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    Clinical Trial Results:
    A Phase 2b, Multicenter, Open-Label Study in Rheumatoid Arthritis Subjects who Completed Preceding Study M13-390 with Adalimumab

    Summary
    EudraCT number
    		 2012-003881-42
    Trial protocol
    		 BE   DE   RO   SK  
    Global end of trial date
    22 Oct 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 May 2016
    First version publication date
    14 Jun 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    potential category issues

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-692
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01752855
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    Abbott House, Vanwall Business Park Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL64XE
    Public contact
    Global Medical Information, AbbVie, 001 800-633-9110,
    Scientific contact
    Andy Payne, AbbVie , andy.payne@abbvie.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
    22 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A Phase 2b, open-label extension (OLE) study in rheumatoid arthritis (RA) patients designed to collect long-term safety, tolerability, efficacy, and immunogenicity data of the proposed new adalimumab formulation.
    Protection of trial subjects
    • Only participants that met all the study inclusion and none of the exclusion criteria were allowed entry into the study. • Participants read and understood information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2012
    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
    Slovakia: 17
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czech Republic: 25
    Country: Number of subjects enrolled
    Germany: 1
    Worldwide total number of subjects
    88
    EEA total number of subjects
    56
    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)
    71
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of the 96 subjects who completed Study M13-390, 88 subjects (92%, 88/96) enrolled in the OLE Study M13-692 at 20 study sites located in North America and Europe.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 New Formulation for 48 weeks
    Arm description
    		 New formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week
    Arm type
    		 Experimental

    Investigational medicinal product name
    New formulation adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of the new formulation of adalimumab 40 mg every other week for 24 weeks

    Arm title
    		 Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Arm description
    		 Current formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week
    Arm type
    		 Experimental

    Investigational medicinal product name
    New formulation adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of the new formulation of adalimumab 40 mg every other week for 24 weeks

    Number of subjects in period 1
    		New Formulation for 48 weeks Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Started
    44
    44
    Completed
    43
    40
    Not completed
    1
    4
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    1
    -
         Lack of efficacy
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    New Formulation for 48 weeks
    Reporting group description
    		 New formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week

    Reporting group title
    Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Reporting group description
    		 Current formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week

    Reporting group values
    		 New Formulation for 48 weeks Current Formulation for 24 Weeks, New Formulation for 24 Weeks Total
    Number of subjects
    		 44 44 88
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.7 ( 10.8 ) 52 ( 12 ) -
    Gender categorical
    Units: Subjects
        Female
    		 37 37 74
        Male
    		 7 7 14
    Subject analysis sets

    Subject analysis set title
    Overall Study
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The study population consisted of all randomized subjects who received at least one dose of adalimumab. All randomized subjects were included in the analyses.

    Subject analysis sets values
    		 Overall Study
    Number of subjects
    88
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.9 ( 11.5 )
    Gender categorical
    Units: Subjects
        Female
    74
        Male
    14

    End points

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    End points reporting groups
    Reporting group title
    New Formulation for 48 weeks
    Reporting group description
    		 New formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week

    Reporting group title
    Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Reporting group description
    		 Current formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week

    Subject analysis set title
    Overall Study
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The study population consisted of all randomized subjects who received at least one dose of adalimumab. All randomized subjects were included in the analyses.

