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    Clinical Trial Results:
    A Phase 3, Randomised, Parallel-Group, Active-Controlled, Double-Blind Study to Compare Efficacy and Safety between CT-P10 and Rituxan in Patients with Low Tumour Burden Follicular Lymphoma

    Summary
    EudraCT number
    		 2014-005324-10
    Trial protocol
    		 CZ   LV   ES   PT   IT  
    Global end of trial date
    04 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2021
    First version publication date
    07 Feb 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CT-P10_3.4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02260804
    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
    Sung Hyun Kim, CELLTRION, Inc., +82 328505000, SungHyun.Kim@celltrion.com
    Scientific contact
    Sung Hyun Kim, CELLTRION, Inc., +82 328505000, 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
    17 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that CT-P10 is similar to Rituxan in terms of efficacy as determined by overal response rate [ORR] (complete response [CR] + unconfirmed complete response [CRu] + partial response [PR]) at 7 months (Prior to Cycle 3 of Maintenance Study Period) according to the Modified Response Criteria for Malignant Lymphoma.
    Protection of trial subjects
    Hypersensitivity was assessed by vital sign monitoring (including systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature) on each dosing day and recorded on each dosing day at the following time points: - Before the beginning of study drug infusion on Day 1 of each cycle (within 15 minutes before the beginning of study drug infusion) - At the end of study drug infusion (within 15 minutes after the end of study drug infusion) - At 60 minutes (±15 minutes) after the end of study drug infusion In addition, hypersensitivity was monitored by routine continuous clinical monitoring including ECG (3-lead or 12-lead) monitoring at 60 minutes (±15 minutes) after the end of study drug infusion. For patients who experienced or developed life-threatening IRR, rituximab treatment was stopped immediately and the patient was withdrawn from the study.
    Background therapy
    		 - Induction Study Period (up to 4 weeks): Patients were to receive study drug at a dose of 375 mg/m2, administered by an intravenous (IV) infusion, weekly for 4 weeks. - Maintenance Study Period (up to a maximum of 12 cycles over 2 years): Patients who experienced a CR, CRu, PR, or stable disease after Cycle 4 of the Induction Study Period (as assessed at the MC1) were eligible to start maintenance therapy with the study drug at a dose of 375 mg/m2 administered by an IV infusion, every 8 weeks. After the 1st year of the Maintenance Period (MP1), once the similarity between the study drugs had been confirmed, additional CT-P10 administration was offered to all patients who had completed MP1, at the discretion of the participating investigator.
    Evidence for comparator
    		 CT P10 is being developed as a proposed biosimilar product of Rituxan (rituximab), a compound with established efficacy in the treatment of NHL. This study is designed to demonstrate similarity in efficacy and safety of CT P10 compared with rituximab in patients with low tumour burden FL
    Actual start date of recruitment
    01 Aug 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 27 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 35
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Belarus: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 38
    Country: Number of subjects enrolled
    Czechia: 11
    Country: Number of subjects enrolled
    India: 10
    Country: Number of subjects enrolled
    Ukraine: 10
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Mexico: 1
    Worldwide total number of subjects
    258
    EEA total number of subjects
    82
    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)
    174
    From 65 to 84 years
    83
    85 years and over
    1

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 258 patients from 96 study centers were randomly assigned to study drug.

    Pre-assignment
    Screening details
    		 Key Inclusion Criteria - 18 year or older - Histologically confirmed CD20+ Follicular Lymphoma grades 1 to 3a - At least 1 measurable tumour mass - Ann Arbor stage II, III, or IV - Low tumour burden by Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria

    Period 1
    Period 1 title
    Induction Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    This study was double-blinded. The study blind was not to be broken except in either a medical emergency (where knowledge of the study drug received was able to affect the treatment of the emergency) or a regulatory requirement, and the overall randomization code will be broken only for reporting purpose. Sponsor and CRO will predefine unblinded team and run them separately to maintain blinding throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CT-P10
    Arm description
    		 Patient treated with CT-P10 (375 mg/m2, IV) weekly for 4 cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 375 mg/m2 diluted in normal saline administered as an IV infusion.

