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    Clinical Trial Results:
    A Randomized, Parallel-Group, Phase I/III Study to Evaluate Efficacy, Pharmacokinetics and Safety between Subcutaneous CT-P13 and Intravenous CT-P13 in Patients with Active Rheumatoid Arthritis

    Summary
    EudraCT number
    2016-002125-11
    Trial protocol
    LV   EE   HU   CZ   BG   ES  
    Global end of trial date
    15 Apr 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Feb 2020
    First version publication date
    23 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CT-P13 3.5
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03147248
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CELLTRION Inc.
    Sponsor organisation address
    23, Academy-ro, Yeonsu-gu, Incheon, Korea, Republic of, 22014
    Public contact
    Su Eun Song, Clinical Operation Department, CELLTRION Inc., +82 32 850 5776, SuEun.Song@celltrion.com
    Scientific contact
    Sung Hyun Kim, Clinical Planning Department, CELLTRION Inc., +82 32 850 5778, SungHyun.Kim@celltrion.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
    15 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1 •To find the optimal dose of CT-P13 subcutaneous (SC) over the first 30 weeks as determined by the area under the concentration-time curve (AUCτ) at steady state between Week 22 and Week 30 Part 2 •To demonstrate that CT-P13 SC is noninferior to CT-P13 intravenous (IV) at Week 22, in terms of efficacy, as determined by clinical response according to change from baseline in disease activity measured by Disease Activity Score using 28 joint counts (DAS28) (C-reactive protein [CRP])
    Protection of trial subjects
    The CT-P13 SC via prefilled syringe (PFS) was injected by the investigator or his/her designee at each study center visit at the time points specified in the schedule of events. CT-P13 SC via PFS was injected at a slow, steady rate. For each new injection, a different injection site was used. The same injection sites could be used only if the other sites were unavailable due to safety reasons and in that case, it was recommended that the new injection was given at least 3 cm away from the most recent area injected. After proper training in injection technique, patients could self-inject with CT-P13 SC via PFS if their investigator determined that it was appropriate. For patients in specific countries in Part 2, CT-P13 SC via auto-injector (AI) was self-injected by the patients after proper training in AI injection technique. If healthcare professional determined or the patient requested it, additional training was given prior to the self-injection of CT-P13 SC via PFS or AI. Hypersensitivity was assessed by vital sign monitoring on each visit day at the time points: Prior to the beginning of the study drug administration and 1h after the end of the study drug administration. Hypersensitivity was assessed at the time points from Week 0 to Week 30 in Part 2: Prior to the beginning of the SC formulation injection and 1h after the end of the IV formulation infusion. Hypersensitivity was monitored by routine continuous clinical monitoring, incl. patient-reported signs and symptoms. In case of hypersensitivity, emergency equipment (adrenaline, antihistamines, corticosteroids, and respiratory support incl. inhalational therapy, oxygen, and artificial ventilation) was available and any types of ECG could have been performed. For patients who experienced or developed life-threatening treatment-related anaphylactic reactions, infliximab treatment was stopped immediately and the patient withdrawn from the study.
    Background therapy
    Throughout the study, methotrexate (MTX) were coadministered at a dosage of between 12.5 to 25 mg/week (between 10 to 25 mg/week in Korea), oral or parenteral dose. Folic acid were co-administered at a dosage of at least 5 mg/week for as long as MTX treatment was continued.
    Evidence for comparator
    CT-P13 IV is an approved biosimilar to EU-approved Remicade and US-licensed Remicade. A new formulation of CT-P13 SC is developed as liquid type filled aseptically into 1 mL PFS and is an alternative to the IV regimen where SC infliximab injection typically takes less than 2 minutes. Therefore, this study was designed to evaluate efficacy, pharmacokinetic (PK), pharmacodynamic (PD) and safety between CT-P13 SC and CT-P13 IV in patients with active Rheumatoid Arthritis (RA).
    Actual start date of recruitment
    12 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Ukraine: 62
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 21
    Country: Number of subjects enrolled
    Bulgaria: 29
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Estonia: 9
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Peru: 44
    Country: Number of subjects enrolled
    Poland: 114
    Country: Number of subjects enrolled
    Russian Federation: 78
    Worldwide total number of subjects
    391
    EEA total number of subjects
    173
    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)
    337
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study consisted of 2 parts. 48 patients from 15 study centers were randomly assigned in 1 of 4 cohorts in Part 1 and 343 patients from 68 study centers were randomly assigned to 1 of 2 treatment arms in Part 2.

