Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   41448   clinical trials with a EudraCT protocol, of which   6808   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Efficacy, safety, and immunogenicity of BI 695501 versus adalimumab in patients with active rheumatoid arthritis: a randomized, double-blind, parallel arm, multiple dose, active comparator trial.

    Summary
    EudraCT number
    2012-002945-40
    Trial protocol
    DE   HU   EE   ES   BG  
    Global end of trial date
    18 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    1297.2
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02137226
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    01 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to establish equivalence in efficacy between BI 695501 and US licensed Humira® in patients with active rheumatoid arthritis (RA) based on a statistical comparison of the proportion of patients meeting the American College of Rheumatology 20% response criteria (ACR20) at Week 12 and at Week 24 between BI 695501 and US licensed Humira.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Other medication considered necessary for the patient's safety (e.g. as a result of an adverse event [AE]) was permitted at the Investigator's discretion.
    Background therapy
    Each patient was to receive 40 mg of trial drug every 2 weeks by SC injection. Regardless of the treatment group they were allocated to, patients were to continue to take their regular methotrexate (MTX) therapy (15 to 25 milligram (mg) / week at a stable dose) and a stable weekly dose of adequate folic acid (at least 5 mg per week or as per local practice) or folinic acid (at least 1 mg per week or as per local practice) from their usual source.
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 86
    Country: Number of subjects enrolled
    Chile: 79
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Estonia: 22
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 201
    Country: Number of subjects enrolled
    Russian Federation: 41
    Country: Number of subjects enrolled
    Serbia: 40
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Ukraine: 129
    Country: Number of subjects enrolled
    United States: 259
    Worldwide total number of subjects
    940
    EEA total number of subjects
    374
    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)
    735
    From 65 to 84 years
    205
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    A randomized, double-blind, parallel arm, multiple dose, active comparator trial to assess efficacy, safety and immunogenicity of BI 695501 versus adalimumab in patients with active rheumatoid arthritis. Patient received background methotrexate (MTX) treatment.

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended a specialist site which ensured that they met all strictly implemented inclusion/exclusion criteria. Subjects were not to be entered to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Period 1 (Initial randomization)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BI 695501
    Arm description
    Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
    Arm type
    Experimental

    Investigational medicinal product name
    BI 695501
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1)

    Arm title
    US-licensed Humira®
    Arm description
    Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
    Arm type
    Active comparator

    Investigational medicinal product name
    BI 695501
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1)

    Number of subjects in period 1 [1]
    BI 695501 US-licensed Humira®
    Started
    324
    321
    Completed
    304
    305
    Not completed
    20
    16
         Other Reason
    1
    3
         Physician decision
    1
    3
         Lack of efficacy
    1
    -
         Adverse event, non-fatal
    3
    3
         Consent withdrawn by subject
    11
    5
         Lost to follow-up
    3
    2
    Notes
    [1] - 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: Baseline characteristics are based on the patients who were randomized after successfully completing the screening period and received at least one of the trial medication.
    Period 2
    Period 2 title
    Period 2 (Re - randomization)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BI 695501 to BI 695501
    Arm description
    Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 695501
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.

    Arm title
    US-licensed Humira® to US-licensed Humira®
    Arm description
    Patients initially randomized to US-licensed Humira® in Period 1 and re-randomized to US-licensed Humira® in Period 2. Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.
    Arm type
    Active comparator

    Investigational medicinal product name
    US-licensed Humira®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients initially randomized to US-licensed Humira® in Period 1 and re-randomized to US-licensed Humira® in Period 2. Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.

    Arm title
    US-licensed Humira® to BI 695501
    Arm description
    Patients initially randomized to US-licensed Humira® in Period 1 and re-randomized to BI 695501 in Period 2. Each patient received 40 mg/0.8 mL US-licenced Humira® in period 1 and 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 695501
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.

    Investigational medicinal product name
    US-licensed Humira®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each patient received 40 mg/0.8 mL US-licenced Humira® in period 1 administered by SC injection every 2 weeks from Week 24 to Week 48.

