Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44338   clinical trials with a EudraCT protocol, of which   7368   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase Ib/II combination trial of acalabrutinib with rituximab, cyclophosphamide, doxorubicin,vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL)

    Summary
    EudraCT number
    		 2015-003213-18
    Trial protocol
    		 GB  
    Global end of trial date
    23 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 May 2025
    First version publication date
    24 May 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RHMCAN1129
    Additional study identifiers
    ISRCTN number
    		 ISRCTN13626902
    US NCT number
    		 NCT03571308
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CR UK Trial Number: CRUKDE/16/006
    Sponsors
    Sponsor organisation name
    University Hospital Southampton NHS Foundation Trust
    Sponsor organisation address
    Clinical Trials Unit, Southampton, United Kingdom, SO16 6YD
    Public contact
    Ailsa Duckworth, University Hospital Southampton NHS Foundation Trust, 44 023 8120 5131 , ailsa.duckworth@uhs.nhs.uk
    Scientific contact
    Ailsa Duckworth, University Hospital Southampton NHS Foundation Trust, 44 023 8120 5131 , ailsa.duckworth@uhs.nhs.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
    30 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective at Stage 1 is to: 1. Examine the safety and toxicity profile of acalabrutinib in combination with R-CHOP and define the dose limiting toxicity (DLT) or maximum administered dose (MAD). The primary objective at Stage 2 is to: 2. To document the anti-tumour activity of acalabrutinib in combination with R-CHOP in patients with previously untreated CD20 positive DLBCL. 3. To determine additional safety information on acalabrutinib in combination with R-CHOP.
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 From 25 May 2017 to 02 Jan 2020, 38 participants (14 in Phase I and 24 in Phase II) were registered at 7 sites, and 7 patients were ineligible.

    Pre-assignment
    Screening details
    		 From May 2017 to Jan 2020, 38 pts. were enrolled (safety population: pts. in receipt of any component of therapy). Seven of the enrolled pts. were found to be ineligible (insufficient material for translational work, 2pts.; taking a proton pump inhibitor during therapy, 2 pts.; follicular histology, 1pt.; abnormal LFTs at baseline, 1pt.; age >65).

    Period 1
    Period 1 title
    Phase 1 and Phase 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 The patients will receive a first cycle of R-CHOP. Acalabrutinib, at a starting dose of 100 mg od, will be added from cycle 2 to 6. This will be followed by cycles 7 and 8 of acalabrutinib only 100mg od for 28 days for each cycle. Dose escalation to 200 mg daily (100 mg bd) of acalabrutinib will be decided by the Safety Review Committee based on safety data and patients’ compliance assessment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Acalabrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Acalabrutinib, at a starting dose of 100 mg od, will be added from cycle 2 to 6. This will be followed by cycles 7 and 8 of acalabrutinib only 100mg od for 28 days for each cycle.

    Arm title
    		 Cohort 2 and Phase 2 patients
    Arm description
    		 The first 6 patients of cohort 2 will start acalabrutinib + R-CHOP at the daily dose of 200mg administered as 100mg bd from cycle 2 after the Safety Review Committee has approved dose escalation based on all the safety data from cohort 1. After all patients of cohort 2 have completed their 2nd cycle of acalabrutinib + R-CHOP (3rd cycle of therapy), and based on patients’ safety data, compliance assessment, PK/PD measures if available, the Safety Review Committee will assess the safety of 200mg. If one or two instances of DLT is observed among the initial six patients of cohort 2, the cohort will be expanded to a further six patients. Depending on tolerability as set out, cohort 2 patients should receive cycle 1 of R-CHOP, cycles 2-6 R-CHOP plus acalabrutinib and then cycles 7 and 8 of acalabrutinib only at 200mg administered as 100mg bd.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Acalabrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The first 6 patients of cohort 2 will start acalabrutinib + R-CHOP at the daily dose of 200mg administered as 100mg bd from cycle 2 after the Safety Review Committee has approved dose escalation based on all the safety data from cohort 1. After all patients of cohort 2 have completed their 2nd cycle of acalabrutinib + R-CHOP (3rd cycle of therapy), and based on patients’ safety data, compliance assessment, PK/PD measures if available, the Safety Review Committee will assess the safety of 200mg. If one or two instances of DLT is observed among the initial six patients of cohort 2, the cohort will be expanded to a further six patients. Depending on tolerability as set out, cohort 2 patients should receive cycle 1 of R-CHOP, cycles 2-6 R-CHOP plus acalabrutinib and then cycles 7 and 8 of acalabrutinib only at 200mg administered as 100mg bd.