    Pre-assignment
    Screening details
    Key Inclusion Criteria: - Patient is male or female between 18 and 75 years old, incl., with a diagnosis of RA according to the 2010 American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR). - Patient has active disease as defined by the presence of ≥6 swollen joints (of 28 assessed), ≥6 tender joints (of 28 assessed).

    Period 1
    Period 1 title
    Part 1 + Part 2 (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Data analyst, Carer, Subject
    Blinding implementation details
    Blinding was not included in Part 1 of the study because it was an open-label study. Part 2 was blinded during the study. All the patient and physician and predefined blinded team remained blinded until all patients had completed the study and the database had been finalized for study termination. The blindness has been maintained throughout the study period except the appointed unblinded teams. The blind should not be broken under normal circumstances.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: CT-P13 IV 3 mg/kg (Part 1)
    Arm description
    CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose.
    Arm type
    Active comparator

    Investigational medicinal product name
    CT-P13 (infliximab)
    Investigational medicinal product code
    Other name
    Infliximab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then administered with further 7 doses of CT-P13 IV at Week 6 and every 8 weeks thereafter. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

    Arm title
    Cohort 2: CT-P13 SC 90 mg (Part 1)
    Arm description
    CT-P13 (90 mg) by single SC injection via PFS.
    Arm type
    Experimental

    Investigational medicinal product name
    CT-P13 (infliximab)
    Investigational medicinal product code
    Other name
    Infliximab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (90 mg) by SC injection via PFS with a 2-week interval from Week 6. The dose of SC 90 mg was adjusted to SC 120 mg every 2 weeks after Week 30 in applicable patients in Cohort 2: CT-P13 SC 90 mg. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

    Arm title
    Cohort 3: CT-P13 SC 120 mg (Part 1)
    Arm description
    CT-P13 (120 mg) by single SC injection via PFS.
    Arm type
    Experimental

    Investigational medicinal product name
    CT-P13 (infliximab)
    Investigational medicinal product code
    Other name
    Infliximab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (120 mg) by SC injection via PFS with a 2-week interval from Week 6. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

    Arm title
    Cohort 4: CT-P13 SC 180 mg (Part 1)
    Arm description
    CT-P13 (180 mg) by double SC injections via PFS.
    Arm type
    Experimental

    Investigational medicinal product name
    CT-P13 (infliximab)
    Investigational medicinal product code
    Other name
    Infliximab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (180 mg) by SC injection via PFS with a 2-week interval from Week 6. The dose of SC 180 mg was adjusted to SC 120 mg every 2 weeks after Week 30 in applicable patients in Cohort 4: CT-P13 SC 180 mg. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

    Arm title
    Arm 1: CT-P13 SC 120 mg (Part 2)
    Arm description
    CT-P13 (120 mg) by single SC injection every other week with placebo IV at Weeks 6, 14 and 22.
    Arm type
    Experimental

    Investigational medicinal product name
    CT-P13 (infliximab)
    Investigational medicinal product code
    Other name
    Infliximab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then CT-P13 SC (120 mg) by SC injection via PFS with a 2-week interval from Week 6 up to Week 54 with placebo IV at Weeks 6, 14 and 22. Patients in specific countries were administered CT-P13 SC via AI at Week 46 and every 2 weeks up to Week 54, and were switched back to CT-P13 SC via PFS at Week 56 and every 2 weeks up to Week 64. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

    Arm title
    Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Arm description
    CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose every 8 weeks with placebo SC at Week 6 and every other week up to Week 28. CT-P13 (120 mg) by single SC injection was administered every other week from Week 30.
    Arm type
    Active comparator