    Number of subjects in period 2 [2]
    BI 695501 to BI 695501 US-licensed Humira® to US-licensed Humira® US-licensed Humira® to BI 695501
    Started
    298
    148
    147
    Completed
    281
    140
    138
    Not completed
    17
    8
    9
         Other Reason
    1
    1
    1
         Physician decision
    -
    1
    -
         Lack of efficacy
    2
    -
    -
         Adverse event, non-fatal
    3
    1
    4
         Consent withdrawn by subject
    8
    5
    4
         Lost to follow-up
    3
    -
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 645 patients were initially randomized and 609 completed the initial randomization phase (Period 1). Out of which 593 patients were re-randomized and 559 completed the re-randomization phase (Period 2) .

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    BI 695501
    Reporting group description
    Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).

    Reporting group title
    US-licensed Humira®
    Reporting group description
    Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).

    Reporting group values
    BI 695501 US-licensed Humira® Total
    Number of subjects
    324 321 645
    Age categorical
    Safety Analysis Set (SAF): The SAF contained all patients who received at least one dose of trial drug.
    Units: Subjects
    Age Continuous
    Safety Analysis Set (SAF): The SAF contained all patients who received at least one dose of trial drug.
    Units: years
        arithmetic mean (standard deviation)
    53.7 ± 12.04 53.6 ± 11.32 -
    Gender, Male/Female
    Safety Analysis Set (SAF): The SAF contained all patients who received at least one dose of trial drug.
    Units: Subjects
        Female
    267 269 536
        Male
    57 52 109

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    BI 695501
    Reporting group description
    Each patient received 40 milligram (mg)/0.8 millilitre (mL) BI 695501 solution for injection, administered by subcutaneous (SC) injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).

    Reporting group title
    US-licensed Humira®
    Reporting group description
    Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks up to and including the first 22 weeks of treatment (Period 1).
    Reporting group title
    BI 695501 to BI 695501
    Reporting group description
    Patients initially randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.

    Reporting group title
    US-licensed Humira® to US-licensed Humira®
    Reporting group description
    Patients initially randomized to US-licensed Humira® in Period 1 and re-randomized to US-licensed Humira® in Period 2. Each patient received 40 mg/0.8 mL US-licenced Humira® solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.

    Reporting group title
    US-licensed Humira® to BI 695501
    Reporting group description
    Patients initially randomized to US-licensed Humira® in Period 1 and re-randomized to BI 695501 in Period 2. Each patient received 40 mg/0.8 mL US-licenced Humira® in period 1 and 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks from Week 24 to Week 48.

    Subject analysis set title
    BI 695501 continuously
    Subject analysis set type
    Full analysis
    Subject analysis set description
    BI 695501 continuously comprised all patients randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 (or not re randomized at Week 24). This group represents all patients who were to receive BI 695501 from Day 1 to Week 48. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks.

    Subject analysis set title
    US-licensed Humira® continuously
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Humira® US continuously comprised all patients randomized to US-licensed Humira® in Period 1 and re-randomized to US-licensed Humira® in Period 2 or not re randomized at Week 24 (e.g. patients who discontinued treatment prior to Week 24). This group represents all patients who were to receive US-licensed Humira® from Day 1 to Week 48. Each patient received 40 mg/0.8 mL US-licensed Humira® solution for injection, administered by SC injection every 2 weeks.

