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    Clinical Trial Results:
    A comparative Study to Assess the Efficacy, Safety and Immunogenicity of YLB113 and Enbrel for the Treatment of Rheumatoid Arthritis

    Summary
    EudraCT number
    		 2015-002809-12
    Trial protocol
    		 HU   LV   CZ   ES   BG  
    Global end of trial date
    02 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Aug 2018
    First version publication date
    17 Aug 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    YLB113-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    YL Biologics Ltd
    Sponsor organisation address
    Gat No. 1156, Village Ghotwade, Mulshi Taluke, Pune, India, 412 115
    Public contact
    Head - Regulatory , YL Biologics Ltd, 91 2066549816, akshayaodak@lupin.com
    Scientific contact
    Head - Regulatory , YL Biologics Ltd, 91 2066549816, akshayaodak@lupin.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
    12 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to compare the efficacy of dosing and safety, 20% improvement according to American College of Rheumatology criteria (ACR20) at Week 24 of treatment with YLB113 50 mg or Enbrel 50 mg given once a week as a subcutaneous (SC) injection along with methotrexate (MTX) in patients with moderate to severe RA and to evaluate the long-term safety and immunogenicity, of YLB113 administration in comparison to Enbrel
    Protection of trial subjects
    The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines, and applicable laws and regulations. The study was also conducted in accordance with the Japanese GCP in Japan and in accordance with ICH-GCP and/or local regulatory GCP in European Union (EU) and India. An ICF approved by each study center’s IRB/IEC was signed by the subject or their legally authorized representative (according to the regulatory and legal requirements of the participating country). The ICF contained all relevant information to be conveyed to the prospective subject in order to assist him/her in making informed decision about participating in the study. Subjects were required to continue MTX, (Note: Reduction in the MTX dose was allowed for safety considerations only). Dosing with folic acid was allowed so as to prevent toxicity associated with MTX administration. For pain and rescue therapy, single-agent NSAIDs were allowed, (Note: Reduction in the dose of NSAIDs was allowed for safety considerations only). Oral corticosteroids (≤10 mg prednisone per day or equivalent corticosteroid) were allowed, (Note: Reduction in the dose of prednisolone was allowed for safety considerations only). Ongoing non-drug therapy started prior to obtaining informed consent (eg, physical therapy) for the purpose of treating the RA affected parts was allowed. A change to the type of such therapy or discontinuation based on an improvement in RA disease activity was allowed.
    Background therapy
    		 Essential Medications (MTX) Subjects were required to continue MTX (6 to 25 mg/week) provided that the dose of MTX was stable for at least 6 weeks prior to screening and remained stable for the duration of the study, except during the follow-up period (Note: Reduction in the MTX dose was allowed for safety considerations only).
    Evidence for comparator
    		 YLB113 (developed by YL Biologics Co., Ltd. hereinafter referred to as YLB) is an investigational biosimilar of Enbrel® (manufactured and marketed by Pfizer, Inc. which has the active ingredient Etanercept. YLB113 is found to be biosimilar to Enbrel based on analytical similarity and preclinical studies conducted to compare with Enbrel. For the development of biosimilars it is necessary to establish the similarity in quality characteristics and to demonstrate equivalence in efficacy and safety with the innovator drug as the control group. YLB113 has demonstrated excellent similarity to Enbrel in terms of quality (CMC) parameters as well as comparability in non-clinical studies. Two comparative Phase I studies, conducted one each in Japan and India, has demonstrated bioequivalence between YLB113 and Enbrel at 25 mg and 50 mg doses, respectively. The current Phase III study was planned to further demonstrate therapeutic equivalence between YLB113 and Enbrel in terms of efficacy, long-term safety and immunogenicity in RA subjects.
    Actual start date of recruitment
    25 Aug 2015
    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
    Romania: 1
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Bulgaria: 48
    Country: Number of subjects enrolled
    Czech Republic: 45
    Country: Number of subjects enrolled
    Hungary: 70
    Country: Number of subjects enrolled
    Latvia: 16
    Country: Number of subjects enrolled
    Ukraine: 28
    Country: Number of subjects enrolled
    Japan: 262
    Country: Number of subjects enrolled
    India: 33
    Worldwide total number of subjects
    528
    EEA total number of subjects
    205
    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)
    445
    From 65 to 84 years
    83
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 874 subjects were screened, and 528 subjects were randomized to YLB113 and Enbrel arms in a 1:1 ratio.

