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    Clinical Trial Results:
    A Randomized, Double-blind Study Evaluating the Efficacy, Safety, and Immunogenicity of ABP 798 Compared with Rituximab in Subjects with CD20 Positive B-cell Non-Hodgkin Lymphoma (NHL)

    Summary
    EudraCT number
    		 2013-005542-11
    Trial protocol
    		 DE   CZ   RO   IT   ES   FR   BG   PL   GR  
    Global end of trial date
    28 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2020
    First version publication date
    12 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20130109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02747043
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    28 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study was to evaluate the efficacy of ABP 798 compared with rituximab.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 May 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
    Italy: 50
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Ukraine: 12
    Country: Number of subjects enrolled
    Czech Republic: 11
    Country: Number of subjects enrolled
    Georgia: 9
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    India: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Japan: 15
    Worldwide total number of subjects
    256
    EEA total number of subjects
    151
    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)
    169
    From 65 to 84 years
    87
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 380 subjects were screened and 256 participants (128 in the ABP 798 treatment group and 128 in the rituximab treatment group) were randomized at 91 centers across 20 countries.

    Pre-assignment
    Screening details
    		 Participants were randomized centrally to receive either ABP 798 or rituximab in a 1:1 manner. The randomization was stratified based on geographic region (Europe, Americas, Japan, Asia Pacific – Other) and age group (> 60 years of age, ≤ 60 years of age).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Since the investigational product containers were different for ABP 798 and rituximab, investigational product (ABP 798 or rituximab) was prepared by an unblinded pharmacist or designee, into a common IV preparation, for administration to the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ABP 798
    Arm description
    		 ABP 798 was administered at a dose of 375 mg/m^2 as an intravenous (IV) infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABP 798
    Investigational medicinal product code
    Other name
    biosimilar to Rituximab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    ABP 798 was supplied as a sterile, preservative-free liquid concentrate for IV infusion at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-dose vials. Subjects were to receive premedications before each infusion. Premedications were to be given according to local practice for administration of rituximab therapy.

    Arm title
    		 Rituximab
    Arm description
    		 Rituximab was administered at a dose of 375 mg/m^2 as an IV infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab was procured from commercial supplies in the US and was supplied as a sterile, clear, colorless, preservative-free liquid concentrate for IV infusion at a concentration of 10 mg/mL in either 100-mg/10 mL or 500-mg/50 mL single-dose vials. Subjects were to receive premedications before each infusion. Premedications were to be given according to local practice for administration of rituximab therapy.

    Number of subjects in period 1
    		ABP 798 Rituximab
    Started
    128
    128
    Treated
    128
    126
    Completed
    118
    123
    Not completed
    10
    5
         Consent withdrawn by subject
    1
    1
         Physician decision
    1
    1
         Disease progression
    4
    -
         Adverse event, non-fatal
    3
    1
         not specified
    1
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ABP 798
    Reporting group description
    		 ABP 798 was administered at a dose of 375 mg/m^2 as an intravenous (IV) infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.

    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab was administered at a dose of 375 mg/m^2 as an IV infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.

    Reporting group values
    		 ABP 798 Rituximab Total
    Number of subjects
    		 128 128 256
    Age Categorical
    Units:
        <= 60 years
    		 71 70 141
        > 60 years
    		 57 58 115
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.6 ± 12.72 58.2 ± 12.20 -
    Sex: Female, Male
    Units:
        Female
    		 68 62 130
        Male
    		 60 66 126
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 102 101 203
        Asian, Non-Japanese
    		 17 14 31
        Asian, Japanese
    		 7 8 15
        Missing
    		 1 2 3
        Other
    		 0 2 2
        American Indian or Alaska Native
    		 1 0 1
        White, Asian-Non-Japanese
    		 0 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        Not Hispanic or Latino
    		 119 119 238
        Hispanic or Latino
    		 8 7 15
        Not allowed to collect
    		 1 2 3
    Eastern Cooperative Oncology Group (ECOG) Status
    Scale used to assess how a patient's disease is progressing, how the disease affects the daily living abilities of the patient: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory, able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self care, confined to a bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        Grade 0
    		 107 110 217
        Grade 1
    		 21 18 39
    Region of Enrollment
    Units: Subjects
        Europe
    		 88 86 174
        Asia Pacific - Other
    		 23 23 46
        Americas
    		 10 11 21
        Japan
    		 7 8 15
    Previous Radiation Treatment
    Units: Subjects
        Yes
    		 3 3 6
        No
    		 125 125 250
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 75.29 ± 19.135 75.19 ± 16.981 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 166.81 ± 10.737 167.64 ± 10.292 -
    Time Since Original Diagnosis
    Units: months
        arithmetic mean (standard deviation)
    		 6.31 ± 16.325 5.17 ± 10.181 -

    End points

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    End points reporting groups
    Reporting group title
    ABP 798
    Reporting group description
    		 ABP 798 was administered at a dose of 375 mg/m^2 as an intravenous (IV) infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.

