination.
    For support, Contact us.
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