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    Clinical Trial Results:
    Phase II trial of ofatumumab, dexamethasone and lenalidomide for high-risk CLL (NCRI CLL210).

    Summary
    EudraCT number
    		 2010-019575-29
    Trial protocol
    		 GB  
    Global end of trial date
    07 Apr 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 Jun 2019
    First version publication date
    27 Jul 2018
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    An MHRA audit found that some SAES were downgraded from possibly related to not related following communication with the CI without evidence of clear clinical rationale. A review of downgraded SUSARs was carried out by the PV committee. One of the CLL210 SAEs was downgraded without clinical justification for the downgrade. This requires an update to the SAE dataset
    Summary report(s)
    		 CLL210 Final Study Report

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLL210 Version 10.1
    Additional study identifiers
    ISRCTN number
    		 ISRCTN40303610
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Michael Stackpoole, Liverpool Cancer Trials Unit, 0151 795 7321, mstack@liverpool.ac.uk
    Scientific contact
    Dr Mel Oates, Molecular and Clinical Cancer Medicine, 0151 706 4845, melly@liv.ac.uk
    Sponsor organisation name
    Royal Liverpool and Broadgreen University Hospitals NHS Trust
    Sponsor organisation address
    Prescot Street, Liverpool, United Kingdom, L7 8XP
    Public contact
    Michael Stackpoole, Liverpool Clinical Trials Unit, 0151 7957321, mstack@liverpool.ac.uk
    Scientific contact
    Dr Mel Oates, Molecular and Clinical Cancer Medicine, 0151 7064845, melly@liv.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
    12 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety and efficacy of combination induction therapy with ofatumumab, dexamethasone and lenalidomide in patients with high-risk CLL. Primary: - CR\CRi and tolerance rate (absence of Grade 3+ infection and no treatment related death) after 6m induction therapy. Secondary: - Overall, complete and partial response rates following induction therapy - Minimal residual disease negativity rate following induction therapy - Overall survival (from start of study treatment to death) - PFS (from initiation of study treatment to progression or death) - Time to treatment failure (from initiation of study treatment to treatment failure defined as progression, death or initiation of alternative treatment due to failure to achieve CR or PR) - Duration of response (from first achievement of CR or PR to first time of progression or death) - Toxicity - Quality of life - Descriptive summary of PFS and overall survival among transplant-eligible patients
    Protection of trial subjects
    Central and on-site monitoring was conducted to help protect patients and to monitor performance relating to trial procedures, trial intervention administration and laboratory/data collection processes. A risk assessment was carried out to determine the level of monitoring required, and subsequently a monitoring plan was developed to document how and when monitoring is conducted and to what extent. Patient safety was also monitored via LCTU pharmacovigilance procedures (reporting and review of adverse event data) and by an ISDMC. A Trial Management Group regularly reviewed central monitoring reports and advised accordingly. Following completion of study treatment, routine follow-up assessments were planned every 2 months until disease progression, second-line induction therapy initiated, or until 12 months after the last patient recruited into the study completed induction treatment, whichever was earliest. Serious adverse events were followed-up until resolution or death. Annual safety reports were submitted to the national regulatory authorities.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    26
    From 65 to 84 years
    37
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The CLL210 trial recruited 64 NHS patients from 19 centres across England, Scotland and Wales between 23/01/2012 and 31/10/2015.

    Pre-assignment
    Screening details
    		 64 of the 92 patients screened were recruited to the study. Patients provided consent and then a series of screening assessments were performed to determine eligibility, within 42 days prior to the first study treatment.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Baseline
    Arm description
    		 Single arm study followed by randomisation to maintenance treatment/no maintenance treatment for responders. • Initially the induction treatment regimen included Alemtuzumab instead of Ofatumumab and a subsequent randomisation to lenalidomide maintenance or no further treatment for eligible patients (2 years follow-up). The study was planned to recruit 85 patients but only 16 were recruited before Alemtuzumab was withdrawn. All 16 patients received treatment and were followed-up as per protocol. • Alemtuzumab was replaced by Ofatumumab; the study was re-initiated with the same design, statistical considerations and recruitment target; 85 more patients were planned to be recruited. • Recruitment target was reduced to 50 patients resulting in new statistical considerations (increased type I error rate). • Randomised part of the study was dropped due to very few patients being eligible and follow-up reduced to one instead of two years. This affected only the last two patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alemtuzumab
    Investigational medicinal product code
    ATC Code: L04AA34
    Other name
    Campath, MabCampath, Lemtrada
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Prior to its withdrawal, alemtuzumab was sourced commercially by each study centre. Alemtuzumab was administered intravenously in clinic to patients being monitored by research staff. Alemtuzumab 30mg sc, three times a week, weeks 7-22