    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab was administered at a dose of 375 mg/m^2 as an IV infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.

    Primary: Percentage of Participants Who Responded (Overall Response Rate - ORR) by Week 28 Based on Independent Central Assessment of Disease

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    End point title
    		 Percentage of Participants Who Responded (Overall Response Rate - ORR) by Week 28 Based on Independent Central Assessment of Disease
    End point description
    Overall response within the first treatment cycle was assessed according to International Working Group – Non-Hodgkin Lymphoma criteria (IWG-NHL criteria [Cheson et al, 1999]) by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement), and bone marrow biopsy (to assess bone marrow infiltration). ORR was the percentage of participants with a best overall response of complete response (CR), unconfirmed complete response (CRu) or partial response (PR). Participants that do not meet the criteria for response were considered non-responders. CR was defined as no evidence of disease. CRu showed nodes in the original sum of the products (SPD) regressed by >75% and/or indeterminate bone marrow results. PR was a ≥ 50% decrease in SPD of the six largest dominant nodes; >=50% decrease in liver and spleen nodes, and no increase in size of other nodes nor any new sites of disease.
    End point type
    Primary
    End point timeframe
    Post treatment up to Week 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    123 [1]
    124 [2]
    Units: percentage of participants
        number (not applicable)
    78.0
    70.2
    Notes
    [1] - The modified full analysis set (mFAS) includes subjects with evidence of disease at baseline
    [2] - mFAS
    Statistical analysis title
    		 Risk Difference analysis of ORR by Week 28: 90% CI
    Statistical analysis description
    Clinical equivalence of the primary endpoint will first be demonstrated by comparing the 1-sided 95% lower confidence limit of the RD of ORR by week 28 between ABP 798 and rituximab with a noninferiority margin of -15%. If this is successful, the 1-sided upper 95% confidence limit of the RD of ORR by week 28 will be compared with a nonsuperiority margin of +35.5%.
    Comparison groups
    Rituximab v ABP 798
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    7.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 16.8
    Statistical analysis title
    		 Risk Difference analysis of ORR by Week 28: 95% CI
    Statistical analysis description
    2-sided 95% confidence interval will be evaluated against a symmetrical margin of 15% for noninferiority and nonsuperiority
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 18.6

    Secondary: Percentage of Participants Who Responded (Overall Response Rate - ORR) at Week 12 Based on Independent Central Assessment of Disease

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    End point title
    		 Percentage of Participants Who Responded (Overall Response Rate - ORR) at Week 12 Based on Independent Central Assessment of Disease
    End point description
    Overall response within the first treatment cycle was assessed according to International Working Group – Non-Hodgkin Lymphoma criteria (IWG-NHL criteria [Cheson et al, 1999]) by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement), and bone marrow biopsy (to assess bone marrow infiltration). ORR was the percentage of participants with a best overall response of complete response (CR), unconfirmed complete response (CRu) or partial response (PR). Participants that do not meet the criteria for response were considered non-responders. CR was defined as no evidence of disease. CRu showed nodes in the original sum of the products (SPD) regressed by >75% and/or indeterminate bone marrow results. PR was a ≥ 50% decrease in SPD of the six largest dominant nodes; >=50% decrease in liver and spleen nodes, and no increase in size of other nodes nor any new sites of disease.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    123 [3]
    124 [4]
    Units: percentage of participants
        number (not applicable)
    59.3
    58.1
    Notes
    [3] - The modified full analysis set (mFAS) includes subjects with evidence of disease at baseline
    [4] - mFAS
    Statistical analysis title
    		 ORR at Week 12 90% CI
    Statistical analysis description
    The 2-sided 90% confidence limits of the risk difference (RD) of ORR at week 12 used a generalized linear model adjusted for the stratification factors (geographic region and age group).
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 11.2
    Statistical analysis title
    		 ORR Week 12 95% CI
    Statistical analysis description
    The 2-sided 95% confidence limits of the risk difference (RD) of ORR at week 12 used a generalized linear model adjusted for the stratification factors (geographic region and age group).
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.3
         upper limit
    		 13.2