    Primary: The proportion of patients meeting the American College of Rheumatology 20% (ACR20) response criteria at week 12

    Close Top of page
    End point title
    The proportion of patients meeting the American College of Rheumatology 20% (ACR20) response criteria at week 12
    End point description
    A patient had an ACR20 response if all of the following occurred: A ≥ 20 % improvement in the swollen joint count (66 joints), A ≥ 20 % improvement in the tender joint count (68 joints), A ≥ 20 % improvement in at least three of the following assessments: Patient’s assessment of pain, Patient’s global assessment of disease activity (equivalent to the General Health component of the Disease Activity Score ([DAS]), Physician’s global assessment of disease activity, Patient’s assessment of physical function, as measured by the Health Assessment Questionnaire – Disability Index (HAQ-DI) Acute phase reactant (C-reactive protein [CRP]). Full Analysis Set (Patients with at least one dose of trial drug and had all relevant efficacy measures). Patients who discontinued treatment prior to the time-point had their binary response imputed as non-responder, a method commonly known as non-responder imputation. For truly missing data at the component level, multiple imputations were used.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    BI 695501 US-licensed Humira®
    Number of subjects analysed
    321 [1]
    318 [2]
    Units: Percentage of Patients
        number (not applicable)
    67
    61.1
    Notes
    [1] - Full Analysis Set
    [2] - Full Analysis Set
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The week 12 confidence interval for the estimated difference in proportion is produced using the cumulative distribution function method of Reeve
    Comparison groups
    BI 695501 v US-licensed Humira®
    Number of subjects included in analysis
    639
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Regression, Logistic
    Parameter type
    Difference in proportions
    Point estimate
    5.9
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    12.7
    Notes
    [3] - The 90% Confidence Interval (CI) for ACR20 at Week 12, rounded to 1 decimal place, had to be entirely contained in the predefined equivalence region [-12.0%, 15.0%]. Results from logistic regression model adjusted for treatment, prior exposure to a biologic agent (yes / no), Baseline DAS28 (ESR). Difference in ACR20 Response Rate (BI695501 – Humira, %) is presented.

    Primary: The proportion of patients meeting ACR20 response criteria at Week 24

    Close Top of page
    End point title
    The proportion of patients meeting ACR20 response criteria at Week 24
    End point description
    ACR20 at Week 12 and Week 24 are standard outcome criteria that are widely accepted for regulatory purposes to demonstrate efficacy in treating the signs and symptoms of Rheumatoid arthritis (RA). The proportion of patients meeting the ACR20 response criteria was assessed at Week 12 and Week 24 to provide a robust comparison with US-licensed Humira® data. A patient had an ACR20 response if all of the following occurred: A ≥ 20 % improvement in the swollen joint count (66 joints), A ≥ 20 % improvement in the tender joint count (68 joints), A ≥ 20 % improvement in at least three of the following assessments: Patient’s assessment of pain, Patient’s global assessment of disease activity (equivalent to the General Health component of the Disease Activity Score ([DAS]), Physician’s global assessment of disease activity, Patient’s assessment of physical function, as measured by the Health Assessment Questionnaire – Disability Index (HAQ-DI) Acute phase reactant (C-reactive protein [CRP]).
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    BI 695501 US-licensed Humira®
    Number of subjects analysed
    321 [4]
    318 [5]
    Units: Percentage of Patients
        number (not applicable)
    69
    64.5
    Notes
    [4] - Full Analysis Set
    [5] - Full Analysis Set
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The week 24 confidence interval for the estimated difference in proportion is produced using the cumulative distribution function method of Reeve
    Comparison groups
    BI 695501 v US-licensed Humira®
    Number of subjects included in analysis
    639
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    Method
    Regression, Logistic
    Parameter type
    Difference in proportions
    Point estimate
    4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.4
         upper limit
    12.5
    Notes
    [6] - The 95% Confidence Interval (CI) for ACR20 at Week 24, rounded to 1 decimal place, had to be entirely contained in the predefined equivalence region [-15.0%;+15.0%]. Results from logistic regression model adjusted for treatment, prior exposure to a biologic agent (yes / no), Baseline DAS28 (ESR). Difference in ACR20 Response Rate (BI695501 – Humira, %) is presented.