    Investigational medicinal product name
    CT-P13 (infliximab)
    Investigational medicinal product code
    Other name
    Infliximab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P13 IV (3 mg/kg) administered as a 2 hour IV infusion at Weeks 0 and 2, then administered with further 3 doses of CT-P13 IV at Week 6 and every 8 weeks thereafter (Weeks 6, 14 and 22) with placebo SC at Week 6 and every 2 weeks up to Week 28. CT-P13 IV was switched to CT-P13 SC via PFS at Week 30, and further doses with CT-P13 SC every other week were given up to Week 54 (up to Week 44 for specific countries). Patients in specific countries were administered CT-P13 SC via AI at Week 46 and every 2 weeks up to Week 54, and were switched back to CT-P13 SC via PFS at Week 56 and every 2 weeks up to Week 64. MTX between 12.5 to 25 mg/week (10 to 25 mg/week in Korea), oral or parenteral dose and folic acid (≥ 5 mg/week) were coadministered.

    Number of subjects in period 1
    Cohort 1: CT-P13 IV 3 mg/kg (Part 1) Cohort 2: CT-P13 SC 90 mg (Part 1) Cohort 3: CT-P13 SC 120 mg (Part 1) Cohort 4: CT-P13 SC 180 mg (Part 1) Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Started
    13
    11
    12
    12
    167
    176
    Completed
    12
    9
    10
    10
    141
    145
    Not completed
    1
    2
    2
    2
    26
    31
         Death
    -
    -
    -
    -
    -
    4
         Protocol deviation
    -
    -
    -
    -
    2
    -
         Other
    -
    -
    -
    -
    3
    5
         Pregnancy
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    2
    2
    2
    6
    11
         Consent withdrawn by subject
    -
    -
    -
    -
    12
    9
         Lost to follow-up
    -
    -
    -
    -
    2
    -
         Patient develops signs of disease progression
    1
    -
    -
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: CT-P13 IV 3 mg/kg (Part 1)
    Reporting group description
    CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose.

    Reporting group title
    Cohort 2: CT-P13 SC 90 mg (Part 1)
    Reporting group description
    CT-P13 (90 mg) by single SC injection via PFS.

    Reporting group title
    Cohort 3: CT-P13 SC 120 mg (Part 1)
    Reporting group description
    CT-P13 (120 mg) by single SC injection via PFS.

    Reporting group title
    Cohort 4: CT-P13 SC 180 mg (Part 1)
    Reporting group description
    CT-P13 (180 mg) by double SC injections via PFS.

    Reporting group title
    Arm 1: CT-P13 SC 120 mg (Part 2)
    Reporting group description
    CT-P13 (120 mg) by single SC injection every other week with placebo IV at Weeks 6, 14 and 22.

    Reporting group title
    Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Reporting group description
    CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose every 8 weeks with placebo SC at Week 6 and every other week up to Week 28. CT-P13 (120 mg) by single SC injection was administered every other week from Week 30.

    Reporting group values
    Cohort 1: CT-P13 IV 3 mg/kg (Part 1) Cohort 2: CT-P13 SC 90 mg (Part 1) Cohort 3: CT-P13 SC 120 mg (Part 1) Cohort 4: CT-P13 SC 180 mg (Part 1) Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2) Total
    Number of subjects
    13 11 12 12 167 176 391
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    12 9 10 10 148 148 337
        Elderly (≥65 years)
    1 2 2 2 19 28 54
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    43.6 (24 to 69) 53.5 (39 to 68) 49.7 (30 to 65) 50.7 (32 to 68) 50.9 (19 to 74) 51.9 (18 to 74) -
    Gender categorical
    Units: Subjects
        Female
    11 9 9 9 130 139 307
        Male
    2 2 3 3 37 37 84
    Subject analysis sets

    Subject analysis set title
    All-randomised population (Part 2)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The all-randomised population consisted of all randomly assigned patients at Week 6, regardless of whether or not any study drug dosing was completed. It was also applied for Part 1.

    Subject analysis set title
    Efficacy population (Part 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The efficacy population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one efficacy evaluation result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 2, the efficacy analysis set consisted of the patients who were included in efficacy population and had DAS28 (CRP) result at Week 22.