    Arm title
    		 Rituxan
    Arm description
    		 Patient treated with US-licensed rituximab (375 mg/m2, IV) weekly for 4 cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituxan 375 mg/m2 diluted in normal saline administered as an IV infusion.

    Number of subjects in period 1
    		CT-P10 Rituxan
    Started
    130
    128
    Completed
    128
    128
    Not completed
    2
    0
         Protocol deviation
    2
    -
    Period 2
    Period 2 title
    1st year of the Maintenance Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    This study was double-blinded. The study blind was not to be broken except in either a medical emergency (where knowledge of the study drug received was able to affect the treatment of the emergency) or a regulatory requirement, and the overall randomization code will be broken only for reporting purpose. Sponsor and CRO will predefine unblinded team and run them separately to maintain blinding throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CT-P10
    Arm description
    		 Patient treated with CT-P10 (375 mg/m2, IV) 2-weekly for 6 cycles (up to 1 year).
    Arm type
    		 Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 375 mg/m2 diluted in normal saline administered as an IV infusion.

    Arm title
    		 Rituxan
    Arm description
    		 Patient treated with US-licensed rituximab (375 mg/m2, IV) 2-weekly for 6 cycles (up to 1 year).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituxan 375 mg/m2 diluted in normal saline administered as an IV infusion.

    Number of subjects in period 2 [1]
    		CT-P10 Rituxan
    Started
    123
    120
    Completed
    111
    105
    Not completed
    12
    15
         Adverse event, serious fatal
    -
    1
         Physician decision
    1
    3
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    3
    1
         Lost to follow-up
    -
    1
         Lack of efficacy
    6
    9
         Protocol deviation
    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: Five patients discontinued study treatment before the initiation of the 1st year of the Maintenance Period after completion of the Induction Period.
    Period 3
    Period 3 title
    2nd year of the Maintenance Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    This study was double-blinded. The study blind was not to be broken except in either a medical emergency (where knowledge of the study drug received was able to affect the treatment of the emergency) or a regulatory requirement, and the overall randomization code will be broken only for reporting purpose. Sponsor and CRO will predefine unblinded team and run them separately to maintain blinding throughout the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintained CT-P10
    Arm description
    		 Patient treated with CT-P10 (375 mg/m2, IV) 2-weekly for 6 cycles after the 1st year of Maintenance Period (MP1). The total infusion of the maintenance treatment will not exceed 12 cycles over 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 375 mg/m2 diluted in normal saline administered as an IV infusion.

    Arm title
    		 Switched to CT-P10
    Arm description
    		 After the 1st year of Maintenance Period (MP1), once the similarity between study drugs is confirmed, additional CT-P10 (375 mg/m2, IV) 2-weekly for 6 cycles will be offered to all patients who have completed MP1 at discretion of participating investigator. The total infusion of the maintenance treatment will not exceed 12 cycles over 2 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 375 mg/m2 diluted in normal saline administered as an IV infusion.

    Number of subjects in period 3 [2]
    		Maintained CT-P10 Switched to CT-P10
    Started
    110
    103
    Completed
    101
    97
    Not completed
    9
    6
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    3
    -
         Lack of efficacy
    6
    5
    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: Eight patients discontinued study treatment before the initiation of the 1st year of the Maintenance Period after completion of the Induction Period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    		 Patient treated with CT-P10 (375 mg/m2, IV) weekly for 4 cycles.

    Reporting group title
    Rituxan
    Reporting group description
    		 Patient treated with US-licensed rituximab (375 mg/m2, IV) weekly for 4 cycles.

    Reporting group values
    		 CT-P10 Rituxan Total
    Number of subjects
    		 130 128 258
    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)
    		 84 90 174
        From 65-84 years
    		 46 37 83
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        median (standard deviation)
    		 57.7 ± 12.68 57.7 ± 11.53 -
    Gender categorical
    Units: Subjects
        Female
    		 64 71 135
        Male
    		 66 57 123

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    		 Patient treated with CT-P10 (375 mg/m2, IV) weekly for 4 cycles.

    Reporting group title
    Rituxan
    Reporting group description
    		 Patient treated with US-licensed rituximab (375 mg/m2, IV) weekly for 4 cycles.
    Reporting group title
    CT-P10
    Reporting group description
    		 Patient treated with CT-P10 (375 mg/m2, IV) 2-weekly for 6 cycles (up to 1 year).