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was sourced commercially by each study centre, biosimilar products were permitted and could be labelled and stored according to local practice. Dexamethasone 40mg, po, od, days 1-4, weeks 1, 3, 5, 7, 9, 11, 13, 15

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    ATC Code: L04AX04
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was provided free by Celgene for the CLL210 trial in the form of hard capsules of Revlimid; 5mg and 10mg capsules with an excipient of 147mg and 294mg of anhydrous lactose respectively. Stock was ordered from Celgene, via the LCTU using controlled documentation, and delivered direct to site. Lenalidomide 5mg, od (weeks 3-4), 10mg od (weeks 5-24)

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    ATC Code: L01XC10
    Other name
    Arzerra
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ofatumumab was supplied free of charge to study centres by GlaxoSmithKline UK (100mg and 1000mg vials for IV infusion). Ofatumumab 300mg IV day 1 week 7, 1000mg IV d1 weeks 8-15, 17, 19, 21.

    Number of subjects in period 1
    		Baseline
    Started
    64
    Completed
    64
    Period 2
    Period 2 title
    Induction Therapy
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Induction therapy
    Arm description
    		 • Initially the induction treatment regimen included Alemtuzumab instead of Ofatumumab and a subsequent randomisation to lenalidomide maintenance or no further treatment for eligible patients (2 years follow-up). The study was planned to recruit 85 patients but only 16 were recruited before Alemtuzumab was withdrawn. All 16 patients received treatment and were followed-up as per protocol. • Alemtuzumab was replaced by Ofatumumab; the study was re-initiated with the same design, statistical considerations and recruitment target; 85 more patients were planned to be recruited. • Recruitment target was reduced to 50 patients resulting in new statistical considerations (increased type I error rate). • Randomised part of the study was dropped due to very few patients being eligible and follow-up reduced to one instead of two years. This affected only the last two patients recruited in the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alemtuzumab
    Investigational medicinal product code
    ATC Code: L04AA34
    Other name
    Campath, MabCampath, Lemtrada
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Prior to its withdrawal, alemtuzumab was sourced commercially by each study centre. Alemtuzumab was administered intravenously in clinic to patients being monitored by research staff. Alemtuzumab 30mg sc, three times a week, weeks 7-22

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was sourced commercially by each study centre, biosimilar products were permitted and could be labelled and stored according to local practice. Dexamethasone 40mg, po, od, days 1-4, weeks 1, 3, 5, 7, 9, 11, 13, 15

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    ATC Code: L04AX04
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was provided free by Celgene for the CLL210 trial in the form of hard capsules of Revlimid; 5mg and 10mg capsules with an excipient of 147mg and 294mg of anhydrous lactose respectively. Stock was ordered from Celgene, via the LCTU using controlled documentation, and delivered direct to site. Lenalidomide 5mg, od (weeks 3-4), 10mg od (weeks 5-24)

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    ATC Code: L01XC10
    Other name
    Arzerra
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ofatumumab was supplied free of charge to study centres by GlaxoSmithKline UK (100mg and 1000mg vials for IV infusion). Ofatumumab 300mg IV day 1 week 7, 1000mg IV d1 weeks 8-15, 17, 19, 21.