    Pre-assignment
    Screening details
    		 Screening period consisted of 28 days during which patients were to undergo an eligibility assessment. All Screening assessments were to be completed within 28 days prior to baseline.

    Period 1
    Period 1 title
    Stage A double-blind phase (24 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    All eligible subjects were randomly assigned the study medication, after all the requiredscreening procedures were completed and all required data were submitted to the interactive web response system (IWRS) system. Subjects who qualified for study randomization received a unique randomization number by IWRS. The IWRS assigned subjects to a treatment group based on a predefined randomization list.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 YLB113 (Lupin Etanercept) - stage A
    Arm description
    		 Eligible subjects randomly assigned to receive YLB113 50 mg once a week as a SC injection for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YLB113
    Investigational medicinal product code
    YLB113
    Other name
    INN ETANERCEPT, CAS 185243-69-0, EV substance code SUB01984MIG
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    YLB113 50 mg prefilled syringe 1.0 mL for SC injection

    Arm title
    		 Enbrel - stage A
    Arm description
    		 Eligible subjects randomly assigned to receive Enbrel 50 mg once a week as a SC injection for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enbrel
    Investigational medicinal product code
    Enbrel
    Other name
    INN ETANERCEPT, CAS 185243-69-0, EV substance code SUB01984MIG
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Enbrel 50 mg prefilled syringe 1.0 mL for SC injection

    Number of subjects in period 1
    		YLB113 (Lupin Etanercept) - stage A Enbrel - stage A
    Started
    266
    262
    Completed
    247
    250
    Not completed
    19
    12
         Consent withdrawn by subject
    8
    2
         Physician decision
    1
    1
         Adverse event, non-fatal
    2
    5
         Ineligible of patient
    3
    1
         Other
    1
    -
         Pregnancy
    1
    -
         Not dosed
    2
    2
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    Stage B double-blind phase (28 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 YLB113 (Lupin Etanercept) - stage B
    Arm description
    		 Subjects administered with YLB113 50 mg who completed evaluations for Week 24 in Stage A and were willing to continue in Stage B, and tolerated the study medications administered in Stage A with no serious adverse events (SAEs), or unresolved Grade 3 or higher AEs related to study medication. The subjects were administered the same drug as Stage A once a week as a SC injection for 28 weeks in this multicenter, comparative study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YLB113
    Investigational medicinal product code
    YLB113
    Other name
    INN ETANERCEPT, CAS 185243-69-0, EV substance code SUB01984MIG
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    YLB113 50 mg prefilled syringe 1.0 mL for SC injection

    Arm title
    		 Enbrel - stage B
    Arm description
    		 Subjects administered with Enbrel 50 mg who completed evaluations for Week 24 in Stage A and were willing to continue in Stage B, and tolerated the study medications administered in Stage A with no serious adverse events (SAEs), or unresolved Grade 3 or higher AEs related to study medication. The subjects were administered the same drug as Stage A once a week as a SC injection for 28 weeks in this multicenter, comparative study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enbrel
    Investigational medicinal product code
    Enbrel
    Other name
    INN ETANERCEPT, CAS 185243-69-0, EV substance code SUB01984MIG
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Enbrel 50 mg prefilled syringe 1.0 mL for SC injection

    Number of subjects in period 2 [1]
    		YLB113 (Lupin Etanercept) - stage B Enbrel - stage B
    Started
    236
    235
    Completed
    227
    227
    Not completed
    9
    8
         Physician decision
    2
    2
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    4
    4
         RA symptoms exacerbation
    -
    1
    Notes
    [1] - 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: A total of 497 subjects completed Stage A (247 in YLB113 arm and 250 in Enbrel arm). Of these 497 subjects, 471 subjects entered in Stage B, 18 in Stage C while 8 subjects did not opt for either stage. Out of the 471 subjects that entered in Stage B, FAS population consisted of 464 subjects. All 18 subjects that entered in Stage C were part of FAS population.
    Period 3
    Period 3 title
    Stage C double-blind phase (28 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Enbrel - stage C
    Arm description
    		 Subjects who received Enbrel 50 mg in Stage A, demonstrated reduction in their baseline DAS28 score by ≥0.6 at Week 12 and/or Week 24 and completed the 24-week period of Stage A, and tolerated the study medications administered in Stage A with no SAEs or unresolved Grade 3 or higher AEs related to study medication were eligible to enter Stage C were crossed over to receive YLB113 50 mg in Stage C
    Arm type
    		 Experimental