    Secondary: Pharmacokinetic Serum Concentrations by Visit

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    End point title
    		 Pharmacokinetic Serum Concentrations by Visit
    End point description
    Pharmacokinetic serum samples were analyzed by a central lab. Participants with PK concentrations below the lower limit of quantification (LLOQ) were excluded from these analyses.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 3, 4, 12 and 20
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    128
    126
    Units: microgram/mL
    geometric mean (geometric coefficient of variation)
        Week 2 (predose) (n=123, 125)
    58.66 ± 50.4
    58.63 ± 76.9
        Week 3 (predose) (n=125, 126)
    105.39 ± 37.8
    108.77 ± 59.1
        Week 4 (predose) (n=126, 121)
    132.70 ± 42.6
    140.23 ± 57.9
        Week 12 (predose) (n=121, 124)
    21.86 ± 156.1
    20.55 ± 194.1
        Week 12 (postdose) (n=113, 117)
    207.05 ± 58.1
    209.14 ± 66.8
        Week 20 (predose) (n=118, 122)
    13.37 ± 138.7
    16.45 ± 115.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Complete Depletion of Clusters of Differentiation 19-Positive (CD19+) Cell Count From Baseline to Day 8

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    End point title
    		 Percentage of Participants with Complete Depletion of Clusters of Differentiation 19-Positive (CD19+) Cell Count From Baseline to Day 8
    End point description
    Complete depletion of CD19+ cell count at any postdose time was defined as CD19+ cell counts < 20 cell/μL (0.02 * 10^9 cell/L). Participants with missing CD19+ cell count at baseline or participants with CD19+ cell count < 20 cell/μL at baseline were to be excluded from the derivation of complete depletion of CD19+ cell count.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Study Day 8
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    115
    116
    Units: percentage of participants
        number (not applicable)
    98.3
    98.3
    No statistical analyses for this end point

    Secondary: Total Immunoglobulin G (IgG) Results by Visit

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    End point title
    		 Total Immunoglobulin G (IgG) Results by Visit
    End point description
    Samples were analyzed by a central lab.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 8 (Week 2), Weeks 3, 4, 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    128
    128
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Baseline (n=127, 123)
    9.740 ± 2.5988
    10.570 ± 2.5970
        Day 8 (Week 2) (n=122, 123)
    9.790 ± 2.5719
    10.486 ± 2.4916
        Week 3 (n=122, 123)
    9.545 ± 2.5933
    10.374 ± 2.3214
        Week 4 (n=124, 121)
    9.744 ± 2.5805
    10.196 ± 2.2842
        Week 28 (n=103, 104)
    9.846 ± 2.6316
    10.281 ± 2.3617
    No statistical analyses for this end point

    Secondary: Total Immunoglobulin M (IgM) Results by Visit

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    End point title
    		 Total Immunoglobulin M (IgM) Results by Visit
    End point description
    Samples were analyzed by a central lab.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 8 (Week 2), Weeks 3, 4, 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    128
    128
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Baseline (n=127, 123)
    1.021 ± 1.0072
    1.247 ± 3.4018
        Day 8 (Week 2) (n=122, 123)
    1.004 ± 1.0300
    1.280 ± 3.7292
        Week 3 (n=122, 122)
    1.001 ± 1.0564
    1.370 ± 5.0250
        Week 4 (n=124, 120)
    0.985 ± 1.0459
    1.385 ± 5.3266
        Week 28 (n=103, 104)
    0.816 ± 0.8505
    1.127 ± 3.6752
    No statistical analyses for this end point

    Secondary: Participants with Treatment-Emergent Adverse Events

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    End point title
    		 Participants with Treatment-Emergent Adverse Events
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial participant. The event does not necessarily have a causal relationship with study treatment. Each AE was graded for severity according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, where Grade 1 = Mild AE Grade 2 = Moderate AE Grade 3 = Severe AE Grade 4 = Life-threatening or disabling AE Grade 5 = Death related to AE. Serious adverse events include any event that is fatal, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or other significant medical hazard. IP = investigational product
    End point type
    Secondary
    End point timeframe
    Day 1 (post treatment) to Week 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    128
    126
    Units: participants
        Any AE
    107
    95
        Any grade >=3 AE
    14
    13
        Any fatal AE
    0
    0
        Any serious AE
    5
    5
        Any AE leading to discontinuation of IP
    4
    1
        Any AE leading to dose delay/withheld IP
    9
    9
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Treatment-emergent Adverse Events of Interest (AEOIs)