    Number of subjects in period 2
    		Induction therapy
    Started
    64
    Completed
    35
    Not completed
    29
         Adverse event, serious fatal
    6
         Change of Diagnosis, and therefore ineligbile
    1
         Physician decision
    1
         Consent withdrawn by subject
    2
         Toxicity
    4
         Adverse event, non-fatal
    3
         Patient developed ITP at beginning of induction
    1
         Patient Decision
    1
         General Condition
    1
         Reason not known
    1
         Richters Transformation
    1
         Disease Progression
    7
    Period 3
    Period 3 title
    Maintenance Therapy
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Maintenance Treatment
    Arm description
    		 Patient receive bi-monlthy Lenalidomide for 2 years
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    ATC Code: L04AX04
    Other name
    Revlimid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10mg capsules were taken orally, once per day. Patients were dipsensed 5mg and 10mg capsules for their own administration, and a durg diary was kept.

    Arm title
    		 No Further treatment
    Arm description
    		 Patient do not receive any further treatment, but are followed up for quality of life and surivival data
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [1]
    		Maintenance Treatment No Further treatment
    Started
    11
    9
    Completed
    3
    9
    Not completed
    8
    0
         Physician decision
    1
    -
         Toxicity
    1
    -
         Progressive Disease
    4
    -
         Later elected for transplant, thus in eligible
    1
    -
         New Primary Malignancy (AML)
    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: The IMP for the study was changed due to the marketing authorisation being wdn for the study disease. Therefore, there are 2 cohorts (17, & 45) of pats listed for induction therapy; though elaborated as to why in the EUDRA-CT data & journal, it was reflected on the system as two inductions arms, even though induction wasn’t bifurcated. Further, the maint arm was randomised & only pats who achieved a certain favourable response &had a test for a certain biomarker were eligible for lenalidomide

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 64 64
    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)
    		 26 26
        From 65-84 years
    		 37 37
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 66 (59 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 18 18
        Male
    		 46 46
    WHO Performance status
    Units: Subjects
        PS 0
    		 34 34
        PS 1
    		 24 24
        PS 2
    		 6 6
    Previous Treatment
    Units: Subjects
        No
    		 29 29
        Yes
    		 35 35
    TP53 defect
    Units: Subjects
        No
    		 11 11
        Yes
    		 53 53
    CIRS Total Score
    Units: CIRS Score
        median (inter-quartile range (Q1-Q3))
    		 2 (1 to 4) -
    CIRS Severity Index
    Units: CIRS Index
        median (inter-quartile range (Q1-Q3))
    		 1 (1 to 1.6) -

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Single arm study followed by randomisation to maintenance treatment/no maintenance treatment for responders. • Initially the induction treatment regimen included Alemtuzumab instead of Ofatumumab and a subsequent randomisation to lenalidomide maintenance or no further treatment for eligible patients (2 years follow-up). The study was planned to recruit 85 patients but only 16 were recruited before Alemtuzumab was withdrawn. All 16 patients received treatment and were followed-up as per protocol. • Alemtuzumab was replaced by Ofatumumab; the study was re-initiated with the same design, statistical considerations and recruitment target; 85 more patients were planned to be recruited. • Recruitment target was reduced to 50 patients resulting in new statistical considerations (increased type I error rate). • Randomised part of the study was dropped due to very few patients being eligible and follow-up reduced to one instead of two years. This affected only the last two patients.
    Reporting group title
    Induction therapy
    Reporting group description
    		 • Initially the induction treatment regimen included Alemtuzumab instead of Ofatumumab and a subsequent randomisation to lenalidomide maintenance or no further treatment for eligible patients (2 years follow-up). The study was planned to recruit 85 patients but only 16 were recruited before Alemtuzumab was withdrawn. All 16 patients received treatment and were followed-up as per protocol. • Alemtuzumab was replaced by Ofatumumab; the study was re-initiated with the same design, statistical considerations and recruitment target; 85 more patients were planned to be recruited. • Recruitment target was reduced to 50 patients resulting in new statistical considerations (increased type I error rate). • Randomised part of the study was dropped due to very few patients being eligible and follow-up reduced to one instead of two years. This affected only the last two patients recruited in the study.
    Reporting group title
    Maintenance Treatment
    Reporting group description
    		 Patient receive bi-monlthy Lenalidomide for 2 years