    Reporting group title
    Rituxan
    Reporting group description
    		 Patient treated with US-licensed rituximab (375 mg/m2, IV) 2-weekly for 6 cycles (up to 1 year).
    Reporting group title
    Maintained CT-P10
    Reporting group description
    		 Patient treated with CT-P10 (375 mg/m2, IV) 2-weekly for 6 cycles after the 1st year of Maintenance Period (MP1). The total infusion of the maintenance treatment will not exceed 12 cycles over 2 years.

    Reporting group title
    Switched to CT-P10
    Reporting group description
    		 After the 1st year of Maintenance Period (MP1), once the similarity between study drugs is confirmed, additional CT-P10 (375 mg/m2, IV) 2-weekly for 6 cycles will be offered to all patients who have completed MP1 at discretion of participating investigator. The total infusion of the maintenance treatment will not exceed 12 cycles over 2 years.

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consisted of all patients enrolled and randomly assigned to receive a study drug, regardless of whether or not any study drug dosing was completed.

    Subject analysis set title
    PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population consisted of all patients who were randomly assigned to study drug, and had at least 1 response evaluation after receiving at least 1 dose (full) of study drug in the Induction Study Period, without any major protocol violation or deviation that may have affected the interpretation of efficacy results.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population consisted of all patients who received at least 1 dose (full or partial) of study drug. For the safety population, patients who received at least 1 dose (full or partial) of CT-P10 up to MP1 were analyzed under the CT-P10 group; all other patients were analyzed under the Rituxan group.

    Subject analysis set title
    PK population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK population consisted of all patients who received at least 1 dose (full) of study drug and had at least 1 posttreatment PK result. All PK analyses were conducted using the PK population.

    Subject analysis set title
    PD population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PD population consisted of all patients who received at least 1 dose (full) of study drug and had at least 1 posttreatment PD result. All PD analyses were conducted using the PD population.

    Primary: ORR (CR+CRu+PR) by 7 months

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    End point title
    		 ORR (CR+CRu+PR) by 7 months
    End point description
    The ORR was defined as the proportion of patients who had a BOR of CR, CRu, or PR (the “responders”). The BOR was derived from the overall responses according to the Modified Response Criteria for Malignant Lymphoma, across all time points up to the 7-month assessment (prior to maintenance cycle 3). Centrally reviewed data was used for the primary efficacy analysis.
    End point type
    Primary
    End point timeframe
    ORR (CR+CRu+PR) by 7 months (prior to the maintenance cycle 3)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    130
    128
    Units: Number of Patients
        ORR
    108
    104
        CR
    36
    43
        CRu
    6
    2
        PR
    66
    59
        SD
    17
    18
        RD/PD
    0
    4
        unable to access
    0
    1
        missing
    5
    1
    Statistical analysis title
    		 Primary Efficacy Endpoint - ORR
    Comparison groups
    CT-P10 v Rituxan
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Difference in proportion
    Point estimate
    1.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.43
         upper limit
    		 10.2
    Notes
    [1] - Equivalence margin: ±17%

    Secondary: ORR (CR+CRu+PR) over study period

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    End point title
    		 ORR (CR+CRu+PR) over study period
    End point description
    The ORR was defined as the proportion of patients who had a BOR of CR, CRu, or PR (the “responders”). The BOR was derived from the overall responses according to the Modified Response Criteria for Malignant Lymphoma. Locally reviewed data was used for the secondary efficacy analyses.
    End point type
    Secondary
    End point timeframe
    Overall study period (median follow-up of 29.2 months)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    130
    128
    Units: Number of Patients
        ORR
    109
    112
        CR
    51
    63
        CRu
    7
    2
        PR
    51
    47
        SD
    15
    12
        RD/PD
    1
    3
        missing
    5
    1
    No statistical analyses for this end point