    Secondary: Change from baseline in Disease Activity Score 28 (DAS28) (Erythrocyte sedimentation rate [ESR]) at Week 12 and Week 24

    Close Top of page
    End point title
    Change from baseline in Disease Activity Score 28 (DAS28) (Erythrocyte sedimentation rate [ESR]) at Week 12 and Week 24
    End point description
    The DAS28 (ESR) score was derived using the following formulae: DAS28 (ESR) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.014*(GH) + 0.7*ln(ESR) Where: • TJC28 = 28 joint count for tenderness • SJC28 = 28 joint count for swelling • Ln (ESR) = natural logarithm of ESR • GH = General Health component of the DAS (patient’s global assessment of disease activity). N is mean number of subjects in the analysis set with DAS28(ESR) results computable across the multiply imputed data sets. Patients who discontinued treatment prior to the time-point had their binary response imputed as non-responder, a method commonly known as non-responder imputation. For truly missing data at the component level, multiple imputation was used. The Full Analysis Set contained all enrolled patients who were randomized to trial drug and who received at least one dose of trial drug and had all efficacy measures relevant for the co-primary efficacy endpoints measured at baseline and at least once post- baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    BI 695501 US-licensed Humira®
    Number of subjects analysed
    321 [7]
    318 [8]
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Week 12 (N= 319.6, 317.1)
    -2.1 (-2.28 to -2.01)
    -2 (-2.18 to -1.91)
        Week 24 (N=313.9, 315.1)
    -2.4 (-2.51 to -2.21)
    -2.4 (-2.54 to -2.24)
    Notes
    [7] - Full Analysis Set
    [8] - Full Analysis Set
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Results based on DAS28 (ESR) mean changes from Baseline after 12 weeks of treatment = overall mean + treatment group + Baseline DAS28 (ESR) + prior exposure to a biologic agent + random error.
    Comparison groups
    BI 695501 v US-licensed Humira®
    Number of subjects included in analysis
    639
    Analysis specification
    Pre-specified
    Analysis type
    [9]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.25
         upper limit
    0.05
    Notes
    [9] - Equivalence margin is not applicable. Difference in least square means of BI 695501 – Humira is presented.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Results based on DAS28 (ESR) mean changes from Baseline after 24 weeks of treatment = overall mean + treatment group + Baseline DAS28 (ESR) + prior exposure to a biologic agent + random error.
    Comparison groups
    BI 695501 v US-licensed Humira®
    Number of subjects included in analysis
    639
    Analysis specification
    Pre-specified
    Analysis type
    [10]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.17
         upper limit
    0.23
    Notes
    [10] - Equivalence margin is not applicable. Difference in least square means of BI 695501 – Humira is presented.

    Secondary: The proportion of patients with Investigator-assessed drug-related adverse events (AEs) during the treatment phase

    Close Top of page
    End point title
    The proportion of patients with Investigator-assessed drug-related adverse events (AEs) during the treatment phase
    End point description
    The analysis of AEs was based on the concept of treatment-emergent AEs (TEAEs). Thus, all AEs with an onset after the first dose of trial drug up to a period of ten weeks after the last dose of trial drug were assigned to the current treatment for evaluation. Investigator-assessed drug related AEs were AEs with a relationship to drug ticked “yes” according to the Investigator. Overall results are presented from Day 1 up to Week 58 and are based on the initial randomization groups. The comparison therefore focuses on patients who received BI 695501 continuously versus patients who received Humira® continuously for the long term assessment of safety. One patient was initially treated with Humira and discontinued prior to Week 24. This patient was mistakenly re randomized to BI 695501 but not treated. For SAF this was counted in Humira not re-randomized group (as treated), and for other analysis sets, this patient was counted in the Humira to BI 695501 group (as randomized).
    End point type
    Secondary
    End point timeframe
    From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks
    End point values
    BI 695501 continuously US-licensed Humira® continuously
    Number of subjects analysed
    324 [11]
    175 [12]
    Units: Percentage of Patients
        number (not applicable)
    19.1
    22.9
    Notes
    [11] - Safety Analysis Set
    [12] - Safety Analysis Set
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 10 weeks after the last drug administration, up to 58 weeks
    Adverse event reporting additional description
    Treatment-emergent adverse events are defined as adverse events that started or worsened on or after the first dose of study medication and prior to the last date of study medication plus 10 weeks (70 days) inclusive. Data is reported from Day 1 to the end of Period 2 (Week 58).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    US-licensed Humira® continuously
    Reporting group description
    Humira® US continuously comprised all patients randomized to US-licensed Humira® in Period 1 and rerandomized to US-licensed Humira® in Period 2 or not re randomized at Week 24 (e.g. patients who discontinued treatment prior to Week 24). This group represents all patients who were to receive US-licensed Humira® from Day 1 to Week 48. Each patient received 40 mg/0.8 mL US-licensed Humira® solution for injection, administered by SC injection every 2 weeks.