    Reporting group title
    No Further treatment
    Reporting group description
    		 Patient do not receive any further treatment, but are followed up for quality of life and surivival data

    Subject analysis set title
    Intention to Treat
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients recruited into the study

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients with a major protocol deviation removed

    Primary: CR/CRi after 6 months of induction therapy

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    End point title
    		 CR/CRi after 6 months of induction therapy
    End point description
    Number of patients reaaching the CR and CRi response criteria following induction therapy.
    End point type
    Primary
    End point timeframe
    Induction therapy - 6 months
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    47 [1]
    47 [2]
    Units: subjects
    2
    2
    Notes
    [1] - 17 Patients unevaluable
    [2] - 17 Patients unevaluable
    Statistical analysis title
    		 Complete response rate
    Statistical analysis description
    Estimate of CR/CRi rate with confidence intervals
    Comparison groups
    Induction therapy v Intention to Treat
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.158
    Method
    		 Clopper-Pearsins exact confidence interc
    Parameter type
    		 Rate
    Point estimate
    0.043
    Confidence interval
         level
    		 68.4%
         sides
    2-sided
         lower limit
    		 0.015
         upper limit
    		 0.096
    Notes
    [3] - Estimation

    Primary: Toleration of Therapy

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    End point title
    		 Toleration of Therapy
    End point description
    End point type
    Primary
    End point timeframe
    Induction period - 6 months
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    60 [4]
    60 [5]
    Units: Subjects
    27
    27
    Notes
    [4] - 4 Unevaluable
    [5] - 4 Unevaluable
    Statistical analysis title
    		 Toleration of therapy
    Comparison groups
    Induction therapy v Intention to Treat
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.164
    Method
    		 Clopper-Pearsins exact confidence interc
    Parameter type
    		 Rate
    Point estimate
    0.45
    Confidence interval
         level
    		 67.2%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.521

    Secondary: Partial Response Rate

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    End point title
    		 Partial Response Rate
    End point description
    Number of patients to achieve PR
    End point type
    Secondary
    End point timeframe
    Induction Treatment - 6 months
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    47 [6]
    47
    Units: Number of
    36
    36
    Notes
    [6] - 17 unevaluable
    No statistical analyses for this end point

    Secondary: Minimal Residual Disease (MRD) negativity rate following induction therapy

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    End point title
    		 Minimal Residual Disease (MRD) negativity rate following induction therapy
    End point description
    The number of patients achieving MRD negativity following complete induction therapy (Measured at WK23 assessment bloods and Bone mrrwo aspirate).
    End point type
    Secondary
    End point timeframe
    Induction Period
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    24
    24
    Units: Subjects
    6
    6
    No statistical analyses for this end point

    Secondary: Overall survival (time from start of study treatment to death)

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    End point title
    		 Overall survival (time from start of study treatment to death)
    End point description
    2 years OS rate with OS defined as the time from recruitment until death by any cause.
    End point type
    Secondary
    End point timeframe
    Duration of the study
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    64
    64
    Units: Time (Months)
        number (confidence interval 95%)
    .63 (.52 to .77)
    .63 (.52 to .77)
    No statistical analyses for this end point

    Secondary: Progression-Free survival (time from initaiton of study treatment to progression or death)

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    End point title
    		 Progression-Free survival (time from initaiton of study treatment to progression or death)
    End point description
    2 year PFS rate. PFS defined as the time from recruitment until disease progression or death by any cause
    End point type
    Secondary
    End point timeframe
    Duration of Study
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    64
    64
    Units: Time (Months)
        number (confidence interval 95%)
    .37 (.26 to .53)
    .37 (.26 to .53)
    No statistical analyses for this end point

    Secondary: Time to treatment failure

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    End point title
    		 Time to treatment failure
    End point description
    2 year TTF rate where TTF is defines as the time from recruitment to treatment failure, disease progression or death by any cause.
    End point type
    Secondary
    End point timeframe
    Duration of Study
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    64
    64
    Units: Time (Months)
        number (confidence interval 95%)
    .33 (.22 to .48)
    .33 (.22 to .48)
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Number of patients to obtain CR/PR
    End point type
    Secondary
    End point timeframe
    Induction Period - 6 months
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    47
    47
    Units: Subjects
    38
    38
    No statistical analyses for this end point

