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    Clinical Trial Results:
    A Phase III, randomized, double-blind, multi-center, multi-national trial to evaluate efficacy and safety of BI 695500 versus rituximab as a first-line immunotherapy treatment in patients with low tumor burden follicular lymphoma

    Summary
    EudraCT number
    		 2014-004544-36
    Trial protocol
    		 BE   ES  
    Global end of trial date
    07 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2016
    First version publication date
    21 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1301.6
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02417129
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127 , clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to evaluate statistical equivalence of efficacy as assessed by Overall Response (measured as Overall Response Rate) at Week 30 for treatment with BI 695500 versus rituximab (Rituxan®) in patients with untreated low tumor burden follicular lymphoma (LTBFL).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Apr 2015
    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
    United States: 2
    Worldwide total number of subjects
    2
    EEA total number of subjects
    0
    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)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 It was planned to randomize approximately 250 patients (125 in each treatment group). Actually two patients were randomized, an additional patient was enrolled but not randomized. Two patient were randomised to BI 695500, thus no patient was treated with rituximab in this trial.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that the subject met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    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, Data analyst, Carer, Assessor

    Arms
    Arm title
    		 BI 695500
    Arm description
    		 Patients received an infusion of 375 milligram (mg)/square meter (m2) of BI 695500 once a week intravenously for 4 weeks treatment. These 4 dosages were administered on Days 1, 8, 15, and 22 with 26 weeks follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 695500
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received an infusion of 375 milligram (mg)/square meter (m2) of BI 695500 once a week intravenously for 4 weeks treatment. These 4 dosages were administered on Days 1, 8, 15, and 22 with 26 weeks follow-up.

    Number of subjects in period 1
    		BI 695500
    Started
    2
    Completed
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BI 695500
    Reporting group description
    		 Patients received an infusion of 375 milligram (mg)/square meter (m2) of BI 695500 once a week intravenously for 4 weeks treatment. These 4 dosages were administered on Days 1, 8, 15, and 22 with 26 weeks follow-up.

    Reporting group values
    		 BI 695500 Total
    Number of subjects
    		 2 2
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 45.5 ( 3.54 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 2 2
        Male
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    BI 695500
    Reporting group description
    		 Patients received an infusion of 375 milligram (mg)/square meter (m2) of BI 695500 once a week intravenously for 4 weeks treatment. These 4 dosages were administered on Days 1, 8, 15, and 22 with 26 weeks follow-up.

    Primary: Overall response measured as overall response rate (ORR) at week 30 for BI 695500 versus rituximab

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    End point title
    		 Overall response measured as overall response rate (ORR) at week 30 for BI 695500 versus rituximab [1]
    End point description
    The primary objective of this trial was to evaluate statistical equivalence of efficacy as assessed by Overall Response (measured as Overall Response Rate (ORR)) at Week 30 for treatment with BI 695500 versus rituximab (Rituxan®) in patients with untreated low tumor burden follicular lymphoma (LTBFL). The overall response measured as Overall Response Rate (ORR), which is the completed response (CR) and the partial response (PR) at Week 30, approximately 26 weeks after the completion of study treatment, as defined by International Working Group (IWG) criteria 2007 via an independent radiology assessment. This endpoint was not summarized for arm ' rituximab ', as two patient were randomized and treated with BI 695500, whereas no patient was treated with rituximab in this trial.
    End point type
    Primary
    End point timeframe
    From first administration of study medication until 30 weeks thereafter.
    Notes
    [1] - 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: As the program was prematurely discontinued and only two patient were randomized and treated with BI 695500. No patient was treated with rituximab. Therefore comparisons cannot be made between treatment groups, thus the planned statistical analysis was not performed.
    End point values
    		 BI 695500
    Number of subjects analysed
    2
    Units: participants
        CR
    0
        PR
    1
    No statistical analyses for this end point

    Secondary: Extrapolated area under the concentration-time curve of BI 695500 or rituximab at steady state over the interval 0 hour (h) to the next dose of trial medication (AUC0-τ, ss)

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    End point title
    		 Extrapolated area under the concentration-time curve of BI 695500 or rituximab at steady state over the interval 0 hour (h) to the next dose of trial medication (AUC0-τ, ss)
    End point description
    Extrapolated area under the concentration-time curve of BI 695500 or rituximab in plasma at steady state over the interval 0 hour (h) to the next dose of trial medication (AUC0-τ, ss) establised by population pharmacokinetics. This endpoint was not summarized for arm ' rituximab ', as two patient were randomized and treated with BI 695500, thus no patient was treated with rituximab in this trial. Therefore, no pharmacokinetic data analysis was performed.
    End point type
    Secondary
    End point timeframe
    Sample timepoints Day 1, 8, 22, 23-24 (24-48 hours from start of Cycle 4 infusion), 24-26 (48-96 hours from start of Cycle 4 infusion), 26-36 (96-336 hours from start of Cycle 4 infusion), 78, 134, 204
    End point values
    		 BI 695500
    Number of subjects analysed
    0 [2]
    Units: NA
        number (not applicable)
    Notes
    [2] - As the program was prematurely discontinued and only two patients were randomized and treated.
    No statistical analyses for this end point

    Secondary: Immunogenicity at Week 30

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    End point title
    		 Immunogenicity at Week 30
    End point description
    Immunogenicity (rate of anti-drug antibodies) at Week 30 presented as the number of participants having Immunogenicity at Week 30. This endpoint was not summarized for arm ' rituximab ', as two patient were randomized and treated with BI 695500, thus no patient was treated with rituximab in this trial. As the program was prematurely discontinued and only two patients were randomized at the time of discontinuation, the planned statistical analysis was not performed.
    End point type
    Secondary
    End point timeframe
    Day 204 or end of study
    End point values
    		 BI 695500
    Number of subjects analysed
    2 [3]
    Units: participants
        number (not applicable)
    0
    Notes
    [3] - Safety analysis set.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first administration of study medication until 26 weeks after last administration of study medication up to 204 days.
    Adverse event reporting additional description
    When the program was prematurely discontinued only two patients were randomized to the arm "BI 695500". There were no patients included in the "Rituximab (US-licensed Rituxan)" arm. It is not possible to add an arm into the adverse event section by entering the number of patient "0" within this arm. Therefore this arm is not presented here.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BI 695500
    Reporting group description
    		 Patients received an infusion of 375 milligram (mg)/square meter (m2) of BI 695500 once a week intravenously for 4 weeks treatment. These 4 dosages were administered on Days 1, 8, 15, and 22 with 26 weeks follow-up.

    Serious adverse events
    		 BI 695500
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BI 695500
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Paraesthesia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Feeling cold
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2015
    Title Page and Synopsis: Name of the Coordinating Investigator was corrected.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Sep 2015
    Program was terminated.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    When the program was prematurely discontinued only 2 patients were randomized to the arm "BI 695500", no patient to the "Rituximab (US-licensed Rituxan)" arm. The planned statistical analysis was not performed.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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