    Secondary: Secondary PK endpoints - Cmax

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    End point title
    		 Secondary PK endpoints - Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    by the primary endpoint (7-months)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    128
    128
    Units: μg/mL
    arithmetic mean (standard deviation)
        Induction Cycle 1
    212.86 ± 50.64
    217.38 ± 56.33
        Induction Cycle 2
    283.35 ± 53.84
    285.98 ± 62.26
        Induction Cycle 3
    327.32 ± 71.05
    341.59 ± 77.95
        Induction Cycle 4
    373.46 ± 70.50
    383.05 ± 83.86
        Maintenance Cycle 1
    256.97 ± 65.61
    265.03 ± 53.73
        Maintenance Cycle 2
    239.70 ± 65.72
    249.86 ± 69.02
    No statistical analyses for this end point

    Secondary: Secondary PK endpoints - Ctrough

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    End point title
    		 Secondary PK endpoints - Ctrough
    End point description
    End point type
    Secondary
    End point timeframe
    by the primary endpoint (7-months)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    128
    128
    Units: μg/mL
    arithmetic mean (standard deviation)
        Induction Cycle 1
    64.66 ± 24.88
    72.94 ± 40.39
        Induction Cycle 2
    113.23 ± 34.60
    120.92 ± 36.02
        Induction Cycle 3
    149.53 ± 43.65
    161.80 ± 43.91
        Induction Cycle 4
    34.78 ± 33.58
    31.38 ± 19.15
        Maintenance Cycle 1
    22.68 ± 37.22
    21.35 ± 20.90
        Maintenance Cycle 2
    16.96 ± 9.61
    18.37 ± 10.86
    No statistical analyses for this end point

    Secondary: Secondary PD endpoints - B-cell kinetics

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    End point title
    		 Secondary PD endpoints - B-cell kinetics
    End point description
    Any values below the LLoQ were set as LLoQ which was 20 cells/μL.
    End point type
    Secondary
    End point timeframe
    Pharmacodynamics (B-cell counts) of rituximab by the primary endpoint (7-months)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    128
    128
    Units: cells/μL
    median (inter-quartile range (Q1-Q3))
        Baseline
    95.0 (56.0 to 171.0)
    120.0 (64.0 to 182.0)
        Induction Cycle 1 (1 hour after end of infusion)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Induction Cycle 2 (predose)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Induction Cycle 3 (predose)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Induction Cycle 4 (predose)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        End of Treatment 1 (anytime)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Maintenance Cycle 1 (predose)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Maintenance Cycle 1 (1 hour after end of infusion)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Maintenance Cycle 2 (predose)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Maintenance Cycle 2 (1 hour after end of infusion)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
        Maintenance Cycle 3 (predose)
    20.0 (20.0 to 20.0)
    20.0 (20.0 to 20.0)
    No statistical analyses for this end point

    Secondary: Secondary Efficacy endpoints - PFS

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    End point title
    		 Secondary Efficacy endpoints - PFS
    End point description
    Progression-free survival was defined as the interval between randomization and disease progression/relapse or death from any cause, whichever occurred first. Locally reviewed data was used for the secondary efficacy analyses.
    End point type
    Secondary
    End point timeframe
    Overall study period (median follow-up of 29.2 months)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    130
    128
    Units: Estimates of survival rates
    number (confidence interval 95%)
        12 months
    0.93 (0.87 to 0.96)
    0.89 (0.82 to 0.93)
        24 months
    0.88 (0.81 to 0.92)
    0.83 (0.75 to 0.89)
        36 months
    0.80 (0.70 to 0.87)
    0.68 (0.54 to 0.79)
    No statistical analyses for this end point

    Secondary: Secondary Efficacy endpoints - OS

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    End point title
    		 Secondary Efficacy endpoints - OS
    End point description
    Overall survival was defined as the interval between randomization and death from any cause. Locally reviewed data was used for the secondary efficacy analyses.
    End point type
    Secondary
    End point timeframe
    Overall study period (median follow-up of 29.2 months)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    130
    128
    Units: Estimates of survival rates
    number (confidence interval 95%)
        12 months
    0.98 (0.93 to 0.99)
    0.98 (0.94 to 1.00)
        24 months
    0.98 (0.93 to 0.99)
    0.98 (0.94 to 1.00)
        36 months
    0.98 (0.93 to 0.99)
    0.97 (0.89 to 0.99)
        42 months
    0.98 (0.93 to 0.99)
    0.97 (0.89 to 0.99)
    No statistical analyses for this end point