    Secondary: Quality of Life

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    End point title
    		 Quality of Life
    End point description
    Quality of Life measures using the EQ5D QoL form
    End point type
    Secondary
    End point timeframe
    During the induction phase of the study
    End point values
    		 Induction therapy Intention to Treat
    Number of subjects analysed
    21
    21
    Units: Subjects
        arithmetic mean (standard deviation)
    .73 ( .19 )
    .73 ( .19 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE/SAEs were reported from Informed Consent until 28 days after last dose of study treatment (or longer if felt to be a long-term side effect of study treatment). Secondary primary malignancies were reported for the duration of the study.
    Adverse event reporting additional description
    Participating centres reported AE / SAE to the LCTU. Centres indicated whether there was a causal relationship in their view between the event and study drugs. A Clinical Coordinator then assessed the event on behalf of the Sponsor.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Alemtuzumab
    Reporting group description
    		 -

    Reporting group title
    Ofatumumab
    Reporting group description
    		 -

    Serious adverse events
    		 Alemtuzumab Ofatumumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 16 (87.50%)
    29 / 48 (60.42%)
         number of deaths (all causes)
    5
    19
         number of deaths resulting from adverse events
    1
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant, unspec (inc cysts, polyps) - Other
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 48 (6.25%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Visceral arterial ischemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thromboembolic event
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General disorders, admin. site conditions - Other
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Creatinine increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders - Other
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 48 (6.25%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Enterocolitis infectious
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations - Other
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    7 / 16 (43.75%)
    11 / 48 (22.92%)
         occurrences causally related to treatment / all
    4 / 8
    5 / 13
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Sepsis
         subjects affected / exposed
    5 / 16 (31.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bronchial infection
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hypercalcemia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Alemtuzumab Ofatumumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    48 / 48 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant, unspec (inc cysts, polyps) - Other
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    2
    2
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Hot flashes
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    2
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Thromboembolic event
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 48 (2.08%)
         occurrences all number
    2
    1
    Edema face
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Edema limbs
         subjects affected / exposed
    8 / 16 (50.00%)
    6 / 48 (12.50%)
         occurrences all number
    13
    7
    Fatigue
         subjects affected / exposed
    5 / 16 (31.25%)
    7 / 48 (14.58%)
         occurrences all number
    9
    14
    Facial pain
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Fever
         subjects affected / exposed
    4 / 16 (25.00%)
    7 / 48 (14.58%)
         occurrences all number
    5
    9
    Flu like symptoms
         subjects affected / exposed
    2 / 16 (12.50%)
    4 / 48 (8.33%)
         occurrences all number
    2
    5
    Gait disturbance
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    General disorders, admin. site conditions - Other
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 48 (4.17%)
         occurrences all number
    2
    4
    Infusion related reaction
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    Localized edema
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 48 (4.17%)
         occurrences all number
    2
    2
    Malaise
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Multi-organ failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    1 / 16 (6.25%)
    4 / 48 (8.33%)
         occurrences all number
    1
    11
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    Allergic reaction
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    3
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders - Other
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Prostatic obstruction
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 16 (43.75%)
    9 / 48 (18.75%)
         occurrences all number
    16
    17
    Atelectasis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Dyspnea
         subjects affected / exposed
    6 / 16 (37.50%)
    8 / 48 (16.67%)
         occurrences all number
    11
    12
    Epistaxis
         subjects affected / exposed
    3 / 16 (18.75%)
    4 / 48 (8.33%)
         occurrences all number
    5
    7
    Hiccups
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    Hoarseness
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Hypoxia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    3
    Laryngeal inflammation
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 48 (2.08%)
         occurrences all number
    3
    1
    Nasal congestion