    Number of subjects in period 1
    		Cohort 1 Cohort 2 and Phase 2 patients
    Started
    7
    24
    Completed
    4
    22
    Not completed
    3
    2
         Consent withdrawn by subject
    1
    1
         Death
    1
    1
         Lost to follow-up
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 The patients will receive a first cycle of R-CHOP. Acalabrutinib, at a starting dose of 100 mg od, will be added from cycle 2 to 6. This will be followed by cycles 7 and 8 of acalabrutinib only 100mg od for 28 days for each cycle. Dose escalation to 200 mg daily (100 mg bd) of acalabrutinib will be decided by the Safety Review Committee based on safety data and patients’ compliance assessment.

    Reporting group title
    Cohort 2 and Phase 2 patients
    Reporting group description
    		 The first 6 patients of cohort 2 will start acalabrutinib + R-CHOP at the daily dose of 200mg administered as 100mg bd from cycle 2 after the Safety Review Committee has approved dose escalation based on all the safety data from cohort 1. After all patients of cohort 2 have completed their 2nd cycle of acalabrutinib + R-CHOP (3rd cycle of therapy), and based on patients’ safety data, compliance assessment, PK/PD measures if available, the Safety Review Committee will assess the safety of 200mg. If one or two instances of DLT is observed among the initial six patients of cohort 2, the cohort will be expanded to a further six patients. Depending on tolerability as set out, cohort 2 patients should receive cycle 1 of R-CHOP, cycles 2-6 R-CHOP plus acalabrutinib and then cycles 7 and 8 of acalabrutinib only at 200mg administered as 100mg bd.

    Reporting group values
    		 Cohort 1 Cohort 2 and Phase 2 patients Total
    Number of subjects
    		 7 24 31
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 18 19
        Over 65
    		 6 6 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.9 ( 4.4 ) 55.7 ( 13.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 6 7
        Male
    		 6 18 24
    ECOG performance status
    Units: Subjects
        Fully active
    		 2 14 16
        Restricted in physically strenuous activity
    		 3 9 12
        Capable of all self-care but unable to work
    		 2 1 3
        Capable of only limited self-care
    		 0 0 0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 The patients will receive a first cycle of R-CHOP. Acalabrutinib, at a starting dose of 100 mg od, will be added from cycle 2 to 6. This will be followed by cycles 7 and 8 of acalabrutinib only 100mg od for 28 days for each cycle. Dose escalation to 200 mg daily (100 mg bd) of acalabrutinib will be decided by the Safety Review Committee based on safety data and patients’ compliance assessment.

    Reporting group title
    Cohort 2 and Phase 2 patients
    Reporting group description
    		 The first 6 patients of cohort 2 will start acalabrutinib + R-CHOP at the daily dose of 200mg administered as 100mg bd from cycle 2 after the Safety Review Committee has approved dose escalation based on all the safety data from cohort 1. After all patients of cohort 2 have completed their 2nd cycle of acalabrutinib + R-CHOP (3rd cycle of therapy), and based on patients’ safety data, compliance assessment, PK/PD measures if available, the Safety Review Committee will assess the safety of 200mg. If one or two instances of DLT is observed among the initial six patients of cohort 2, the cohort will be expanded to a further six patients. Depending on tolerability as set out, cohort 2 patients should receive cycle 1 of R-CHOP, cycles 2-6 R-CHOP plus acalabrutinib and then cycles 7 and 8 of acalabrutinib only at 200mg administered as 100mg bd.