    Subject analysis set title
    Pharmacokinetics population (Part 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PK concentration result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 1, the PK analysis set consisted of the patients who received all doses (full) of study drug up to Week 30 (prior to Week 30) in the PK population.

    Subject analysis set title
    Pharmacodynamics population (Part 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PD result (rheumatoid factor, anti-cyclic citrullinated peptide [anti-CCP], CRP, or erythrocyte sedimentation rate) after Week 6 or thereafter treatment. It was also applied for Part 1.

    Subject analysis set title
    Safety population (Part 2)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population consisted of all patients who received at least one dose (partial or full) of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter. It was also applied for Part 1.

    Subject analysis sets values
    All-randomised population (Part 2) Efficacy population (Part 2) Pharmacokinetics population (Part 2) Pharmacodynamics population (Part 2) Safety population (Part 2)
    Number of subjects
    343
    339
    340
    343
    343
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    296
    292
    293
    296
    296
        Elderly (≥65 years)
    47
    47
    47
    47
    47
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    51.4 (18 to 74)
    51.4 (18 to 74)
    51.4 (18 to 74)
    51.4 (18 to 74)
    51.4 (18 to 74)
    Gender categorical
    Units: Subjects
        Female
    269
    265
    267
    269
    269
        Male
    74
    74
    73
    74
    74

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: CT-P13 IV 3 mg/kg (Part 1)
    Reporting group description
    CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose.

    Reporting group title
    Cohort 2: CT-P13 SC 90 mg (Part 1)
    Reporting group description
    CT-P13 (90 mg) by single SC injection via PFS.

    Reporting group title
    Cohort 3: CT-P13 SC 120 mg (Part 1)
    Reporting group description
    CT-P13 (120 mg) by single SC injection via PFS.

    Reporting group title
    Cohort 4: CT-P13 SC 180 mg (Part 1)
    Reporting group description
    CT-P13 (180 mg) by double SC injections via PFS.

    Reporting group title
    Arm 1: CT-P13 SC 120 mg (Part 2)
    Reporting group description
    CT-P13 (120 mg) by single SC injection every other week with placebo IV at Weeks 6, 14 and 22.

    Reporting group title
    Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Reporting group description
    CT-P13 (3 mg/kg) by IV infusion administered as a 2 hour IV infusion per dose every 8 weeks with placebo SC at Week 6 and every other week up to Week 28. CT-P13 (120 mg) by single SC injection was administered every other week from Week 30.

    Subject analysis set title
    All-randomised population (Part 2)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The all-randomised population consisted of all randomly assigned patients at Week 6, regardless of whether or not any study drug dosing was completed. It was also applied for Part 1.

    Subject analysis set title
    Efficacy population (Part 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The efficacy population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one efficacy evaluation result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 2, the efficacy analysis set consisted of the patients who were included in efficacy population and had DAS28 (CRP) result at Week 22.

    Subject analysis set title
    Pharmacokinetics population (Part 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PK concentration result after Week 6 or thereafter treatment. It was also applied for Part 1. Additionally, for the primary endpoint of Part 1, the PK analysis set consisted of the patients who received all doses (full) of study drug up to Week 30 (prior to Week 30) in the PK population.

    Subject analysis set title
    Pharmacodynamics population (Part 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD population consisted of the all-randomised population who received at least one full dose of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter and who had at least one PD result (rheumatoid factor, anti-cyclic citrullinated peptide [anti-CCP], CRP, or erythrocyte sedimentation rate) after Week 6 or thereafter treatment. It was also applied for Part 1.

    Subject analysis set title
    Safety population (Part 2)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population consisted of all patients who received at least one dose (partial or full) of study drug (CT-P13 SC or CT-P13 IV) at Week 6 or thereafter. It was also applied for Part 1.