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Postnasal drip
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Respiratory failure
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders - Other
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Sore throat
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 48 (2.08%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Confusion
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Depression
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    Euphoria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    3 / 16 (18.75%)
    10 / 48 (20.83%)
         occurrences all number
    4
    10
    Mania
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Psychosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    2
    Psychiatric disorders - Other, specify
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Alkaline phosphatase increased
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    9
    Blood bilirubin increased
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    7
    27
    GGT increased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    2
    Creatinine increased
         subjects affected / exposed
    0 / 16 (0.00%)
    5 / 48 (10.42%)
         occurrences all number
    0
    14
    Investigations - Other, specify
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    9
    Neutrophil count decreased
         subjects affected / exposed
    8 / 16 (50.00%)
    20 / 48 (41.67%)
         occurrences all number
    20
    86
    Platelet count decreased
         subjects affected / exposed
    7 / 16 (43.75%)
    11 / 48 (22.92%)
         occurrences all number
    27
    58
    Urine output decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    White blood cell decreased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 48 (0.00%)
         occurrences all number
    29
    0
    Weight loss
         subjects affected / exposed
    2 / 16 (12.50%)
    5 / 48 (10.42%)
         occurrences all number
    2
    5
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 48 (6.25%)
         occurrences all number
    4
    3
    Injury, poisoning, procedural complications - Other
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    5
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Ventricular fibrillation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Nervous system disorders
    Concentration impairment
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 16 (12.50%)
    6 / 48 (12.50%)
         occurrences all number
    2
    11
    Depressed level of consciousness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Dysarthria
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    4 / 16 (25.00%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    Headache
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 48 (6.25%)
         occurrences all number
    4
    5
    Neuralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Lethargy
         subjects affected / exposed
    3 / 16 (18.75%)
    7 / 48 (14.58%)
         occurrences all number
    5
    15
    Oculomotor nerve disorder
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Paresthesia
         subjects affected / exposed
    2 / 16 (12.50%)
    4 / 48 (8.33%)
         occurrences all number
    3
    8
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 48 (6.25%)
         occurrences all number
    2
    4
    Sinus pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Presyncope
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Spasticity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    Stroke
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 48 (0.00%)
         occurrences all number
    5
    0
    Vasovagal reaction
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    5 / 16 (31.25%)
    12 / 48 (25.00%)
         occurrences all number
    17
    70
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders - Other
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Febrile neutropenia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    2
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Haemolysis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    2
    Lymph node pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    4
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Hearing impaired
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Eye disorders
    Blurred vision
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Eye disorders - Other, specify
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    2
    Retinal vascular disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Optic nerve disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 48 (4.17%)
         occurrences all number
    2
    5
    Anal pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Bloating
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    3 / 16 (18.75%)
    9 / 48 (18.75%)
         occurrences all number
    4
    12
    Diarrhea
         subjects affected / exposed
    12 / 16 (75.00%)
    15 / 48 (31.25%)
         occurrences all number
    24
    28
    Dry mouth
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    5
    Flatulence
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Gastrointestinal disorders - Other
         subjects affected / exposed
    2 / 16 (12.50%)
    4 / 48 (8.33%)
         occurrences all number
    2
    5
    Lower Gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Mucositis oral
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 48 (6.25%)
         occurrences all number
    7
    4
    Nausea
         subjects affected / exposed
    5 / 16 (31.25%)
    10 / 48 (20.83%)
         occurrences all number
    7
    17