    Investigational medicinal product name
    YLB113
    Investigational medicinal product code
    YLB113
    Other name
    INN ETANERCEPT, CAS 185243-69-0, EV substance code SUB01984MIG
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    YLB113 50 mg prefilled syringe 1.0 mL for SC injection

    Arm title
    		 YLB113 (Lupin Etanercept) - stage C
    Arm description
    		 Subjects who received YLB113 50 mg in Stage A, demonstrated reduction in their baseline DAS28 score by ≥0.6 at Week 12 and/or Week 24 and completed the 24-week period of Stage A, and tolerated the study medications administered in Stage A with no SAEs or unresolved Grade 3 or higher AEs related to study medication were eligible to enter Stage C were crossed over to receive Enbrel 50 mg in Stage C.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enbrel
    Investigational medicinal product code
    Enbrel
    Other name
    INN ETANERCEPT, CAS 185243-69-0, EV substance code SUB01984MIG
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Enbrel 50 mg prefilled syringe 1.0 mL for SC injection.

    Number of subjects in period 3 [2]
    		Enbrel - stage C YLB113 (Lupin Etanercept) - stage C
    Started
    8
    10
    Completed
    8
    9
    Not completed
    0
    1
         RA symptoms exacerbation
    -
    1
    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: A total of 497 subjects completed Stage A (247 in YLB113 arm and 250 in Enbrel arm). Of these 497 subjects, 471 subjects entered in Stage B, 18 in Stage C while 8 subjects did not opt for either stage. Out of the 471 subjects that entered in Stage B, FAS population consisted of 464 subjects. All 18 subjects that entered in Stage C were part of FAS population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    YLB113 (Lupin Etanercept) - stage A
    Reporting group description
    		 Eligible subjects randomly assigned to receive YLB113 50 mg once a week as a SC injection for 24 weeks.

    Reporting group title
    Enbrel - stage A
    Reporting group description
    		 Eligible subjects randomly assigned to receive Enbrel 50 mg once a week as a SC injection for 24 weeks.