    Primary: Analysis of Change (Decrease) From Baseline of Disease Activity Score Using 28 Joint Counts (DAS28) (CRP) at Week 22 (ANCOVA) (Part 2)

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    End point title
    Analysis of Change (Decrease) From Baseline of Disease Activity Score Using 28 Joint Counts (DAS28) (CRP) at Week 22 (ANCOVA) (Part 2) [1]
    End point description
    The primary efficacy endpoint was the mean change (decrease) from baseline of DAS28 (CRP) at Week 22 (ANCOVA) for the efficacy population. All patients included in the efficacy population were analyzed according to the treatment they received. The least squares means and standard errors, estimate of treatment difference (CT-P13 SC 120 mg - CT-P13 IV 3 mg/kg), and 2-sided 95% CI obtained from the ANCOVA model.
    End point type
    Primary
    End point timeframe
    At Week 22
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: ANCOVA Statistical analysis was presented for this endpoint of Part 2.
    End point values
    Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Number of subjects analysed
    162
    168
    Units: Score
        least squares mean (standard error)
    2.21 ± 0.221
    1.94 ± 0.209
    Statistical analysis title
    ANCOVA Statistical analysis
    Statistical analysis description
    Primary efficacy analysis were analyzed using an ANCOVA considering the treatment as fixed effect and country, serum CRP concentration at Week 2 (≤0.6 mg/dL vs. >0.6 mg/dL), and body weight at Week 6 (≤100 kg vs. >100 kg) as covariates. The non-inferiority was to be concluded if the lower limit of the two-sided 95% CI for the difference in the mean change (decrease) from baseline of DAS28 (CRP) at Week 22 was greater than the pre-specified non-inferiority margin of -0.6.
    Comparison groups
    Arm 2: CT-P13 IV 3 mg/kg (Part 2) v Arm 1: CT-P13 SC 120 mg (Part 2)
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    ANCOVA
    Parameter type
    Difference of Least square means
    Point estimate
    0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    0.52

    Primary: Descriptive Statistics of AUCτ of Infliximab at Steady State (Part 1)

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    End point title
    Descriptive Statistics of AUCτ of Infliximab at Steady State (Part 1) [2] [3]
    End point description
    For Part 1, the primary PK endpoint of the AUCτ at steady state between Week 22 and Week 30 was analyzed in patients who received all doses (full) of study drug up to Week 30 (prior to Week 30) in the PK population. AUCτ is calculated at Week 22 for the IV cohort, Week 22 and 26 for Group A of SC cohorts, and Week 24 and 28 for Group B of SC cohorts.
    End point type
    Primary
    End point timeframe
    From Week 22 to Week 30. Week 24, 26 and 28 are not applicable for cohort 1.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive Statistics was presented for this endpoint of Part 1.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive Statistics was presented for this endpoint of Part 1.
    End point values
    Cohort 1: CT-P13 IV 3 mg/kg (Part 1) Cohort 2: CT-P13 SC 90 mg (Part 1) Cohort 3: CT-P13 SC 120 mg (Part 1) Cohort 4: CT-P13 SC 180 mg (Part 1)
    Number of subjects analysed
    13
    10
    11
    12
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Week 22
    12032957.514 ± 5345598.5883
    5047724.204 ± 2449771.8620
    7333766.999 ± 2765064.1854
    9930696.560 ± 3208367.3670
        Week 24
    0 ± 0
    3272936.820 ± 2847811.5999
    4835631.915 ± 2156587.2518
    9322764.345 ± 2704651.4449
        Week 26
    0 ± 0
    4722645.212 ± 2434832.1852
    7295570.506 ± 2261574.6345
    10402980.887 ± 3316415.1055
        Week 28
    0 ± 0
    3231316.559 ± 2582286.8805
    5076458.747 ± 2733359.4502
    10578411.810 ± 3443240.8206
    No statistical analyses for this end point

    Secondary: Descriptive Statistics for Actual Value in Serum CRP Concentration (Pharmacodynamic Parameter) (Part 2)