    Oral dysesthesia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Oral pain
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    3 / 16 (18.75%)
    6 / 48 (12.50%)
         occurrences all number
    5
    13
    Toothache
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    1
    3
    Alopecia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    5 / 16 (31.25%)
    3 / 48 (6.25%)
         occurrences all number
    8
    3
    Pain of skin
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 48 (6.25%)
         occurrences all number
    5
    4
    Rash Papular
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders - Other
         subjects affected / exposed
    6 / 16 (37.50%)
    7 / 48 (14.58%)
         occurrences all number
    17
    10
    Skin ulceration
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Urticaria
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    2
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Cystitis noninfective
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Renal and urinary disorders - Other, specify
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Urinary frequency
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    Urinary retention
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Urinary tract pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    3
    Arthritis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    2
    7
    Back pain
         subjects affected / exposed
    2 / 16 (12.50%)
    5 / 48 (10.42%)
         occurrences all number
    2
    7
    Bone pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Chest wall pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Generalized muscle weakness
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Muscle weakness lower limb
         subjects affected / exposed
    3 / 16 (18.75%)
    3 / 48 (6.25%)
         occurrences all number
    4
    3
    Musculoskeletal, connective tissue disorder - Other
         subjects affected / exposed
    4 / 16 (25.00%)
    5 / 48 (10.42%)
         occurrences all number
    5
    8
    Myalgia
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 48 (2.08%)
         occurrences all number
    6
    1
    Neck pain
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 16 (6.25%)
    4 / 48 (8.33%)
         occurrences all number
    3
    6
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Bronchial infection
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    Encephalitis infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Infections and infestations - Other
         subjects affected / exposed
    9 / 16 (56.25%)
    11 / 48 (22.92%)
         occurrences all number
    17
    19
    Lung infection
         subjects affected / exposed
    5 / 16 (31.25%)
    6 / 48 (12.50%)
         occurrences all number
    5
    7
    Mucosal infection
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 48 (2.08%)
         occurrences all number
    4
    1
    Pharyngitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Rash pustular
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Sepsis
         subjects affected / exposed
    7 / 16 (43.75%)
    4 / 48 (8.33%)
         occurrences all number
    9
    4
    Skin infection
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 48 (4.17%)
         occurrences all number
    3
    3
    Sinusitis
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Tooth infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 48 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Upper respiratory infection
         subjects affected / exposed
    4 / 16 (25.00%)
    15 / 48 (31.25%)
         occurrences all number
    6
    36
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 16 (6.25%)
    5 / 48 (10.42%)
         occurrences all number
    1
    5
    Dehydration
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    2
    Glucose intolerance
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    0
    2
    Hypercalcemia
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Hyperglycemia
         subjects affected / exposed
    4 / 16 (25.00%)
    3 / 48 (6.25%)
         occurrences all number
    4
    26
    Hyperkalemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    2
    Hypermagnesemia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    Hyperuricemia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1
    Hypoalbuminemia
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    1
    10
    Hypocalcemia
         subjects affected / exposed
    1 / 16 (6.25%)
    9 / 48 (18.75%)
         occurrences all number
    5
    29
    Hypoglycemia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    3
    Hypokalemia
         subjects affected / exposed
    0 / 16 (0.00%)
    7 / 48 (14.58%)
         occurrences all number
    0
    29
    Hypomagnesemia
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 48 (4.17%)
         occurrences all number
    1
    2
    Hyponatremia
         subjects affected / exposed
    1 / 16 (6.25%)
    3 / 48 (6.25%)
         occurrences all number
    1
    8
    Hypophosphatemia
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    27
    Metabolism and nutrition disorders - Other
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 48 (6.25%)
         occurrences all number
    2
    7
    Tumor lysis syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2011
