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    Clinical Trial Results:
    A Phase II trial of broad spectrum antibiotic therapy for early stage chronic lymphocytic leukaemia.

    Summary
    EudraCT number
    		 2010-022260-12
    Trial protocol
    		 GB  
    Global end of trial date
    21 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2018
    First version publication date
    31 Oct 2018
    Other versions
    Summary report(s)
    		 FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    1947
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01279252
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC Number: 10/H0715/75
    Sponsors
    Sponsor organisation name
    King's College Hospital NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE5 9RS
    Public contact
    Professor Stephen Devereux, King's College Hospital, 0044 2032999000, stephen.devereux@kcl.ac.uk
    Scientific contact
    Professor Stephen Devereux, King's College Hospital, 0044 2032999000, stephen.devereux@kcl.ac.uk
    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
    01 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether patients with previously untreated, early stage chronic lymphocytic leukaemia (CLL) respond to empirical broad spectrum antibiotics and therefore test the hypothesis that occult bacterial infection is responsible for the induction and maintenance of CLL.
    Protection of trial subjects
    The study will be stopped if more than 27 patients (15% of 180) experience grade 3-4 severe adverse reactions
    Background therapy
    		 none
    Evidence for comparator
    		 n/a
    Actual start date of recruitment
    05 Jul 2011
    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
    United Kingdom: 98
    Worldwide total number of subjects
    98
    EEA total number of subjects
    98
    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)
    80
    From 65 to 84 years
    16
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from 8 NHS clinical sites in the United Kingdom between 2011 and 2016.

    Pre-assignment
    Screening details
    		 Previously untreated patients with monoclonal B lymphocytosis and stage A CLL

    Period 1
    Period 1 title
    Whole Group (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N,A

    Arms
    Arm title
    		 Single Arm
    Arm description
    		 Single arm phase II study in previously untreated patients with monoclonal B lymphocytosis and stage A CLL
    Arm type
    		 Experimental

    Investigational medicinal product name
    METRONIDAZONE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400mg orally twice each day for 14 days.

    Investigational medicinal product name
    CLARYTHROMYCIN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Clarithromycin 500mg orally twice per day for 14 days

    Investigational medicinal product name
    CIPROFLOXACIN
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ciprofloxacin 500mg orally twice per day for 14 days

    Investigational medicinal product name
    LANSOPRAZOLE
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lansoprazole 30mg orally twice per day for 14 days.

    Number of subjects in period 1
    		Single Arm
    Started
    98
    Completed
    88
    Not completed
    10
         Adverse event, non-fatal
    10

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Single Arm
    Reporting group description
    		 Single arm phase II study in previously untreated patients with monoclonal B lymphocytosis and stage A CLL

    Primary: Overall response rate

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    End point title
    		 Overall response rate [1]
    End point description
    Overall response rate [Complete Remission (CR) + Partial Remission (PR)] at 6 months.
    End point type
    Primary
    End point timeframe
    First dose to 6months
    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: See attached document for results. Primary endpoint was not met.
    End point values
    		 Single Arm
    Number of subjects analysed
    88
    Units: whole
    88
    No statistical analyses for this end point

    Secondary: Incidence of CTCAE grade 2 or above treatment related toxicity from day 1 to 6 weeks.

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    End point title
    		 Incidence of CTCAE grade 2 or above treatment related toxicity from day 1 to 6 weeks.
    End point description
    Incidence of CTCAE grade 2 or above treatment related toxicity from day 1 to 6 weeks.
    End point type
    Secondary
    End point timeframe
    Until 6 weeks post dose.
    End point values
    		 Single Arm
    Number of subjects analysed
    88
    Units: whole
    88
    No statistical analyses for this end point

    Secondary: Bone marrow minimal Residual Disease (MRD) status in patients who achieve CR at 6 months.

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    End point title
    		 Bone marrow minimal Residual Disease (MRD) status in patients who achieve CR at 6 months.
    End point description
    Bone marrow minimal Residual Disease (MRD) status in patients who achieve CR at 6 months.
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months post dose
    End point values
    		 Single Arm
    Number of subjects analysed
    88
    Units: whole
    88
    No statistical analyses for this end point

    Secondary: Overall response rate [Complete Remission (CR) + Partial Remission (PR)]

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    End point title
    		 Overall response rate [Complete Remission (CR) + Partial Remission (PR)]
    End point description
    Overall response rate [Complete Remission (CR) + Partial Remission (PR)] at 12 months based on clinical and peripheral blood measurements.
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months post dose
    End point values
    		 Single Arm
    Number of subjects analysed
    88
    Units: whole
    88
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline until 30 days post completion of antibiotic treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Whole Trial
    Reporting group description
    		 All participants in single arm trial.

    Serious adverse events
    		 Whole Trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 98 (3.06%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Transischaemic event
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Palpitations and shortness of breath
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 98 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    hallucinations, bad dreams and change in mood.
         subjects affected / exposed
    1 / 98 (1.02%)
         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
    		 Whole Trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 98 (71.43%)
    Nervous system disorders
    neurological
         subjects affected / exposed
    6 / 98 (6.12%)
         occurrences all number
    6
    General disorders and administration site conditions
    Lethargy
         subjects affected / exposed
    8 / 98 (8.16%)
         occurrences all number
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    60 / 98 (61.22%)
         occurrences all number
    60
    Nausea & vomiting
         subjects affected / exposed
    40 / 98 (40.82%)
         occurrences all number
    40
    Dysguesia
         subjects affected / exposed
    17 / 98 (17.35%)
         occurrences all number
    17
    generic GI
         subjects affected / exposed
    14 / 98 (14.29%)
         occurrences all number
    14
    Skin and subcutaneous tissue disorders
    skin issues
         subjects affected / exposed
    2 / 98 (2.04%)
         occurrences all number
    2
    Psychiatric disorders
    Psychological
         subjects affected / exposed
    5 / 98 (5.10%)
         occurrences all number
    5
    Infections and infestations
    infection
         subjects affected / exposed
    6 / 98 (6.12%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Feb 2012
    Protocol changed to allow sites a choice of proton pump inhibitor as not all sites stock Lansoprazole. Protocol changed to include secondary endpoint of response rate at 12 months. An extra visit has been added as patients may achieve remission after 6 months. 12 month evaluation visit added
    21 Dec 2012
    Addition of three subgroups of participants:- 1. Monoclonal B lymphocytosis (MBL) with a raised lymphocyte count and CLL phenotype. This condition is considered to be a precursor of CLL and is associated with a 1% per year risk of developing disease requiring therapy. 2. Good risk Binet stage A CLL with fewer than two poor prognostic markers and an absence of adverse cytogenetics. 3. Poor risk Binet stage A CLL with 2 or more adverse prognostic markers.
    14 Nov 2013
    Expansion of Primary Endpoint to - "Overall response rate [Complete Remission (CR) + Partial Remission (PR)] at 6 months as defined by the International Workshop on CLL and the National Cancer Institute"
    25 Jun 2014
    Clarification of IMP and permitted concomitant medication:- All patients will receive a 14 day course of the following agents: Metronidazole 400mg tablets. One to be taken po twice a day. Clarithromycin 500mg tablets. One to be taken po twice a day. Ciprofloxacin 500mg tablets. One to be taken po twice a day. Lansoprazole 30mg tablets. One to be taken po twice a day orOmeprazole 20mg tablets/capsules. One to be taken po twice a day

    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.
    The primary endpoint was not met.
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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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