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    End point title
    Descriptive Statistics for Actual Value in Serum CRP Concentration (Pharmacodynamic Parameter) (Part 2) [4]
    End point description
    For evaluation of pharmacodynamic (PD), the secondary endpoint was defined as concentration of CRP between 2 treatment groups up to Week 54. The blood samples for CRP were collected at Weeks 0, 2 and 6, and every 8 weeks up to Week 54. All enrolled patients received CT-P13 IV infusions at Weeks 0 and 2. Then, patients in CT-P13 SC group were administered with CT-P13 SC at Week 6 and every 2 weeks thereafter up to Week 54. Patients in the CT-P13 IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22 (Weeks 14 and 22). And then, CT-P13 IV was switched to CT-P13 SC at Week 30, and further doses with CT-P13 SC were given up to Week 54. All patients in the PD population were analyzed according to the treatment they received. The actual PD population was 168 for CT-P13 SC arm and 175 for CT-P13 IV arm. One patient in the CT-P13 IV arm who was mis-randomized was analyzed as CT-P13 SC arm.
    End point type
    Secondary
    End point timeframe
    Up to Week 54
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive Statistics was presented for this endpoint of Part 2.
    End point values
    Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Number of subjects analysed
    167
    176
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline
    1.822 ± 2.3669
    2.230 ± 3.5181
        Week 2
    0.474 ± 0.7761
    0.619 ± 1.4288
        Week 6
    0.740 ± 1.3774
    0.977 ± 1.8369
        Week 14
    0.811 ± 1.9631
    1.144 ± 2.5256
        Week 22
    0.723 ± 1.3343
    1.161 ± 2.1265
        Week 30
    0.666 ± 1.2609
    1.168 ± 2.1426
        Week 38
    0.714 ± 1.2759
    1.078 ± 2.9450
        Week 46
    0.600 ± 1.0143
    0.786 ± 1.4681
        Week 54
    0.601 ± 1.0051
    0.779 ± 1.4846
    No statistical analyses for this end point

    Secondary: Descriptive Statistics of Observed Ctrough (Trough Concentration [Before the Next Study Drug Administration] of Infliximab (Part 2)

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    End point title
    Descriptive Statistics of Observed Ctrough (Trough Concentration [Before the Next Study Drug Administration] of Infliximab (Part 2) [5]
    End point description
    For evaluation of pharmacokinetics (PK), the secondary endpoint was defined as the analysis of trough concentration of Infliximab up to Week 54. The samples were collected at Weeks 0, 2 and 6, and every 8 weeks up to Week 54. During PK monitoring visit (Weeks 22-30), samples were collected every 2 weeks according steady state PK sampling time point. All enrolled patients received CT-P13 IV infusions at Weeks 0 and 2. Patients in SC group were administered with CT-P13 SC at Week 6 and every 2 weeks thereafter up to Week 54. Patients in IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22. Then, CT-P13 IV was switched to CT-P13 SC at Week 30, and further doses with CT-P13 SC were given up to Week 54. No PK results were obtained at Weeks 6 and 14 for SC group and Weeks 12, 20, 24, 26 and 28 for IV group due to 2 weeks and 8 weeks dosing interval, respectively. All patients in PK population were analyzed according to the treatment they received.
    End point type
    Secondary
    End point timeframe
    Up to Week 54. Not applicable visits are as follows: Arm 1 - Week 6 and 14; Arm 2 - Week 12, 20, 24, 26 and 28.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive Statistics was presented for this endpoint of Part 2.
    End point values
    Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Number of subjects analysed
    166
    174
    Units: μg/mL
    arithmetic mean (standard deviation)
        Week 0
    15.7346 ± 5.83064
    16.0028 ± 5.98981
        Week 2
    8.6402 ± 5.96562
    8.8058 ± 7.13489
        Week 6
    0 ± 0
    1.8922 ± 2.61129
        Week 12
    12.3338 ± 8.20393
    0 ± 0
        Week 14
    0 ± 0
    3.2044 ± 11.13945
        Week 20
    12.7203 ± 9.13334
    0 ± 0
        Week 22
    13.1921 ± 10.56596
    1.0302 ± 1.85362
        Week 24
    12.3212 ± 8.54834
    0 ± 0
        Week 26
    10.7290 ± 7.07566
    0 ± 0
        Week 28
    12.2747 ± 9.75026
    0 ± 0
        Week 36
    12.2038 ± 9.43936
    8.7911 ± 8.62922
        Week 44
    11.2449 ± 8.50602
    9.9692 ± 9.65035
        Week 52
    10.9761 ± 8.81064
    10.2342 ± 10.08052
    No statistical analyses for this end point