    Changes made following REC and regulatory review of version 1: o Justification for the use of subcutaneous alemtuzumab added to section 3.2. o Alteration to maintenance phase: trial medication (and pharmacovigilance and follow-up) will continue until disease progression or death for any patients that have not progressed by the time of the primary analysis (2.5 years after the last patient has been recruited). It was intended that Revlimid would continue to be made available to those patients off-trial but they remained on-trial until progression. Changes made to sections 2, 8.4 and 10.1. • Miscellaneous spelling, punctuation and grammar corrections and other minor admin changes.
    30 Jun 2011
    • Changes made to translational research to bring it in line with another CLL trial with sample being collected by the UKCLL biobank o Section 7.4 updated to include details of collection of and tests to be performed on translational samples collected at baseline o Section 9.2.4 updated with details of how bone marrow trephine biopsies are to be processed centrally o Section 9.5 updated to emphasise that patients can consent to having baseline and sequential samples taken, or baseline samples only • Miscellaneous spelling, punctuation and grammar corrections and other minor administrative changes.
    26 Sep 2011
    • Changes made to contact details and list of TSC members. • Details of specific tests to be performed at study visits added to section 7.1 and section 9 • Added details regarding retention of bone marrow trephine samples for future research to section 7.4. • Updated links and references to CTCAE v4 (rather than v3 which was used previously) • Section 11 (Pharmacovigilance) updated to reflect move to on-line reporting of SAEs and AEs, and annual submission of Development Safety Update Report. • Replace QLQ C30 Questionnaire (Appendix E) with CLL210 Health & Quality of Life Questionnaire, and updated references in protocol. • Miscellaneous spelling, punctuation and grammar corrections and other minor admin changes.
    09 Feb 2012
    • Section 2 (and 6.2) - Extra qualification on exclusion criterion “Seropositivity for HIV, HCV or HBV (surface antigen and core antibody)” added. • Section 8.2.4 (and 8.4.4 and 8.5) - Allow sites to give alternative equivalent co-trimoxazole regimens according to local practice. • Section 8.2.4 - Changed days that patient should receive alendronic acid to 70mg on day 1 of weeks 1, 3, 5, 7, 9, 11, 13 and 15 of treatment, on advice from pharmacists. • Section 8.4.2 - Changed references from lenalidomide SPC to lenalidomide IB. • Miscellaneous spelling, punctuation and grammar corrections and other minor admin changes.
    25 Nov 2012
    • Changed study title to reflect substitution of alemtuzumab for ofatumumab. • Section 2. Clarified that an estimated 58 patients will be randomised to lenalidomide maintenance versus no further treatment (changed from 54). • Sections 2, 6.1. Qualified inclusion criterion relating to previous treatment episodes for CLL by adding “excluding chlorambucil-based regimen. • Sections 3.1, 3.2. - Rewritten study objectives and rationale and combined into new section. • Section 8 - Major updates to this section to reflect replacement of alemtuzumab with ofatumumab in induction treatment regimen. • Section 10.5.1 - Added futility analysis to stopping guidelines.
    19 Sep 2013
    • Update to contact details for Professor Andrew Pettitt and Dr Lukas Smolej • Dr Arvind Arumainathan added as co-investigator • Serum biochemistry assessments chloride, bicarbonate, γGT no longer required. Uric Acid required at baseline only. • Section 8.2.4, 8.4.4 LMW heparin can be given as an alternative to aspirin if patients at high risk of thrombosis.
    27 Nov 2013
    • Removed exclusion criterion “Hepatic impairment (serum bilirubin more than twice the upper limit of normal unless due to Gilbert’s syndrome)” as already covered by another criterion. • Section 8.2 - Allow local investigators the discretion to extend tapering dexamethasone dose for patients who have steroid withdrawal symptoms, and to allow a tapering dose if patient had grade 3/4 steroid related toxicities prior to starting on study treatment. • Section 8.2.3.1 - Allow lenalidomide to be started and dose increased if low platelet and neutrophil counts are due to underlying CLL.
    04 Aug 2014
    • Section 6.1 - Removed the inclusion criterion “No more than 3 previous treatment episodes for CLL (excluding chlorambucil-based regiments)”. • Section 9.6 - Added details of Genomics England 10,000 Genomes Project to sub-studies section.
    27 Oct 2014
    • Removed references to maintenance part of study from all parts of protocol (including in study title). • Change to protocol to reduce target recruitment from 85 to 50 and remove maintenance part of study. Affects sections 2, 5, 7.3, 8, 10, 12, 14.4.5 • Section 2, 6.2. Changes to the wording of the exclusion criterion relating to women of childbearing potential. • Section 8.5 Updates to the pregnancy prevention plan text. • Update to primary endpoints and major changes to section 10 (statistical considerations), as a result of the above changes. • Section 17.3 Change to timing of ISDMC meetings
    07 Aug 2015
    • Section 2, 6.2. Reverted final exclusion criterion to state that women of children bearing potential who do are “unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol” are excluded from the study, instead of “study start to 28 days after the last dose of protocol” as in version 10.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Sep 2012
    The Original Protocol of the CLL210 trial used Alexmtuzumab in the induction therapy. Marketing Authorisation for the indication of CLL was withdrawn and so the study suspended recruitment. The Study was then restarted using Ofatumumab instead. The study continued from restart to end of study declaration without any further interruption.
    -

    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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