    Reporting group values
    		 YLB113 (Lupin Etanercept) - stage A Enbrel - stage A Total
    Number of subjects
    		 266 262 528
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 224 221 445
        From 65-84 years
    		 42 41 83
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.0 ( 12.46 ) 52.6 ( 11.46 ) -
    Gender categorical
    Units: Subjects
        Female
    		 202 210 412
        Male
    		 64 52 116
    Region
    Units: Subjects
        Japan
    		 132 130 262
        India
    		 16 17 33
        Europe
    		 118 115 233
    Acute Phase Reactant selected for patient in calculating for ACR20 and DAS28
    Units: Subjects
        CRP
    		 103 90 193
        ESR
    		 163 172 335
    ACR Global Functional Status of RA
    Units: Subjects
        Class I
    		 38 41 79
        Class II
    		 183 177 360
        Class III
    		 45 44 89
        Class IV
    		 0 0 0
    Tender joint counts (TJC) at Baseline
    68 Total Score
    Units: rating scale
        arithmetic mean (standard deviation)
    		 18.1 ( 10.02 ) 18.9 ( 10.38 ) -
    Tender joint counts (TJC) at Baseline
    28 Total Score
    Units: rating scale
        arithmetic mean (standard deviation)
    		 12.7 ( 6.36 ) 12.6 ( 6.06 ) -
    Swollen joint counts (SJC) at Baseline
    66 Total Score
    Units: rating scale
        arithmetic mean (standard deviation)
    		 13.3 ( 7.07 ) 14.2 ( 7.17 ) -
    Swollen joint counts (SJC) at Baseline
    28 Total Score
    Units: rating scale
        arithmetic mean (standard deviation)
    		 10.3 ( 4.92 ) 10.5 ( 4.93 ) -
    Patient global assessment of disease activity (Visual Analog Scale) at Baseline
    Units: rating scale
        arithmetic mean (standard deviation)
    		 61.3 ( 21.47 ) 63.4 ( 21.60 ) -
    Patient assessment of pain (VAS) at Baseline
    Units: rating scale
        arithmetic mean (standard deviation)
    		 60.6 ( 22.26 ) 63.1 ( 21.76 ) -
    Physician global assessment of disease activity (Visual Analog Scale) at Baseline
    Units: rating scale
        arithmetic mean (standard deviation)
    		 59.8 ( 19.13 ) 60.6 ( 19.71 ) -
    Health Assessment Questionnaire(HAQ) at Baseline
    Units: rating scale
        arithmetic mean (standard deviation)
    		 1.06 ( 0.712 ) 1.13 ( 0.685 ) -
    Disease Activity (DAS28) score at Baseline based on investigator chosen patient specific Acute Phase
    Units: rating scale
        arithmetic mean (standard deviation)
    		 5.756 ( 1.1112 ) 5.771 ( 1.0448 ) -
    Disease Activity (DAS28) score at Baseline based on patient-specific Acute Phase reactant
    DAS28-CRP
    Units: rating scale
        arithmetic mean (standard deviation)
    		 5.191 ( 1.0013 ) 5.237 ( 0.9222 ) -
    Disease Activity (DAS28) score at Baseline based on patient-specific Acute Phase reactant
    DAS28-ESR
    Units: rating scale
        arithmetic mean (standard deviation)
    		 6.108 ( 1.0306 ) 6.057 ( 0.9955 ) -
    Erythrocyte Sedimentation Rate(ESR) results (mm/hr)
    Units: rating scale
        arithmetic mean (standard deviation)
    		 35.5 ( 21.45 ) 32.8 ( 20.60 ) -
    C-reactive protein (CRP) (mg/dl)
    Units: rating scale
        arithmetic mean (standard deviation)
    		 1.299 ( 2.0762 ) 1.015 ( 1.4559 ) -
    MTX dose at Baseline
    Units: rating scale
        arithmetic mean (standard deviation)
    		 11.37 ( 3.967 ) 11.82 ( 4.021 ) -
    Body Mass Index (kg/m2)
    Units: rate scaling
        arithmetic mean (standard deviation)
    		 24.8 ( 5.24 ) 25.0 ( 5.14 ) -

    End points

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    End points reporting groups
    Reporting group title
    YLB113 (Lupin Etanercept) - stage A
    Reporting group description
    		 Eligible subjects randomly assigned to receive YLB113 50 mg once a week as a SC injection for 24 weeks.

    Reporting group title
    Enbrel - stage A
    Reporting group description
    		 Eligible subjects randomly assigned to receive Enbrel 50 mg once a week as a SC injection for 24 weeks.
    Reporting group title
    YLB113 (Lupin Etanercept) - stage B
    Reporting group description
    		 Subjects administered with YLB113 50 mg who completed evaluations for Week 24 in Stage A and were willing to continue in Stage B, and tolerated the study medications administered in Stage A with no serious adverse events (SAEs), or unresolved Grade 3 or higher AEs related to study medication. The subjects were administered the same drug as Stage A once a week as a SC injection for 28 weeks in this multicenter, comparative study.

