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    Clinical Trial Results:
    Phase II study of High-Dose Rituximab in High Risk Chronic Lymphocytic Leukemia in Suboptimal Response after Induction Immunochemotherapy

    Summary
    EudraCT number
    		 2011-005174-27
    Trial protocol
    		 BE  
    Global end of trial date
    30 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Mar 2021
    First version publication date
    17 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HYDRIC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01625741
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cliniques universitaires Saint-Luc- Université Catholique de Louvain
    Sponsor organisation address
    Avenue Hippocrate 10, Brussels, Belgium, 1200
    Public contact
    Eric Van Den Neste, Cliniques universitaires Saint Luc, 32 27641875, eric.vandenneste@uclouvain.be
    Scientific contact
    Eric Van Den Neste, Cliniques universitaires Saint Luc, 32 27641875, eric.vandenneste@uclouvain.be
    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
    30 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluate the rate of conversion into MRD negativity 3 months after the administration of 4 monthly courses of high-dose (2000 mg) rituximab in high-risk CLL patients with suboptimal response after ICT, or MRD relapse after ICT.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, United States Food and Drug Administration (FDA) regulations/guidelines, and country-specific national and local laws. A copy of the protocol proposed informed consent form (ICF), other written subject information, and any proposed advertising material was submitted to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for written approval. A copy of the IEC/IRB approval was received by the sponsor before recruitment of subjects into the study. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.
    Background therapy
    		 Rituximab was administered intravenously monthly, for four months, at a dose of 2000 mg total (total of 4 doses of 2000 mg each), starting within one month of signing the ICF.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    01 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    4
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The subjects were recruited from eleven sites in Belgium between July 2012 and January 2013.13 patients in total have ben screened for inclusion. Six patients have been included and treated. The remainder had negative MRD (n=4), positive MRD but with exclusion criteria (n=1), or refused inclusion (n=2).

    Pre-assignment
    Screening details
    		 This study is reserved for patients with residual disease at the end of therapy at the level of Minimal Residual Disease (MRD-positive either in the peripheral blood at least 6 months after the last dose of rituximab-containing immunochemotherapy or in the bone marrow at least 3 months after the last dose of rituximab-containing immunochemotherapy)

    Period 1
    Period 1 title
    RITUXIMAB (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RITUXIMAB
    Arm description
    		 Patients receiving rituximab 2000 mg intravenously once a month for 4 months (with a total of 4 doses).
    Arm type
    		 Experimental

    Investigational medicinal product name
    RITUXIMAB
    Investigational medicinal product code
    SUB12570MIG
    Other name
    MABTHERA
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab is given intravenously at a monthly dose of 2000 mg for four months (a total of 4 doses of 2000 mg each). *First infusion (approximately 8 hours infusion): The infusions were administered at an initial rate of 50 mg / hr and increased in 50 mg / hr increments at 30 minutes intervals, depending on tolerance, up to a maximum rate of 400 mg / hr. *Second and following infusions (approximately 6 hours infusion): The infusions were administered at an initial rate of 100 mg / hr and increased in increments of 100 mg / hr at 30 minute intervals, depending on tolerance, up to a maximum rate of 400 mg / hr.

    Number of subjects in period 1
    		RITUXIMAB
    Started
    6
    Completed
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RITUXIMAB
    Reporting group description
    		 Patients receiving rituximab 2000 mg intravenously once a month for 4 months (with a total of 4 doses)

    Reporting group values
    		 RITUXIMAB Total
    Number of subjects
    		 6 6
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 4 4
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63 ± 4.6 -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    RITUXIMAB
    Reporting group description
    		 Patients receiving rituximab 2000 mg intravenously once a month for 4 months (with a total of 4 doses).

    Primary: Rate of conversion of MRD-positivity into eradication of MRD (MRD-negative) using sensitive flow cytometry at 3 months after 4 courses of high-dose rituximab

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    End point title
    		 Rate of conversion of MRD-positivity into eradication of MRD (MRD-negative) using sensitive flow cytometry at 3 months after 4 courses of high-dose rituximab [1]
    End point description
    The primary endpoint was the Rate of conversion of MRD-positivity into eradication of MRD (MRD-negative) using sensitive flow cytometry at 3 months after 4 courses of high-dose rituximab. The assessment of this endpoint was performed during administration of rituximab therapy and follow-up visits.
    End point type
    Primary
    End point timeframe
    3 months after 4 courses of high-dose rituximab.
    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: A Fleming’s Single Stage Phase II Procedure was used to determine patient need. Descriptive statistics were performed on the primary and secondary endpoints.
    End point values
    		 RITUXIMAB
    Number of subjects analysed
    6
    Units: Number
        number (not applicable)
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events have been reported from the first dose of rituximab up to 3 months after the last administration.
    Adverse event reporting additional description
    All grade 2 to 4 infectious events occurring in the year following the last administration of rituximab were recorded, unless they are clearly related to the initiation of a new treatment. Any AEs that occurred during study treatment AND up to the last follow-up visit were reported on the CRF AE form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE GRADE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    RITUXIMAB
    Reporting group description
    		 Patients receiving rituximab 2000 mg intravenously once a month for 4 months (with a total of 4 doses)

    Serious adverse events
    		 RITUXIMAB
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Progressive multifocal leucoencephalopathy
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 RITUXIMAB
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Upper air way infection
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 May 2015
    It was decided to close the study because it was not possible to recruit patients in a reasonable time (inclusion rate 3/ years) for several reasons.
    -

    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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    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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