    Secondary: Descriptive Statistics for Actual Value of DAS28 (CRP) (Part 2)

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    End point title
    Descriptive Statistics for Actual Value of DAS28 (CRP) (Part 2) [6]
    End point description
    For evaluation of efficacy, the secondary endpoint was defined as descriptive statistics of actual value in disease activity measured by DAS28 (CRP) up to Week 54 (efficacy population) between 2 treatment groups. The results up to Week 6 represented the efficacy of CT-P13 IV loading dose (3 mg/kg) regardless of randomized treatment group (CT-P13 SC or CT-P13 IV) in both treatment groups. Patients in the CT-P13 IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22. And then, CT-P13 IV was switched to CT-P13 SC at Week 30. All patients in the efficacy population were analyzed according to the treatment they received.
    End point type
    Secondary
    End point timeframe
    Up to Week 54
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive Statistics was presented for this endpoint of Part 2.
    End point values
    Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Number of subjects analysed
    165
    174
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    6.008 ± 0.7541
    5.863 ± 0.8090
        Week 2
    4.702 ± 0.9361
    4.643 ± 1.0460
        Week 6
    3.983 ± 1.2021
    4.112 ± 1.2105
        Week 14
    3.483 ± 1.1996
    3.677 ± 1.2510
        Week 22
    3.338 ± 1.0958
    3.482 ± 1.2329
        Week 30
    3.047 ± 1.1272
    3.521 ± 1.2339
        Week 54
    2.796 ± 1.1414
    2.913 ± 1.1648
    No statistical analyses for this end point

    Secondary: Patients achieving Response according to ACR20 Criteria (Part 2)

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    End point title
    Patients achieving Response according to ACR20 Criteria (Part 2) [7]
    End point description
    For evaluation of efficacy, the secondary endpoint was defined as proportions of patients achieving clinical response according to ACR20 (20% response, as defined by the ACR) between CT-P13 SC and CT-P13 IV groups. The results up to Week 6 represented the efficacy of CT-P13 IV loading dose (3 mg/kg) regardless of randomized treatment group (CT-P13 SC or CT-P13 IV) in both treatment groups. Patients in the CT-P13 IV group were administered with CT-P13 IV at Week 6 and every 8 weeks thereafter up to Week 22. And then, CT-P13 IV was switched to CT-P13 SC at Week 30. All patients in the efficacy population were analyzed according to the treatment they received.
    End point type
    Secondary
    End point timeframe
    Up to Week 54
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was presented for this endpoint of Part 2.
    End point values
    Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Number of subjects analysed
    165
    174
    Units: Patients
        Week 2
    63
    57
        Week 6
    107
    103
        Week 14
    124
    130
        Week 22
    139
    137
        Week 30
    142
    133
        Week 54
    132
    125
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed from the date the informed consent form was signed until the last assessment date or End-of-Study visit (Treatment period).
    Adverse event reporting additional description
    The investigator was responsible for reporting all AEs that were observed or reported during the study, regardless of their relationship to the study drug or clinical significance. A participant is counted once if they reported 1 or more events. Only the most severe events is counted. TEAEs collected from Part 2 are shown in this table.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Arm 1: CT-P13 SC 120 mg (Part 2)
    Reporting group description
    -

    Reporting group title
    Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Reporting group description
    -