    Reporting group title
    Enbrel - stage B
    Reporting group description
    		 Subjects administered with Enbrel 50 mg who completed evaluations for Week 24 in Stage A and were willing to continue in Stage B, and tolerated the study medications administered in Stage A with no serious adverse events (SAEs), or unresolved Grade 3 or higher AEs related to study medication. The subjects were administered the same drug as Stage A once a week as a SC injection for 28 weeks in this multicenter, comparative study.
    Reporting group title
    Enbrel - stage C
    Reporting group description
    		 Subjects who received Enbrel 50 mg in Stage A, demonstrated reduction in their baseline DAS28 score by ≥0.6 at Week 12 and/or Week 24 and completed the 24-week period of Stage A, and tolerated the study medications administered in Stage A with no SAEs or unresolved Grade 3 or higher AEs related to study medication were eligible to enter Stage C were crossed over to receive YLB113 50 mg in Stage C

    Reporting group title
    YLB113 (Lupin Etanercept) - stage C
    Reporting group description
    		 Subjects who received YLB113 50 mg in Stage A, demonstrated reduction in their baseline DAS28 score by ≥0.6 at Week 12 and/or Week 24 and completed the 24-week period of Stage A, and tolerated the study medications administered in Stage A with no SAEs or unresolved Grade 3 or higher AEs related to study medication were eligible to enter Stage C were crossed over to receive Enbrel 50 mg in Stage C.

    Primary: ACR20 response rate at week 24 between YLB113 and Enbrel

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    End point title
    		 ACR20 response rate at week 24 between YLB113 and Enbrel
    End point description
    Estimate and Confidence Intervals for Differences in ACR20 Response Rate at Week 24
    End point type
    Primary
    End point timeframe
    The ACR20 respose rate was determined at week24
    End point values
    		 YLB113 (Lupin Etanercept) - stage A Enbrel - stage A
    Number of subjects analysed
    263
    254
    Units: response rate
    263
    254
    Statistical analysis title
    		 Differences in ACR20 Response Rate at Week 24
    Statistical analysis description
    Statistical analysis description: ACR20 response rate after the first 24 weeks of treatment (Stage A) was the primary endpoint to assess equivalence between YLB113 and Enbrel®. Therapeutic equivalence in terms of ACR20 could be concluded if the exact 95% confidence interval for the difference in the ACR20 rates is completely contained within the interval [−15%; 15%]. A binomial regression model was to be employed.
    Comparison groups
    YLB113 (Lupin Etanercept) - stage A v Enbrel - stage A
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 < 0.025
    Method
    		 Binomial Regression
    Parameter type
    		 95% CI for the difference in ACR20
    Point estimate
    -5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.6
         upper limit
    		 0.5
    Notes
    [1] - The analysis of the primary variable was based on the FAS.

    Secondary: ACR20 Response Rate by Visit (Week) between YLB113 and Enbrel

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    End point title
    		 ACR20 Response Rate by Visit (Week) between YLB113 and Enbrel
    End point description
    Estimate and Confidence Intervals for Differences in ACR20 Response Rate by Visit (Week)
    End point type
    Secondary
    End point timeframe
    At each visit (Week) Day 29 (Week 4) - Day 57 (Week 8) - Day 85 (Week 12)
    End point values
    		 YLB113 (Lupin Etanercept) - stage A Enbrel - stage A
    Number of subjects analysed
    263
    254
    Units: Response to treatment at each Visit-Week
        Week 4
    263
    254
        Week 57
    263
    254
        Week 12
    263
    254
    Statistical analysis title
    		 Differences in ACR20 Response Rate at Week 4
    Statistical analysis description
    ACR20 response rate in each treatment group (Stage A) at Week 4 was one of the secondary endpoint. A binomial regression model was to be employed to calculate 95% CI.
    Comparison groups
    YLB113 (Lupin Etanercept) - stage A v Enbrel - stage A
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 < 0.025
    Method
    		 binomial regression model
    Parameter type
    		 95% CI for the difference in ACR20
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 10.2
    Notes
    [2] - The analysis of this secondary variable was based on the FAS.
    Statistical analysis title
    		 Differences in ACR20 Response Rate at Week 8
    Statistical analysis description
    ACR20 response rate in each treatment group (Stage A) at Week 8 was one of the secondary endpoint. A binomial regression model was to be employed to calculate 95% CI.
    Comparison groups
    YLB113 (Lupin Etanercept) - stage A v Enbrel - stage A
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 < 0.025
    Method
    		 binomial regression model
    Parameter type
    		 95% CI for the difference in ACR20
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.2
         upper limit
    		 1.2
    Notes
    [3] - The analysis of this secondary variable was based on the FAS.
    Statistical analysis title
    		 Differences in ACR20 Response Rate at Week 12
    Statistical analysis description
    ACR20 response rate in each treatment group (Stage A) at Week 12 was one of the secondary endpoint. A binomial regression model was to be employed to calculate 95% CI.
    Comparison groups
    YLB113 (Lupin Etanercept) - stage A v Enbrel - stage A
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 < 0.025
    Method
    		 binomial regression model
    Parameter type
    		 95% CI for the difference in ACR20
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 3.1
    Notes
    [4] - The analysis of this secondary variable was based on the FAS.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During Stage A (up to 24 weeks) During Stage B and C (up to 28 weeks)
    Adverse event reporting additional description
    AEs collected from date of informed consent until completion of the final visit (28 days follow up visit) and SAEs occurring after the time of informed consent until the final visit (28 days follow up visit) have been reported. SAEs occurring after end of study should be reported if PI considers that there is a casual relationship with study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Stage A YLB113
    Reporting group description
    		 Patient receiving at least one dose of experimental drug YLB113 during stage A