    Primary: Overall response rate (efficacy population)

    		 Close Top of page
    End point title
    		 Overall response rate (efficacy population)
    End point description
    The overall response has been assessed, the overall response according to the investigator’s overall response assessment at the end of treatment and, the primary endpoint, the overall response rate (patients with a complete or partial response). This is summarised by the groups below using the efficacy population: • Phase 1 Cohort 1 patients only • Phase 2 Cohort 2 patients and phase 2 patients combined
    End point type
    Primary
    End point timeframe
    From May 2017 to June 2022 (follow up)
    End point values
    		 Cohort 1 Cohort 2 and Phase 2 patients
    Number of subjects analysed
    6 [1]
    24
    Units: Number of patients
        Complete response
    4
    19
        Partial response
    1
    4
        Stable disease
    0
    1
        Progressive disease
    1
    0
    Notes
    [1] - Cohort 1 - 1 Subject withdrawal (EOT visit did not take place)
    Statistical analysis title
    		 Primary endpoint - Overall response rate - Cohort1
    Statistical analysis description
    Primary endpoint - Overall response rate of the combination acalabrutinib and R-CHOP - Cohort 1 only
    Comparison groups
    Cohort 1 v Cohort 2 and Phase 2 patients
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 95% confidence intervals exact method
    Parameter type
    		 Response rate
    Point estimate
    83.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 35.9
         upper limit
    		 99.6
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Cohort 2 Primary endpoint - Overall response
    Statistical analysis description
    Primary endpoint - Overall response rate of the combination acalabrutinib and R-CHOP for Cohort 2 only
    Comparison groups
    Cohort 2 and Phase 2 patients v Cohort 1
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 95% confidence intervals exact method
    Parameter type
    		 Response rate
    Point estimate
    95.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 78.9
         upper limit
    		 99.9
    Variability estimate
    Standard deviation

    Secondary: Deaths, Progressions and Event Information (efficacy population)

    		 Close Top of page
    End point title
    		 Deaths, Progressions and Event Information (efficacy population)
    End point description
    The post-treatment survival and progression information which includes the number of deaths, number of progressions, number of EFS events and the number of TTF events on the trial. This includes any deaths or progressions or events that were recorded at any time from date of treatment initiation to the end of study. The tables and secondary endpoint analysis have been carried out using the efficacy population split by the following two groups: • Cohort 1 patients only • Cohort 2 patients and phase 2 patients combined
    End point type
    Secondary
    End point timeframe
    From May 2017 to June 2022 (follow up)
    End point values
    		 Cohort 1 Cohort 2 and Phase 2 patients
    Number of subjects analysed
    7
    24
    Units: Number of patients
        Number of deaths
    1
    1
        Number of progressions
    1
    1
        Number of PFS events
    1
    1
        Number of EFS events
    2
    2
        Number of TTF events (any treatment failure includ
    4
    6
    No statistical analyses for this end point

    Secondary: PFS at 6, 9, 12 and 24 months (efficacy population)

    		 Close Top of page
    End point title
    		 PFS at 6, 9, 12 and 24 months (efficacy population)
    End point description
    End point type
    Secondary
    End point timeframe
    From May 2017 to June 2022
    End point values
    		 Cohort 1 Cohort 2 and Phase 2 patients
    Number of subjects analysed
    7
    24
    Units: percent
    number (confidence interval 95%)
        PFS at 6 months
    80 (20.40 to 96.9)
    100 (100 to 100)
        PFS at 9 months
    80 (20.4 to 96.9)
    100 (100 to 100)
        PFS at 12 months
    80 (20.4 to 96.9)
    94.7 (68.1 to 99.2)
        PFS at 24 months
    80 (20.4 to 96.9)
    94.7 (68.1 to 99.2)
    No statistical analyses for this end point