    Primary: Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 36 and 48

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    End point title
    		 Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 36 and 48 [1]
    End point description
    The Disease Activity Score (DAS28) is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C-reactive protein, and general health are included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission.
    End point type
    Primary
    End point timeframe
    Baseline (Study NCT01712178 Week 0 Visit), Weeks 36 and 48
    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: Within-group analyses:(Mean change [2-sided 95%CI]) for New Formulation for 48 wks from baseline to Wk 36: -2.4 (-2.7, -2); (Mean change [2-sided 95%CI]) for New Formulation for 48 wks-from baseline to Wk 48: -2.4 (-2.8, -2); (Mean change [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks-from baseline to Wk 36: -2.2 (-2.5, -1.9); (Mean change [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks-from baseline to Wk 48: -2.3 (-2.7, -1.9)
    End point values
    		 New Formulation for 48 weeks Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Number of subjects analysed
    44 [2]
    44 [3]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 36
    -2.4 ( 1.17 )
    -2.2 ( 1.05 )
        Week 48
    -2.4 ( 1.29 )
    -2.2 ( 1.28 )
    Notes
    [2] - All available data were included. The last available values were used to replace any missing values.
    [3] - All available data were included. The last available values were used to replace any missing values.
    No statistical analyses for this end point

    Primary: Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Weeks 36 and 48

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    End point title
    		 Percentage of Participants With an American College of Rheumatology (ACR) 20 Response at Weeks 36 and 48 [4]
    End point description
    American College of Rheumatology 20% (ACR20) response. A participant is a responder if the following 3 criteria for improvement from baseline are met: ≥ 20% improvement in tender joint count; ≥ 20% improvement in swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: o Physician global assessment of disease activity o Patient global assessment of disease activity o Patient assessment of pain o Disability Index of the Health Assessment o CRP (Acute phase reactant (Erythrocyte sedimentation rate/C-reactive protein))
    End point type
    Primary
    End point timeframe
    Baseline (Study NCT01712178 Week 0 Visit), Weeks 36 and 48
    Notes
    [4] - 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: Within-group analyses: (Percentage [2-sided 95%CI]) for New Formulation for 48 wks at Week 36: (72.7 (57.2, 85); (Percentage [2-sided 95%CI]) for New Formulation for 48 Wks at Week 48: 74.4 (58.8, 86.5); (Percentage [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks at Week 36: 76.7 (61.4, 88.2); (Percentage [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks at Week 48: 80 (64.4, 90.9)
    End point values
    		 New Formulation for 48 weeks Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Number of subjects analysed
    44 [5]
    44 [6]
    Units: percentage of participants
    number (not applicable)
        Week 36
    72.7
    76.7
        Week 48
    74.4
    80
    Notes
    [5] - All participants who received at least one dose of study drug
    [6] - All participants who received at least one dose of study drug
    No statistical analyses for this end point

    Primary: Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Weeks 36 and 48

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    End point title
    		 Percentage of Participants With an American College of Rheumatology (ACR) 50 Response at Weeks 36 and 48 [7]
    End point description
    American College of Rheumatology 50% (ACR50) response. A participant is a responder if the following 3 criteria for improvement from baseline are met: ≥ 50% improvement in tender joint count; ≥ 50% improvement in swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: o Physician global assessment of disease activity o Patient global assessment of disease activity o Patient assessment of pain o Disability Index of the Health Assessment o CRP (Acute phase reactant (Erythrocyte sedimentation rate/C-reactive protein))
    End point type
    Primary
    End point timeframe
    Baseline (Study NCT01712178 Week 0 Visit), Weeks 36 and 48
    Notes
    [7] - 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: Within-group analyses: (Percentage [2-sided 95%CI]) for New Formulation for 48 wks at Week 36: (50 (34.6, 65.4); (Percentage [2-sided 95%CI]) for New Formulation for 48 Wks at Week 48: 53.5 (37.7, 68.8); (Percentage [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks at Week 36: 51.2 (35.5, 66.7); (Percentage [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks at Week 48: 57.5 (40.9, 73.0)
    End point values
    		 New Formulation for 48 weeks Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Number of subjects analysed
    44 [8]
    44 [9]
    Units: percentage of participants
    number (not applicable)
        Week 36
    50
    51.2
        Week 48
    53.5
    57.5
    Notes
    [8] - All participants who received at least one dose of study drug
    [9] - All participants who received at least one dose of study drug
    No statistical analyses for this end point

    Primary: Mean Change From Baseline in Health Assessment Questionnaire (HAQ-DI) at Weeks 36 and 48