    Reporting group title
    Stage A Enbrel
    Reporting group description
    		 Patient receiving at least one dose of comparator Enbrel during stage A

    Reporting group title
    Stage B YLB113
    Reporting group description
    		 Patient receiving at least one dose of experimental drug YLB113 during stage B

    Reporting group title
    Stage B Enbrel
    Reporting group description
    		 Patient receiving at least one dose of comparator drug Enbrel during stage B

    Reporting group title
    Stage C YLB113
    Reporting group description
    		 Patient receiving at least one dose of experimental drug YLB113 during stage C

    Reporting group title
    Stage C Enbrel
    Reporting group description
    		 Patient receiving at least one dose of comparator drug Enbrel during stage C

    Serious adverse events
    		 Stage A YLB113 Stage A Enbrel Stage B YLB113 Stage B Enbrel Stage C YLB113 Stage C Enbrel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 263 (3.04%)
    4 / 254 (1.57%)
    8 / 235 (3.40%)
    5 / 229 (2.18%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lobular breast carcinoma in situ
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    1 / 229 (0.44%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    1 / 229 (0.44%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VIth nerve paresis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    1 / 229 (0.44%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 254 (0.39%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural cyst
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Still's disease adult onset
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 254 (0.39%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 254 (0.79%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    1 / 229 (0.44%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    1 / 229 (0.44%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    1 / 235 (0.43%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Stage A YLB113 Stage A Enbrel Stage B YLB113 Stage B Enbrel Stage C YLB113 Stage C Enbrel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 263 (54.75%)
    166 / 254 (65.35%)
    120 / 235 (51.06%)
    143 / 229 (62.45%)
    3 / 10 (30.00%)
    3 / 8 (37.50%)
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    5 / 263 (1.90%)
    25 / 254 (9.84%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    5
    25
    0
    0
    0
    1
    Injection site reaction
         subjects affected / exposed
    10 / 263 (3.80%)
    35 / 254 (13.78%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    10
    35
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    1 / 10 (10.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    0 / 10 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    30 / 263 (11.41%)
    25 / 254 (9.84%)
    35 / 235 (14.89%)
    44 / 229 (19.21%)
    0 / 10 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    30
    25
    35
    44
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 263 (0.00%)
    0 / 254 (0.00%)
    0 / 235 (0.00%)
    0 / 229 (0.00%)
    1 / 10 (10.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2015
    Protocol Version 1.0 was submitted to the PMDA. Protocol Version 1.0 was the first protocol approved by the IRB. It was implemented only in Japan.
    16 Jul 2015
    Protocol Amendment Version 1.1 was an amendment of Protocol Version 1.0, which was modified as per the PMDA advice. It was implemented only in Japan.
    29 Jul 2015
    Protocol Amendment Version 1.1.1 was an amendment of Protocol Version 1.1, and was implemented in Europe and India, but not in Japan. This amendment concerned the changes of washout period of auranofin and hydroxychloroquine (annexure 15 of the protocol), from 5 months and 8 months, respectively, to 4 weeks for both, based on reconsideration of their maximum half-lives.
    10 Feb 2016