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    End point title
    		 Percentage of Participants with Treatment-emergent Adverse Events of Interest (AEOIs)
    End point description
    The AEOIs prespecified for this study were infusion reactions including hypersensitivity, cardiac disorders, serious infections, progressive multifocal leukoencephalopathy, hematological reactions, hepatitis B reactivation, opportunistic infections, severe mucocutaneous reactions, tumor lysis syndrome, gastrointestinal perforation, and reversible posterior leukoencephalopathy syndrome. Infusion reactions including hypersensitivity adverse events of interest must have start date the same as, or one day after, an investigational product administration start date.
    End point type
    Secondary
    End point timeframe
    Day 1 (post treatment) to Week 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    128
    126
    Units: percentage of participants
    number (not applicable)
        Any AEOI
    49.2
    45.2
        Infusion reactions including hypersensitivity
    43.0
    42.9
        Hematological reactions
    5.5
    4.8
        Cardiac disorders
    2.3
    1.6
        Serious infections
    1.6
    0
        Severe mucocutaneous reactions
    0.8
    0
        Gastrointestinal perforation
    0
    0
        Hepatitis B reactivation
    0
    0
        Opportunistic infection
    0
    0
        Progressive multifocal leukoencephalopathy
    0
    0
        Reversible posterior leukoencephalopathy
    0
    0
        Tumor lysis syndrome
    0
    0
    Statistical analysis title
    		 Risk Difference: Any AEOI
    Statistical analysis description
    Risk difference (ABP 798 – Rituximab) and CIs were estimated by Wald asymptotic confidence limits, or exact confidence limits if n < 25 for either treatment.
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 16.3
    Statistical analysis title
    		 Risk Difference: Infusion Reactions
    Statistical analysis description
    Risk difference (ABP 798 – Rituximab) and CIs were estimated by Wald asymptotic confidence limits, or exact confidence limits if n < 25 for either treatment.
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.1
         upper limit
    		 12.3
    Statistical analysis title
    		 Risk Difference: Hematological Reactions
    Statistical analysis description
    Risk difference (ABP 798 – Rituximab) and CIs were estimated by Wald asymptotic confidence limits, or exact confidence limits if n < 25 for either treatment.
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 13
    Statistical analysis title
    		 Risk Difference: Cardiac Disorders
    Statistical analysis description
    Risk difference (ABP 798 – Rituximab) and CIs were estimated by Wald asymptotic confidence limits, or exact confidence limits if n < 25 for either treatment.
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.8
         upper limit
    		 13.2
    Statistical analysis title
    		 Risk Difference: Serious Infections
    Statistical analysis description
    Risk difference (ABP 798 – Rituximab) and CIs were estimated by Wald asymptotic confidence limits, or exact confidence limits if n < 25 for either treatment.
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 14
    Statistical analysis title
    		 Risk Difference: Severe Mucocutaneous Reactions
    Statistical analysis description
    Risk difference (ABP 798 – Rituximab) and CIs were estimated by Wald asymptotic confidence limits, or exact confidence limits if n < 25 for either treatment.
    Comparison groups
    ABP 798 v Rituximab
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.7
         upper limit
    		 13.2

    Secondary: Number of Participants Who Developed Anti-drug Antibodies

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    End point title
    		 Number of Participants Who Developed Anti-drug Antibodies
    End point description
    Samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect antibodies capable of binding to ABP 798/rituximab (Binding Antibody Assay). Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based assay to determine neutralizing activity against ABP 798/rituximab (Neutralizing Antibody Assay). Developing antibody incidence was defined as participants with a negative or no binding antibody result at baseline and a positive antibody result at any post-baseline time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 12, 20 and 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    126 [5]
    123 [6]
    Units: participants
        Binding antibody positive postbaseline
    3
    1
        Neutralizing antibody positive postbaseline
    1
    1
    Notes
    [5] - Subjects with a binding antibody negative or no result at baseline and a post baseline result.
    [6] - Subjects with a binding antibody negative or no result at baseline and a post baseline result.
    No statistical analyses for this end point