    Secondary: Secondary Efficacy endpoints - TTP

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    End point title
    		 Secondary Efficacy endpoints - TTP
    End point description
    Time to progression was defined as the interval between randomization and disease progression/relapse or death as a result of lymphoma, whichever occurred first. Locally reviewed data was used for the secondary efficacy analyses.
    End point type
    Secondary
    End point timeframe
    Overall study period (median follow-up of 29.2 months)
    End point values
    		 CT-P10 Rituxan
    Number of subjects analysed
    130
    128
    Units: Estimates of survival rates
    number (confidence interval 95%)
        12 months
    0.94 (0.88 to 0.97)
    0.89 (0.83 to 0.94)
        24 months
    0.89 (0.82 to 0.94)
    0.84 (0.76 to 0.89)
        36 months
    0.82 (0.72 to 0.88)
    0.68 (0.54 to 0.79)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study period (median follow-up of 29.2 months)
    Adverse event reporting additional description
    All TESAEs and non-serious AEs reported for more than 5% of the patients in either treatment group are summarized for the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    		 -

    Reporting group title
    Rituxan
    Reporting group description
    		 -

    Serious adverse events
    		 CT-P10 Rituxan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 130 (10.77%)
    14 / 128 (10.94%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal neoplasm benign
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Surgical and medical procedures
    Gastrointestinal surgery
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal polyp
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer perforation
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Genital prolapse
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Localised infection
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 128 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CT-P10 Rituxan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 130 (71.54%)
    86 / 128 (67.19%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 130 (5.38%)
    3 / 128 (2.34%)
         occurrences all number
    7
    4
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    42 / 130 (32.31%)
    39 / 128 (30.47%)
         occurrences all number
    59
    51
    Vascular disorders
    Hypertension
         subjects affected / exposed
    10 / 130 (7.69%)
    6 / 128 (4.69%)
         occurrences all number
    13
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 130 (4.62%)
    7 / 128 (5.47%)
         occurrences all number
    6
    8
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    10 / 130 (7.69%)
    7 / 128 (5.47%)
         occurrences all number
    12
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 130 (7.69%)
    13 / 128 (10.16%)
         occurrences all number
    12
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 130 (4.62%)
    7 / 128 (5.47%)
         occurrences all number
    6
    10
    Diarrhoea
         subjects affected / exposed
    9 / 130 (6.92%)
    11 / 128 (8.59%)
         occurrences all number
    11
    16
    Nausea
         subjects affected / exposed
    7 / 130 (5.38%)
    11 / 128 (8.59%)
         occurrences all number
    8
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 130 (6.92%)
    12 / 128 (9.38%)
         occurrences all number
    10
    13
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 130 (6.15%)
    5 / 128 (3.91%)
         occurrences all number
    8
    5
    Infections and infestations
    Herpes virus infection
         subjects affected / exposed
    7 / 130 (5.38%)
    5 / 128 (3.91%)
         occurrences all number
    7
    5
    Influenza
         subjects affected / exposed
    3 / 130 (2.31%)
    8 / 128 (6.25%)
         occurrences all number
    3
    8
    Lower respiratory tract infection
         subjects affected / exposed
    6 / 130 (4.62%)
    11 / 128 (8.59%)
         occurrences all number
    7
    13
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 130 (23.85%)
    29 / 128 (22.66%)
         occurrences all number
    42
    41
    Urinary tract infection
         subjects affected / exposed
    9 / 130 (6.92%)
    13 / 128 (10.16%)
         occurrences all number
    10
    18

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2015
    Summary of significant change included the following: - Added a single transition from Rituxan to CT-P10 after 1 year maintenance therapy to assess the safety profiles. - Recalculated the sample size according to the updated statistical assumption.
    06 Sep 2016
    Summary of significant change included the following: - Inclusion criterion (#2) was revised to extend the FL tissue biopsy period based on literature references and discussion with KOLs. - Updated the efficacy assessment method for patients who developed an allergy to a contrast agent during the study period.

    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.
    In this study, TTE endpoints were secondary endpoints and were not powered. As medians of PFS, TTP, and OS were not reached in both treatment groups, longer follow-up is needed to ascertain the median time for TTE parameters of PFS, TTP, and OS.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30389036
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