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    End point title
    		 Mean Change From Baseline in Health Assessment Questionnaire (HAQ-DI) at Weeks 36 and 48 [10]
    End point description
    The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The minimal clinically important difference (MCID) defined for the HAQ-DI is 0.22. HAQ remission indicating normal physical function is defined by HAQ-DI < 0.5.
    End point type
    Primary
    End point timeframe
    Baseline (Study NCT01712178 Week 0 Visit), Weeks 36 and 48
    Notes
    [10] - 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: Within-group analyses:(Mean change [2-sided 95%CI]) for New Formulation for 48 wks from baseline to Wk 36: -0.5 (–0.7, –0.3); (Mean change [2-sided 95%CI]) for New Formulation for 48 wks-from baseline to Wk 48: -0.5 (–0.7, –0.4); (Mean change [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks-from baseline to Wk 36: -0.5 (–0.7, –0.3); (Mean change [2-sided 95%CI]) for Current Formulation for 24 wks, New Formulation for 24 wks-from baseline to Wk 48: -0.5 (–0.7, -0.3)
    End point values
    		 New Formulation for 48 weeks Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Number of subjects analysed
    44 [11]
    43 [12]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 36
    -0.5 ( 0.6 )
    -0.5 ( 0.69 )
        Week 48
    -0.5 ( 0.57 )
    -0.5 ( 0.58 )
    Notes
    [11] - Data were analyzed for 44 and 43 participants, respectively, at weeks 36 and 48.
    [12] - Data were analyzed for 43 participants at week 36 and 40 participants at week 48.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Positive for Anti-adalimumab Antibody

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    End point title
    		 Percentage of Participants Positive for Anti-adalimumab Antibody
    End point description
    Percentage of participants with anti-adalimumab antibody
    End point type
    Secondary
    End point timeframe
    Week 24 through Week 48
    End point values
    		 New Formulation for 48 weeks Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Number of subjects analysed
    44 [13]
    44 [14]
    Units: percentage of participants
        number (not applicable)
    13.6
    18.2
    Notes
    [13] - All participants who received at least one dose of study drug
    [14] - All participants who received at least one dose of study drug
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of study drug administration until 70 days following the last dose, approximately 58 weeks. Serious adverse events were collected from the time the participant signed the informed consent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Current Formulation for 24 Weeks, New Formulation for 24 Weeks
    Reporting group description
    		 Current formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week

    Reporting group title
    New Formulation for 48 weeks
    Reporting group description
    		 New formulation of adalimumab 40 mg every other week for 24 weeks in Study NCT01712178, followed by 24 weeks of treatment with the new formulation of adalimumab 40 mg every other week

    Serious adverse events
    		 Current Formulation for 24 Weeks, New Formulation for 24 Weeks New Formulation for 48 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 44 (4.55%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Current Formulation for 24 Weeks, New Formulation for 24 Weeks New Formulation for 48 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 44 (43.18%)
    18 / 44 (40.91%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 44 (4.55%)
         occurrences all number
    3
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 44 (6.82%)
    3 / 44 (6.82%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    3 / 44 (6.82%)
    3 / 44 (6.82%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 44 (0.00%)
         occurrences all number
    3
    0
    Rheumatoid arthritis
         subjects affected / exposed
    4 / 44 (9.09%)
    3 / 44 (6.82%)
         occurrences all number
    5
    3
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 44 (9.09%)
         occurrences all number
    3
    7
    Nasopharyngitis
         subjects affected / exposed
    7 / 44 (15.91%)
    6 / 44 (13.64%)
         occurrences all number
    12
    10
    Oral herpes
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 44 (6.82%)
         occurrences all number
    2
    3
    Upper respiratory tract Infection
         subjects affected / exposed
    4 / 44 (9.09%)
    4 / 44 (9.09%)
         occurrences all number
    4
    5

    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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    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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