    Reporting group title
    BI 695501
    Reporting group description
    BI 695501 continuously comprised all patients randomized to BI 695501 in Period 1 and re-randomized to BI 695501 in Period 2 (or not re randomized at Week 24). This group represents all patients who were to receive BI 695501 from Day 1 to Week 48. Each patient received 40 mg/0.8 mL BI 695501 solution for injection, administered by SC injection every 2 weeks.‌

    Serious adverse events
    US-licensed Humira® continuously BI 695501
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 174 (9.77%)
    18 / 324 (5.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive cardiomyopathy
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Chronic gastritis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint destruction
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 324 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 174 (1.72%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 324 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    US-licensed Humira® continuously BI 695501
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 174 (13.79%)
    35 / 324 (10.80%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 174 (9.77%)
    19 / 324 (5.86%)
         occurrences all number
    19
    24
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 174 (5.17%)
    17 / 324 (5.25%)
         occurrences all number
    9
    22

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2014
    Amendment 1: The endpoint ‘number of patients with injection site pain’ was removed from other endpoints as this was a safety endpoint. The wording ‘EU-sourced Humira’ was deleted from the description of the single dose PK study in cynomolgus monkeys as this study was not using EU-sourced Humira. Screening period was revised to 46 days and a pre randomization phase of up to ten days was added. It was clarified that the process for randomization and pre-randomization was dependent on site and country. It was clarified that patients were to be randomly assigned to trial drug according to both the randomization ratio and the stratification factors and that the same process was to be used for both the initial randomization and for re randomization. The requirement for patients with a history of hypersensitivity to adalimumab to be excluded from the trial was removed because patients who had received Humira before were not eligible, regardless of whether they had developed an immune reaction. It was clarified that the PPD or IGRA test could be performed at Week 48 for TB assessment; samples for the TB test was updated from 1 to 2 and blood volumes were revised accordingly. Only unblinded personnel were responsible for ensuring drug accountability and compliance; a unique drug number was to be assigned for each drug administration; syringes were not pre prepared but were provided to the sites pre filled; data for primary analysis were to be unblinded only for the team members involved in the primary analysis as well as PPK analysis. New template text was added for the definitions and reporting of cancers and protocol specified AESIs and reporting of AE/SAEs. In the statistical methods, text stating ‘if a patient misses an entire visit the missing data will not be imputed’ was deleted and updated to include ‘Baseline’ to clarify the process for handling of missing data. The power was updated to correct the calculations for DAS28 to reflect the power for 2 sided tests.
    04 Nov 2014
    Amendment 2: The primary objective updated to replace the co-primary endpoint of ‘change in DAS28-ESR at 24 weeks compared to baseline’ with ‘proportion of patients meeting ACR20 response rate at Week 24’. Primary, secondary and other endpoints were updated based on the changes to the objectives. Sample size was increased to 650 patients to take into account the updated margins resulting from the change in primary endpoints. Safety endpoints were updated to state ‘the proportion’ instead of ‘number and proportion’, as only 1 item should be measured in an endpoint. The endpoint relating to injection site pain was deleted from the safety endpoints; this assessment was not deemed to provide relevant information for the trial as all injection site reactions were to be captured as AEs. A self administration arm was added to collect patient data on real life experience of self injection; the secondary and exploratory objectives were updated accordingly with a reference to this new arm. Injection-related endpoints were added to the ‘other’ endpoints category to allow assessment of self administration. Patients who discontinued the trial early were to be followed for efficacy until Week 48. Only qualified patients were to be offered participation in the OLE trial, not all patients. AEs were to be reported until the last per protocol visit. Patients who discontinued early were required to be followed up until Week 58. The hypotheses for the equivalence test, and the associated statistical margins, were updated to reflect the revised primary objective and endpoints. Secondary analysis was updated to include the new endpoints of the mean changes from baseline in DAS28-ESR after 12 weeks and was based on the FAS and used the LOCF method for missing values. Data reporting was amended to clarify that all efficacy data were to be reported at 24 weeks in a CTR and that a follow up analysis was to be conducted when all data were available and would be reported in follow up CTR.
    20 Feb 2015
    Amendment 3: It was implemented prior to IRB approval as the changes involved only logistical or administrative aspects. This amendment was implemented after the start of patient enrollment. Based on FDA feedback, the following changes were made throughout the CTP: The term US-sourced Humira was replaced by US-licensed Humira. References to Humira or adalimumab were updated to US-licensed Humira and/or EU approved Humira, as applicable. The term adalimumab was used for general mode of action descriptions of the molecule. The synopsis and trial flow chart were updated in line with the above mentioned changes, as appropriate.
    27 Apr 2015
    Amendment 4: Based on feedback from the FDA the following changes were implemented: Removal of the self administration arm. This was based on FDA feedback that self administration data from the use of pre filled syringes was not required and could have potentially compromised the blinding of the trial. The process of trial drug administration was changed such that the trial personnel responsible for administration were to be blinded. It was clarified that every effort should be made to follow up patients who discontinued trial drug for efficacy. The description of the analysis of the co primary endpoint of ACR20 at Week 12 was updated to state the use of 90% CIs and an equivalence margin of ± 12%. Additional safety ECG monitoring was implemented at Weeks 4, 12, 24, 40, 48, and 58. The criteria for withdrawal from the trial, discontinuation from trial drug, and the requirements for follow up of patients who discontinued treatment were clarified. The definitions and processes of AE collection and reporting were clarified; pregnancy reporting requirements were expanded to include female partners of male patients; aminotransferase was added as a parameter for identifying hepatic injury.
    05 Jan 2016
    Amendment 5: It was specified that the Week 48 efficacy endpoints would not be analyzed as part of the primary analysis of efficacy and safety in the current Week 32 CTR as not all Week 48 ACR20 data would be available at the data cut off for the primary analysis. The margins for the Week 12 primary efficacy assessment were updated from [-12%; 12%] to [-12%; 15%]. This slightly higher upper bound (+15%) allowed for variations in the imputation techniques and response rates used in the calculation of the margins and was agreed to by the FDA. The -12% lower bound was maintained in case the response rate for BI 695501 was lower than that for US-licensed Humira. The fixed categorical effect ‘region’ was removed from the primary efficacy endpoint models in order to prevent any potential issues due to sparse data from a region. The primary analysis cut off was changed from Week 24 to Week 32 to allow for an early evaluation of the initial 8 weeks of safety and immunogenicity data following transition for those patients who switched treatments at Week 24. Exclusion criterion 2 was updated to include ‘per Investigator discretion’ for consistency with the rest of the CTP. It was clarified that protocol deviations would be handled on a case by case basis; the term ‘severe’ in relation to protocol deviations was removed accordingly. It was clarified that the primary efficacy endpoint analysis would use two separate logistic regression models to address FDA feedback. The missing data imputation method for the primary and secondary analyses was changed from LOCF to MI to address FDA feedback.

    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
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA