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    Clinical Trial Results:
    The VOLTAIRE-X trial looks at the effect of switching between Humira® and BI 695501 in patients with plaque psoriasis.

    Summary
    EudraCT number
    		 2016-002254-20
    Trial protocol
    		 LV   HU   DE   PL  
    Global end of trial date
    18 Apr 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    24 Sep 2021
    First version publication date
    01 May 2020
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1297-0009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03210259
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim Call Center, Boehringer Ingelheim, +1 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
    02 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to assess the pharmacokinetic (PK) similarity between patients receiving United States (US)-licensed Humira continuously versus those who switched between BI 695501 and US-licensed Humira in patients with moderate to severe chronic plaque psoriasis.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be 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. Rescue medication was allowed for all patients as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jul 2017
    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
    Germany: 18
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Latvia: 34
    Country: Number of subjects enrolled
    Poland: 87
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Ukraine: 15
    Country: Number of subjects enrolled
    United States: 81
    Worldwide total number of subjects
    259
    EEA total number of subjects
    152
    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)
    236
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a 58-week, multiple-dose, active comparator trial of BI 695501 and US-licensed Humira in patients with moderate to severe chronic plaque psoriasis. The trial was conducted at 49 trial centers in 7 countries (Germany, Hungary, Latvia, Poland, Russian Federation, Ukraine, and the United States [US]).

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. The trial consisted of a single-arm run-in period of 14 weeks for all patients, followed by a randomized, double-blind, 2-arm period of 34 weeks. The total treatment period was 48 weeks followed by 10 weeks of safety follow up (SFU).

    Period 1
    Period 1 title
    Period 1: Run-In Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Run-In Period (Humira)
    Arm description
    		 All patients received US-licensed Humira during the run-in period (Period 1). Patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. Trial medication was administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes containing 40 mg of adalimumab per 0.8 milliliter (mL).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    US-licensed Humira
    Investigational medicinal product code
    Other name
    Adalimumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    US-licensed Humira was provided in single-use pre-filled syringes (PFS) containing 40 milligrams (mg) of adalimumab per 0.8 milliliter (mL). 2 syringes (80 mg) were used at Day 1 (Week 1) as loading dose. 40 mg was used every other week from Week 2 to Week 12.

    Number of subjects in period 1
    		Run-In Period (Humira)
    Started
    259
    Completed
    238
    Not completed
    21
         Adverse event, serious fatal
    1
         Missed study visits
    3
         Consent withdrawn by subject
    8
         Adverse event, non-fatal
    1
         Lost to follow-up
    3
         Lack of efficacy
    5
    Period 2
    Period 2 title
    Period 2: Post-Randomization Period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Switching Arm
    Arm description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the switching arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg BI 695501 at Week 14 and Week 16 (2 injections), followed by 40 mg US-licensed Humira at Week 18 and Week 20 (2 injections), and subsequently 40 mg BI 695501 every other week from Week 22 to Week 48 (14 injections). Trial medication were administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes (PFS) containing 40 mg of adalimumab or BI 695501 per 0.8 milliliter (mL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 695501
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    BI 695501 was provided in single-use PFS containing 40 mg of BI 695501 per 0.8 mL. One syringe was used per injection. Patients received 40 mg of BI 695501 at Week 14 and Week 16 (2 injections), and every other week from Week 22 to Week 48 (14 injections).

    Investigational medicinal product name
    US-licensed Humira
    Investigational medicinal product code
    Other name
    Adalimumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    US-licensed Humira was provided in single-use PFS containing 40 mg of adalimumab per 0.8 mL. One syringe was used per injection. Patients received 40 mg US-licensed Humira at Week 18 and Week 20 (2 injections).

    Arm title
    		 Continuous Humira
    Arm description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the continuous Humira arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 mg US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg US-licensed Humira every other week from Week 14 to Week 48 (18 injections). Trial medication were administered by s.c. injection providing in single-use PFS containing 40 mg of adalimumab per 0.8 mL.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    US-licensed Humira
    Investigational medicinal product code
    Other name
    Adalimumab
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    US-licensed Humira was provided in single-use PFS containing 40 mg of adalimumab per 0.8 mL. One syringe was used per injection. Patients received 40 mg US-licensed Humira every other week from Week 14 to Week 48.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics are reported based on the randomised set.
    Number of subjects in period 2 [2]
    		Switching Arm Continuous Humira
    Started
    118
    120
    Completed
    107
    91
    Not completed
    11
    29
         Missed study visits
    1
    2
         Consent withdrawn by subject
    5
    17
         Physician decision
    -
    1
         Adverse event, non-fatal
    1
    1
         Pregnancy
    1
    -
         Lost to follow-up
    3
    8
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All patients received US-licensed Humira during the run-in period followed by randomized, parallel-arm period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Switching Arm
    Reporting group description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the switching arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg BI 695501 at Week 14 and Week 16 (2 injections), followed by 40 mg US-licensed Humira at Week 18 and Week 20 (2 injections), and subsequently 40 mg BI 695501 every other week from Week 22 to Week 48 (14 injections). Trial medication were administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes (PFS) containing 40 mg of adalimumab or BI 695501 per 0.8 milliliter (mL).

    Reporting group title
    Continuous Humira
    Reporting group description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the continuous Humira arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 mg US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg US-licensed Humira every other week from Week 14 to Week 48 (18 injections). Trial medication were administered by s.c. injection providing in single-use PFS containing 40 mg of adalimumab per 0.8 mL.

    Reporting group values
    		 Switching Arm Continuous Humira Total
    Number of subjects
    		 118 120 238
    Age categorical
    The Treated Set (TS) contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 104 112 216
        From 65-84 years
    		 14 8 22
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.1 ± 13.95 43.7 ± 13.69 -
    Sex: Female, Male
    The Treated Set (TS) contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    Units:
        Female
    		 37 44 81
        Male
    		 81 76 157
    Ethnicity (NIH/OMB)
    The Treated Set (TS) contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    Units: Subjects
        Hispanic or Latino
    		 18 18 36
        Not Hispanic or Latino
    		 100 102 202
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    The Treated Set (TS) contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 2 0 2
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 2 0 2
        White
    		 113 119 232
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Run-In Period (Humira)
    Reporting group description
    		 All patients received US-licensed Humira during the run-in period (Period 1). Patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. Trial medication was administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes containing 40 mg of adalimumab per 0.8 milliliter (mL).
    Reporting group title
    Switching Arm
    Reporting group description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the switching arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg BI 695501 at Week 14 and Week 16 (2 injections), followed by 40 mg US-licensed Humira at Week 18 and Week 20 (2 injections), and subsequently 40 mg BI 695501 every other week from Week 22 to Week 48 (14 injections). Trial medication were administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes (PFS) containing 40 mg of adalimumab or BI 695501 per 0.8 milliliter (mL).

    Reporting group title
    Continuous Humira
    Reporting group description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the continuous Humira arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 mg US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg US-licensed Humira every other week from Week 14 to Week 48 (18 injections). Trial medication were administered by s.c. injection providing in single-use PFS containing 40 mg of adalimumab per 0.8 mL.

    Primary: Area Under the Plasma Concentration time Curve Over Dosing Interval of Week 30 to 32 (AUCτ, 30-32) for Adalimumab in plasma

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    End point title
    		 Area Under the Plasma Concentration time Curve Over Dosing Interval of Week 30 to 32 (AUCτ, 30-32) for Adalimumab in plasma
    End point description
    Area Under the Plasma Concentration Time Curve Over the 2 weeks Dosing Interval of Week 30 to 32 for Adalimumab in plasma. The PK Set (PKS) included all patients from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK.
    End point type
    Primary
    End point timeframe
    Pre-dose at Week 30, at 72, 120, 168 and 240 hours after the Week 30 dosing, and pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    102
    93
    Units: microgram * hours /milliliter
        arithmetic mean (standard deviation)
    2040 ± 1420
    1980 ± 1600
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The null hypothesis was that the ratio of expected means for Switching vs. Continuous Humira is less than 80.00% or more than 125.00%. Equivalence was concluded if the confidence interval (CI) for the least square (LS) means ratio was included in the pre-defined equivalence range of 80.00% to 125.00%. The number 195 reflects the descriptive analysis of the endpoint values. The number of subjects contributing to the statistical analysis was 187.
    Comparison groups
    Switching Arm v Continuous Humira
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Least squares means ratio
    Point estimate
    105.19
    Confidence interval
         level
    		 90.2%
         sides
    2-sided
         lower limit
    		 96.58
         upper limit
    		 114.64
    Notes
    [1] - The least squares means were from ANCOVA. Ratio calculated with the switching arm as numerator and the continuous arm as the denominator.

    Primary: Maximum Observed Concentration during the dosing interval Week 30-32 (Cmax, 30-32) for Adalimumab in plasma

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    End point title
    		 Maximum Observed Concentration during the dosing interval Week 30-32 (Cmax, 30-32) for Adalimumab in plasma
    End point description
    Maximum observed concentration during the 2 weeks dosing interval of Week 30-32 for Adalimumab in plasma. The PK Set (PKS) included all patients from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK.
    End point type
    Primary
    End point timeframe
    Pre-dose at Week 30, at 72, 120, 168 and 240 hours after the Week 30 dosing, and pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    104
    99
    Units: microgram /milliliter
        arithmetic mean (standard deviation)
    7.13 ± 4.63
    7.14 ± 5.37
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The null hypothesis was that the ratio of expected means for Switching vs. Continuous Humira is less than 80.00% or more than 125.00%. Equivalence was concluded if the confidence interval (CI) for the least square (LS) means ratio was included in the pre-defined equivalence range of 80.00% to 125.00%. The number 203 reflects the descriptive analysis of the endpoint values. The number of subjects contributing to the statistical analysis was 197.
    Comparison groups
    Switching Arm v Continuous Humira
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Least squares means ratio
    Point estimate
    101.14
    Confidence interval
         level
    		 90.2%
         sides
    2-sided
         lower limit
    		 93.26
         upper limit
    		 109.7
    Notes
    [2] - The least squares means were from ANCOVA. Ratio calculated with the switching arm as numerator and the continuous arm as the denominator.

    Secondary: Minimum Observed Concentration During the Dosing Interval of Week 30 to 32 (Cmin, 30-32) for Adalimumab in plasma

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    End point title
    		 Minimum Observed Concentration During the Dosing Interval of Week 30 to 32 (Cmin, 30-32) for Adalimumab in plasma
    End point description
    Minimum Observed Concentration During the 2 weeks Dosing Interval of Week 30 to 32 for Adalimumab in plasma. The PK Set (PKS) included all patients from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Week 30, at 72, 120, 168 and 240 hours after the Week 30 dosing, and pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    104
    98
    Units: micogram / milliliter
        arithmetic mean (standard deviation)
    5.04 ± 3.89
    4.66 ± 4.19
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    No hypothesis was defined and no statistical test was performed. The number of subjects contributing to the statistical analysis was 195.
    Comparison groups
    Switching Arm v Continuous Humira
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Least squares mean ratio
    Point estimate
    107.31
    Confidence interval
         level
    		 90.2%
         sides
    2-sided
         lower limit
    		 97.33
         upper limit
    		 118.43
    Notes
    [3] - The least squares means were from ANCOVA. Ratio calculated with the switching arm as numerator and the continuous arm as the denominator.

    Secondary: Time to Maximum Observed Concentration During the Dosing Interval of Week 30 to 32 (tmax, 30-32) for Adalimumab in plasma

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    End point title
    		 Time to Maximum Observed Concentration During the Dosing Interval of Week 30 to 32 (tmax, 30-32) for Adalimumab in plasma
    End point description
    Time to Maximum Observed Concentration During the Dosing Interval of Week 30 to 32 for Adalimumab in plasma. The PK Set (PKS) included all patients from the TS who provided at least 1 primary PK parameter that was not excluded due to a protocol violation relevant to the evaluation of PK.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Week 30, at 72, 120, 168 and 240 hours after the Week 30 dosing, and pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    104
    99
    Units: hours
        median (full range (min-max))
    72.7 (66.0 to 336)
    72.3 (46.8 to 240)
    No statistical analyses for this end point

    Secondary: Percentage of Patients With a 75% Reduction in Psoriasis Area and Severity Index (PASI75) Response at Week 32

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    End point title
    		 Percentage of Patients With a 75% Reduction in Psoriasis Area and Severity Index (PASI75) Response at Week 32
    End point description
    PASI is a measure of clinical efficacy for psoriasis medications via numeric scores for overall psoriasis disease state, with scores ranging from 0 to 72. It is a linear combination of percent (%) of surface area of affected skin and the severity of erythema, induration, and desquamation over four body regions (head, trunk, upper extremities and lower extremities). Higher PASI scores indicate more severe psoriasis. PASI is summarized as a dichotomous outcome based on achieving over an X% reduction from baseline (PASIX), where X is 50, 75, 90, and 100. Percentage of patients with a PASI75 response at Week 32 was reported. The Per-protocol Analysis Set (PPS) contained all patients from the TS who did not experience any important protocol violations relevant for efficacy. Missing data were imputed via non-responder imputation for patients who discontinued treatment early and multiple imputation (MI) for missing at random value. There were no cases where it was required to implement MI.
    End point type
    Secondary
    End point timeframe
    At week 32
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    118
    119
    Units: Percentage of patients
        number (not applicable)
    84.75
    78.99
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    No hypothesis was tested. Risk difference was calculated as Switching arm minus Continuous Humira.
    Comparison groups
    Switching Arm v Continuous Humira
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.75
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.45
         upper limit
    		 13.96

    Secondary: Percentage of Patients With a Static Physician’s Global Assessment (sPGA) Score ≤ 1 (Clear or Almost Clear) at Week 32

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    End point title
    		 Percentage of Patients With a Static Physician’s Global Assessment (sPGA) Score ≤ 1 (Clear or Almost Clear) at Week 32
    End point description
    The sPGA is a 5-point score ranging from 0 to 4, based on the physician’s assessment of the average thickness, erythema, and scaling of all psoriatic lesions. The assessment is considered “static”, which refers to the patient’s disease state at the time of the assessments, without comparison to any of the patient’s previous disease states (dynamic), whether at baseline or at a previous visit. A lower score indicates less body coverage and a higher score indicates more severe disease (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe). Percentage of patients with a sPGA score of ≤ 1 (clear or almost clear) at Week 32 was reported. The PPS contained all patients from the TS who did not experience any important protocol violations relevant for efficacy. Missing data were imputed via non-responder imputation for patients who discontinued treatment early and multiple imputation (MI) for missing at random value. There were no cases where it was required to implement MI.
    End point type
    Secondary
    End point timeframe
    At week 32
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    118
    119
    Units: Percentage of patients
        number (not applicable)
    70.34
    64.71
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    No hypothesis was tested. Risk difference was calculated as Switching arm minus Continuous Humira.
    Comparison groups
    Switching Arm v Continuous Humira
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    5.63
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4.35
         upper limit
    		 15.62

    Secondary: Number of Patients With Anti-drug Antibodies (ADA) to Adalimumab at Week 32