    Serious adverse events
    Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 168 (3.57%)
    14 / 175 (8.00%)
         number of deaths (all causes)
    1
    4
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 175 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Congenital, familial and genetic disorders
    Hereditary haemochromatosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 175 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device loosening
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Arm 1: CT-P13 SC 120 mg (Part 2) Arm 2: CT-P13 IV 3 mg/kg (Part 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 168 (45.24%)
    73 / 175 (41.71%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 168 (1.19%)
    9 / 175 (5.14%)
         occurrences all number
    3
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 168 (4.76%)
    11 / 175 (6.29%)
         occurrences all number
    8
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 168 (1.79%)
    7 / 175 (4.00%)
         occurrences all number
    3
    8
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    6 / 168 (3.57%)
    4 / 175 (2.29%)
         occurrences all number
    6
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 168 (4.17%)
    11 / 175 (6.29%)
         occurrences all number
    9
    13
    General disorders and administration site conditions
    Localised injection site reaction
         subjects affected / exposed
    30 / 168 (17.86%)
    22 / 175 (12.57%)
         occurrences all number
    119
    61
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    8 / 168 (4.76%)
    8 / 175 (4.57%)
         occurrences all number
    9
    8
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    13 / 168 (7.74%)
    16 / 175 (9.14%)
         occurrences all number
    16
    17
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 168 (5.36%)
    13 / 175 (7.43%)
         occurrences all number
    12
    16
    Latent tuberculosis
         subjects affected / exposed
    8 / 168 (4.76%)
    10 / 175 (5.71%)
         occurrences all number
    8
    10
    Urinary tract infection
         subjects affected / exposed
    9 / 168 (5.36%)
    9 / 175 (5.14%)
         occurrences all number
    14
    11
    Bronchitis
         subjects affected / exposed
    7 / 168 (4.17%)
    4 / 175 (2.29%)
         occurrences all number
    8
    5
    Oral herpes
         subjects affected / exposed
    7 / 168 (4.17%)
    4 / 175 (2.29%)
         occurrences all number
    7
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2016
    Summary of significant changes included the following: • Deleted primary PK objective for Part 2, therefore DAS28 (CRP) would only be considered as primary endpoint for Part 2. • Added biomarker as one of the secondary objective assessment item for Part 2. • Updated the study design for Part 2 with double-blind and double-dummy design. • Revised the cut-off point of body weight at Week 6 for Part 2. • Specified the unbinding process. • Allowed one more rescreening. • Added the joint count assessments by an independent joint count assessor to minimize bias. • Revised the PK sampling time point table for Part 2 to reflect the design change (double-blind). • Specified the assessment time points of hypersensitivity monitoring for Part 2 to reflect the design change (double-blind). • Specified the assessment time points of patient’s assessments of local site pain to reflect the design change (double-blind). • Updated the method of assigning patients to treatment arms and treatments administered for Part 2 as per the updated design. • Added the identity of CT-P13 placebo product as per the updated design (double-blind, double-dummy). • Other administrative changes.
    13 Jan 2017
    Summary of significant changes included the following: • Revised biomarker to the tertiary objective assessment item for Part 2, and not limited to FcgRIIIa. • Specified the sampling time point in case of the patient who could not be possible to be dispensed on the dosing day. • Revised the exclusion condition for diabetes mellitus to match with the updated condition in the exclusion criteria. • Added the exclusion condition for hepatitis C, HIV-1 and HIV-2 to provide more specific information. • Added the storage condition for keeping CT-P13 SC PFS. • Updated the New York Heart Association Functional Classification followed by the latest version • Other administrative changes
    21 Jul 2017
    Summary of significant changes included the following: • Revised the posology for part 2 from ‘every 4 weeks’ to ‘every 2 weeks’ as per the result of interim PK-PD modelling analysis. • Other administrative changes.
    02 Feb 2018
    Summary of significant changes included the following: • Updated the ICH guideline E6. • Modified the time point of EOS visit from ‘8 weeks from the last dose was received’ to ‘2 weeks from the last dose was received’ considering administration of CT-P13 SC. • Specified the description about study drug randomisation for Part 2 and added the table. • Clarified the premedication for Part 1 and Part 2. • Added the word ‘PFS’ to clarify the study product regimen for Part 2. • Revised visit window for Part 2. • Added the description that joint taken any surgical procedure would be excluded from the joint count assessment, and to reflect this change, the description also added that patient history would be informed to independent joint assessor. • Added PK endpoints for Part 1 to sufficiently investigate PK of CT-P13 SC. • Revised PK endpoints for Part 2 to clarify. • Revised to collect detailed 12-lead ECG results for safety investigation. • Revised to inhibit IGRA retest during the study. Guide added for resume of study drug and in case of exposure to person with active TB. • Added case of not to take IGRA test if it was not needed. • Added the reporting and follow-up of serious adverse drug reactions for part 2 since the EOS visit was done only after 2 weeks from last dose of study drug. • Other administrative changes.

    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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