    In addition to the changes made in the Protocol Amendment Version 1.1, the following changes were made in the Protocol Amendment Version 1.1.2. This protocol amendment was implemented only in Japan. • The exclusion criterion No. 7 (Section 4.3) was revised as follows (underlined below) according to the Investigators’ opinions that remission is indicated for a patient with a history of cancer who remained cancer-free for 5 years. Patients with active or prior history of malignancies within 5 years prior to Screening (except for successfully treated non-metastatic basal or squamous cell carcinoma of the skin and carcinoma in situ of the cervix). • The following phrase (underlined) was deleted from the description of the pregnancy test in Section 9.6 to be consistent with the actual logistic arrangement. Pregnancy test for females of childbearing potential will be performed at Screening, 24 weeks (or ED) and 52 weeks (or ED) at each clinical site and analyzed in central laboratory. • The following change (“approximately”) was made to the target number of patients enrolled in Stage A (Section 10.1.1) because the competitive patient recruitment across 14 countries made it difficult to end recruitment precisely at the target. Approximately 500 patients will be randomized for this study in consideration of the dropouts and deviations. • This amendment concerned the changes of washout period of auranofin and hydroxychloroquine (annexure 15 of the protocol), from 5 months and 8 months, respectively, to 4 weeks for both, based on reconsideration of their maximum half-lives.
    26 May 2016
    Protocol Amendment Version 2.0 was implemented only in Japan. In this amendment, the study objective was changed to include an additional objective for assessing the sustainability of efficacy of Enbrel and YLB113 after crossing over the treatments. For this purpose, Stage C was added, which, however, was not to be conducted in Japan. Sections across the protocol were amended in line with this change in the objective. Please refers to underlined sentences reported in the Protocol Amendment and full CSR in the following sections: • Study objectives in synopsis and in Section 2.1 • Study population in synopsis • Number of patients in synopsis • Study duration and treatment period in synopsis • Inclusion criteria in synopsis and in Section 4.2. • Exclusion criteria in synopsis and in Section 4.3. • Re-consenting procedure was newly added to the synopsis • Footnote of Table 2 for Stage B or Stage C • Section 3.2.1. • Section 3.2.3. Stage C • Section 6.1.2. • Section 6.3.3. Stage C • Section 7.2.2. • Section 7.2.3. • Refer Section 7.2.5: ‘Continuation of Stage B or Stage C treatment’ for visits beyond Week 36 for the description of the assessments. • Section 10.1.3. The following changes were also made to the protocol: • The target number of participating sites (Synopsis, Section 4.4.2) was changed to 140 based on the forecasted accruals at the time. • A sentence was deleted in Section 6.4.1 to be consistent with the inclusion criteria. • A phrase was added to Section 4.5.1 to further define study-completed patients, and the phrase in italic was deleted • A phrase was added to Section 6.4.2 to allow study drug continuation beyond 52 weeks up to the follow-up visit for patients participating in an extension study, if conducted.
    01 Jul 2016
    Protocol Amendment Version 2.1 was implemented in all regions, except that Stage C was not to be conducted in Japan. In this amendment, the following changes were made to the Protocol Amendment Version 2.0. • The target enrolled patient number in Sections 4.4.1 and in 10.1.1 were changed as follows (underlined) since the competitive recruitment made it unlikely that the target number in each region would be as planned. Planned number of enrolled patients: 500 (250 in each arm) Randomization, YLB113:Enbrel = 1:1. The number of enrolled patients in Japan, EU and India is expected to be 500 with a competitive recruitment aiming to recruit approximately half the patients in Japan and half in Europe and India. • The following underlined sentence was added to Section 6.1.1, since the drastically different screening failure rates between the regions prevented stopping screening in order to ensure enrollment of 500 patients, forcing the Sponsor to deny randomization for some screened and eligible patients to ensure that the total numbers specified in the protocol (500 randomized) was not exceeded by 10%. • The treatment assignment will occur at the time of randomization, after all the required screening procedures have been completed and all required data have been submitted to the IWRS system. Patients who qualify for study randomization will receive a unique randomization number by IWRS (see IWRS manual). After completion of required numbers (500 randomized), some patients who qualify in screening may not be randomized.

    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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