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    End point title
    		 Number of Patients With Anti-drug Antibodies (ADA) to Adalimumab at Week 32
    End point description
    Number of patients with a confirmed positive anti-drug antibody (ADA) response to Adalimumab (BI 695501 or Humira) at Week 32. A participant was considered “ADA positive” if the blank normalized signal in the ADA screening assay was equal to or above the study specific ADA screening cut point factor of 1.06 and the signal inhibition by drug in the ADA confirmatory assay was equal to or above the study specific ADA confirmatory cut points (11.4% for signal inhibition with Humira and 12.0% for signal inhibition with BI 695501). Patients in the TS who had non-missing endpoints. The treated set (TS) contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    End point type
    Secondary
    End point timeframe
    Immunogenicity samples were collected pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    112
    112
    Units: Participants
        Negative
    11
    6
        Positive
    101
    104
        Total reportable
    112
    110
        Not reportable
    0
    2
    No statistical analyses for this end point

    Secondary: Number of Patients With Neutralizing Anti-drug Antibodies (nAb) to Adalimumab at Week 32

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    End point title
    		 Number of Patients With Neutralizing Anti-drug Antibodies (nAb) to Adalimumab at Week 32
    End point description
    Number of patients with a positive neutralizing anti-drug antibody (nAb) response to Adalimumab (BI 695501 or Humira) at Week 32. A participant was considered “nAb positive” if the blank normalized signal in the nAb screening assay was equal to or below the study specific nAb screening cut point factor of 0.836. Patients in the TS who had non-missing endpoints. The treated set (TS) contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    End point type
    Secondary
    End point timeframe
    Immunogenicity samples were collected pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    112
    112
    Units: Participants
        Negative
    66
    64
        Positive
    46
    46
        Total Reportable
    112
    110
        Not Reportable
    0
    2
    No statistical analyses for this end point

    Secondary: Anti-drug antibody (ADA) titer of patients with ADA at Week 32

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    End point title
    		 Anti-drug antibody (ADA) titer of patients with ADA at Week 32
    End point description
    Anti-drug antibody (ADA) titer of patients with a confirmed positive ADA response to Adalimumab (BI 695501 or Humira) at Week 32. Analysis was on patients in the treated set (TS) with positive ADAs at week 32. The TS contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    End point type
    Secondary
    End point timeframe
    Immunogenicity samples were collected pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    101
    104
    Units: Titer
        median (inter-quartile range (Q1-Q3))
    64.0 (32.00 to 256.00)
    128.0 (16.00 to 256.00)
    No statistical analyses for this end point

    Secondary: Neutralizing Anti-drug Antibody (nAb) titer of patients with nAb at Week 32

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    End point title
    		 Neutralizing Anti-drug Antibody (nAb) titer of patients with nAb at Week 32
    End point description
    Neutralizing anti-drug antibody (nAb) titer of patients with a positive nAb response to Adalimumab (BI 695501 or Humira) at Week 32. Analysis was on patients in the treated set (TS) with positive nAb at week 32. The TS contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    End point type
    Secondary
    End point timeframe
    Immunogenicity samples were collected pre-dose at Week 32.
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    46
    46
    Units: Titer
        median (inter-quartile range (Q1-Q3))
    2.0 (1.00 to 4.00)
    2.0 (1.00 to 2.00)
    No statistical analyses for this end point

    Secondary: Percentage of Patients With Drug-related adverse events (AEs) During the Post-Randomization Period

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    End point title
    		 Percentage of Patients With Drug-related adverse events (AEs) During the Post-Randomization Period
    End point description
    Analysis of AEs focused on treatment-emergent adverse events (TEAEs) and is presented here for the post-randomization period (Week 14 to 58). For the post-randomization period analysis, TEAEs were defined as AEs that started or worsened on or after the first dose of trial post-randomization medication and prior to the last dose of trial post-randomization medication + 10 weeks. Endpoint was measured on treated set (TS) that contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period.
    End point type
    Secondary
    End point timeframe
    From first dose of trial post-randomization medication until 10 weeks after last dose of trial post-randomization medication, up to 44 weeks
    End point values
    		 Switching Arm Continuous Humira
    Number of subjects analysed
    118
    120
    Units: Percentage of patients
        number (not applicable)
    11.9
    18.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first post-randomized trial medication until 10 weeks after last dose, up to 44 weeks (Post-Randomization Period). From first dose of Humira and prior to the first dose of post-randomization medication+10 weeks, up to 24 weeks (Run-In Period).
    Adverse event reporting additional description
    Safety analyses were performed based on the Treated Set (TS) and Run-in Treated Set (RTS). The TS contained all randomized patients who received at least 1 dose of trial medication administered in the post-randomization period. The RTS contained all enrolled patients treated with at least 1 dose of US-licensed Humira during the run-in period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Humira containing all RTS subjects (Run-In Period)
    Reporting group description
    		 All patients received US-licensed Humira during the run-in period of 14 weeks (Period 1). Patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. Trial medication were administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes (PFS) containing 40 mg of adalimumab per 0.8 milliliter (mL).

    Reporting group title
    Switching Arm (Post-Randomization Period)
    Reporting group description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the switching arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg BI 695501 at Week 14 and Week 16 (2 injections), followed by 40 mg US-licensed Humira at Week 18 and Week 20 (2 injections), and subsequently 40 mg BI 695501 every other week from Week 22 to Week 48 (14 injections). Trial medication were administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes (PFS) containing 40 mg of adalimumab or BI 695501 per 0.8 milliliter (mL).

    Reporting group title
    Continuous Humira (Post-Randomization Period)
    Reporting group description
    		 Patients initially received US-licensed Humira during the run-in period of 14 weeks (Period 1) and were then randomized to the continuous Humira arm for the randomized treatment period of 34 weeks (Period 2) followed by 10 weeks of safety follow-up. During Period 1, patients were administered with a loading dose of 80 milligram (mg) US-licensed Humira on Day 1 (Week 1), followed by 40 mg every other week from Week 2 to Week 12. During Period 2, patients received 40 mg US-licensed Humira every other week from Week 14 to Week 48 (18 injections).Trial medication were administered by subcutaneous (s.c.) injection providing in single-use pre-filled syringes (PFS) containing 40 mg of adalimumab per 0.8 milliliter (mL).

    Serious adverse events
    		 Humira containing all RTS subjects (Run-In Period) Switching Arm (Post-Randomization Period) Continuous Humira (Post-Randomization Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 259 (2.32%)
    5 / 118 (4.24%)
    4 / 120 (3.33%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Diffuse axonal injury
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 259 (0.00%)
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 259 (0.00%)
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 259 (0.00%)
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Demyelination
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Psoriatic arthropathy
         subjects affected / exposed
    1 / 259 (0.39%)
    0 / 118 (0.00%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 259 (0.00%)
    1 / 118 (0.85%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia chlamydial
         subjects affected / exposed
    0 / 259 (0.00%)
    0 / 118 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Humira containing all RTS subjects (Run-In Period) Switching Arm (Post-Randomization Period) Continuous Humira (Post-Randomization Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 259 (9.27%)
    17 / 118 (14.41%)
    11 / 120 (9.17%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 259 (3.86%)
    6 / 118 (5.08%)
    6 / 120 (5.00%)
         occurrences all number
    10
    7
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 259 (6.18%)
    11 / 118 (9.32%)
    5 / 120 (4.17%)
         occurrences all number
    20
    12
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2017
    Number of sites increased from 75 to 80; (administrative) corrections and updates to screening procedures, PK sampling procedures and specifications, and schedule of events; further PK endpoints added; change in bioanalytical lab.
    18 Apr 2019
    The actual date of the amendment was 25 Jul 2019. Based on a pre-defined blinded interim analysis, the primary statistical analysis method was adapted based on the discussion with USFDA after the global end of trial; The trial remained fully blinded; BLQ plasma concentrations were replaced by 1/2 LLOQ of the bioanalytical assay (except samples taken at Baseline Visit 2).

    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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