    Secondary: Participants' Progression-Free Survival (PFS) Status Based on the Independent Central Assessment of Disease

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    End point title
    		 Participants' Progression-Free Survival (PFS) Status Based on the Independent Central Assessment of Disease
    End point description
    PFS was based on disease assessments determined by the central, independent, blinded radiologists’ and oncologist’s review.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    128
    126
    Units: percentage of participants
    number (not applicable)
        Participants with disease progression or death
    3.1
    2.4
        Participants alive and progression-free
    96.9
    97.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Survived -- Overall Survival (OS)

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    End point title
    		 Percentage of Participants Who Survived -- Overall Survival (OS)
    End point description
    Percentage of participants who were alive at the end of the study.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 28
    End point values
    		 ABP 798 Rituximab
    Number of subjects analysed
    128
    126
    Units: percentage of participants
    100
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (post treatment) to Week 28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    ABP 798
    Reporting group description
    		 ABP 798 was administered at a dose of 375 mg/m^2 as an intravenous (IV) infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.

    Reporting group title
    Rituximab
    Reporting group description
    		 Rituximab was administered at a dose of 375 mg/m^2 as an IV infusion once weekly for 4 weeks followed by dosing at weeks 12 and 20.

    Serious adverse events
    		 ABP 798 Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 128 (3.91%)
    5 / 126 (3.97%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery stenosis
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ABP 798 Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 128 (46.09%)
    61 / 126 (48.41%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 128 (11.72%)
    12 / 126 (9.52%)
         occurrences all number
    18
    24
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 128 (9.38%)
    6 / 126 (4.76%)
         occurrences all number
    14
    9
    Fatigue
         subjects affected / exposed
    13 / 128 (10.16%)
    12 / 126 (9.52%)
         occurrences all number
    20
    23
    Pyrexia
         subjects affected / exposed
    8 / 128 (6.25%)
    8 / 126 (6.35%)
         occurrences all number
    9
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 128 (3.13%)
    9 / 126 (7.14%)
         occurrences all number
    4
    16
    Diarrhoea
         subjects affected / exposed
    3 / 128 (2.34%)
    9 / 126 (7.14%)
         occurrences all number
    3
    11
    Nausea
         subjects affected / exposed
    6 / 128 (4.69%)
    14 / 126 (11.11%)
         occurrences all number
    7
    22
    Respiratory, thoracic and mediastinal disorders
    Throat irritation
         subjects affected / exposed
    9 / 128 (7.03%)
    8 / 126 (6.35%)
         occurrences all number
    10
    12
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    6 / 128 (4.69%)
    12 / 126 (9.52%)
         occurrences all number
    6
    16
    Rash
         subjects affected / exposed
    9 / 128 (7.03%)
    6 / 126 (4.76%)
         occurrences all number
    12
    7
    Urticaria
         subjects affected / exposed
    7 / 128 (5.47%)
    2 / 126 (1.59%)
         occurrences all number
    7
    6
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 128 (5.47%)
    1 / 126 (0.79%)
         occurrences all number
    7
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2015
     modified subject inclusion/exclusion criteria  specified CT of the neck (if palpable lymph node > 1.0 cm or if performed at baseline) chest, abdomen, and pelvis at week 12 and week 28  added standard 12-lead ECG to the week-28 (EOS) procedures  added reference to possible follow-up testing for subjects testing positive for neutralizing antibodies at the final scheduled study visit  clarified that disease progression should not be reported as an adverse event, but that symptoms of progression should be reported  removed end-of-infusion PK sampling at week 4 and week 20
    07 Jan 2016
    - corrected sample size power
    24 Jun 2016
    - modified subject inclusion criteria - specified that the dose of ABP 798/rituxima would be calculated based on height and weight obtained at baseline, and that the dose would remain the same throughout the study - added stopping criteria for infusion-related reactions - added additional monitoring requirements for infusion-related hypersensitivity reactions - specified that clinical disease assessments should be performed by investigator or sub-investigator
    17 Jul 2017
    - added details regarding optional additional PK sampling visit - modified subject inclusion/exclusion criteria - specified visits for physical examination and PK sapling procedures - clarified that the end of study (EOS) biopsies for complete response confirmation were required if bone marrow involvement was identified at baseline, and if not obtained then complete response subjects were to be classified as partial responders

    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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