    Secondary: OS at 6, 9, 12 and 24 months (efficacy population)

    		 Close Top of page
    End point title
    		 OS at 6, 9, 12 and 24 months (efficacy population)
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Cohort 1 Cohort 2 and Phase 2 patients
    Number of subjects analysed
    7
    24
    Units: percent
    number (confidence interval 95%)
        OS at 6 months
    100 (100 to 100)
    100 (100 to 100)
        OS at 9 months
    100 (100 to 100)
    100 (100 to 100)
        OS at 12 months
    80.0 (20.4 to 96.9)
    100 (100 to 100)
        OS at 24 months
    80.0 (20.4 to 96.9)
    95.7 (72.9 to 99.4)
    No statistical analyses for this end point

    Secondary: EFS at 6, 9, 12 and 24 months (efficacy population)

    		 Close Top of page
    End point title
    		 EFS at 6, 9, 12 and 24 months (efficacy population)
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Cohort 1 Cohort 2 and Phase 2 patients
    Number of subjects analysed
    7
    24
    Units: percent
    number (confidence interval 95%)
        EFS at 6 months
    80.0 (20.4 to 96.9)
    100 (100 to 100)
        EFS at 9 months
    60.0 (12.6 to 88.2)
    95.2 (70.7 to 99.3)
        EFS at 12 months
    60.0 (12.6 to 88.2)
    90.2 (66.2 to 97.5)
        EFS at 24 months
    60.0 (12.6 to 88.2)
    90.2 (66.2 to 97.5)
    No statistical analyses for this end point

    Secondary: TTF at 6, 9, 12 and 24 months

    		 Close Top of page
    End point title
    		 TTF at 6, 9, 12 and 24 months
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Cohort 1 Cohort 2 and Phase 2 patients
    Number of subjects analysed
    7
    24
    Units: percent
    number (confidence interval 95%)
        TTF at 6 months
    57.1 (17.2 to 83.7)
    83.3 (61.5 to 93.4)
        TTF at 9 months
    42.9 (9.8 to 73.4)
    79.2 (57 to 90.8)
        TTF at 12 months
    42.9 (9.8 to 73.4)
    74.8 (52.2 to 87.8)
        TTF at 24 months
    42.9 (9.8 to 73.4)
    74.8 (52.2 to 87.8)
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    The reporting requirement for SAEs affecting participants applies for all events occurring up to 30 days after the last administration of trial drugs. All adverse events should be recorded in the relevant eCRF and submitted to SCTU.
    Adverse event reporting additional description
    All unresolved adverse events should be followed by the investigator until resolved, the participant is lost to follow-up, or the adverse event is otherwise explained. At the last scheduled visit, each participant to report any subsequent event(s) that the participant believes might reasonably be related to participation in this trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Cohort 2
    Reporting group description
    		 -

    Reporting group title
    Cohort 1
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort 2 Cohort 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 24 (50.00%)
    6 / 7 (85.71%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
    Additional description: Infusion related reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
    Additional description: Dystonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
    Additional description: Peripheral motor neuropathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
    Additional description: Febrile neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
    Additional description: Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    Additional description: Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
    Additional description: Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
    Additional description: Small intestinal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    Additional description: Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    Additional description: Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Viral infection
    Additional description: Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    Additional description: Infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
    Additional description: Rhinovirus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
    Additional description: Respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
    Additional description: Hypokalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 2 Cohort 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 24 (100.00%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
    Additional description: Basal cell carcinoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Vascular disorders
    Hypertension
    Additional description: Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Hypotension
    Additional description: Hypotension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 7 (42.86%)
         occurrences all number
    1
    3
    Lymphoedema
    Additional description: Lymphoedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Haematoma
    Additional description: Haematoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Adverse drug reaction
    Additional description: Adverse drug reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hernia
    Additional description: Hernia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Pain
    Additional description: Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Fatigue
    Additional description: Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 24 (45.83%)
    4 / 7 (57.14%)
         occurrences all number
    18
    9
    Chest pain
    Additional description: Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Chest discomfort
    Additional description: Chest discomfort
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Oedema
    Additional description: Oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
    Additional description: Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Axillary pain
    Additional description: Axillary pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
    Additional description: Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Nipple pain
    Additional description: Nipple pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Breast swelling
    Additional description: Breast swelling
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gynaecomastia
    Additional description: Gynaecomastia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Sinus congestion
    Additional description: Sinus congestion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Chronic obstructive pulmonary disease
    Additional description: Chronic obstructive pulmonary disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Dyspnoea
    Additional description: Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    5
    2
    Upper respiratory tract congestion
    Additional description: Upper respiratory tract congestion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea exertional
    Additional description: Dyspnoea exertional
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
    Additional description: Rhinorrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Cough
    Additional description: Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    Epistaxis
    Additional description: Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
    Additional description: Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    3
    1
    Insomnia
    Additional description: Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 7 (14.29%)
         occurrences all number
    2
    2
    Claustrophobia
    Additional description: Claustrophobia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Depression
    Additional description: Depression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Mood swings
    Additional description: Mood swings
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Weight decreased
    Additional description: Weight decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    White blood cell count decreased
    Additional description: White blood cell count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Lymphocyte count decreased
    Additional description: Lymphocyte count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    Alanine aminotransferase increased
    Additional description: Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood sodium decreased
    Additional description: Blood sodium decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Blood potassium decreased
    Additional description: Blood potassium decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Aspartate aminotransferase increased
    Additional description: Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Hip fracture
    Additional description: Hip fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Fall
    Additional description: Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Eye contusion
    Additional description: Eye contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Arthropod bite
    Additional description: Arthropod bite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Infusion related reaction
    Additional description: Infusion related reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 24 (29.17%)
    0 / 7 (0.00%)
         occurrences all number
    7
    0
    Contusion
    Additional description: Contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    Tooth fracture
    Additional description: Tooth fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Femoral neck fracture
    Additional description: Femoral neck fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nail injury
    Additional description: Nail injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Myocardial infarction
    Additional description: Myocardial infarction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Supraventricular tachycardia
    Additional description: Supraventricular tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    Tachycardia
    Additional description: Tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Peripheral sensory neuropathy
    Additional description: Peripheral sensory neuropathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    Headache
    Additional description: Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 24 (37.50%)
    2 / 7 (28.57%)
         occurrences all number
    13
    5
    Taste disorder
    Additional description: Taste disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
    Additional description: Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    3
    2
    Dizziness postural
    Additional description: Dizziness postural
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Syncope
    Additional description: Syncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
    Additional description: Hypoaesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Neuropathy peripheral
    Additional description: Neuropathy peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    Dizziness
    Additional description: Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    2 / 7 (28.57%)
         occurrences all number
    5
    4
    Presyncope
    Additional description: Presyncope
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Peroneal nerve palsy
    Additional description: Peroneal nerve palsy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Spontaneous haematoma
    Additional description: Spontaneous haematoma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Neutropenia
    Additional description: Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 24 (45.83%)
    5 / 7 (71.43%)
         occurrences all number
    13
    5
    Increased tendency to bruise
    Additional description: Increased tendency to bruise
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Anaemia
    Additional description: Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 24 (29.17%)
    1 / 7 (14.29%)
         occurrences all number
    9
    2
    Thrombocytopenia
    Additional description: Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    7
    1
    Ear and labyrinth disorders
    Vertigo
    Additional description: Vertigo
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Eye pain
    Additional description: Eye pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Visual impairment
    Additional description: Visual impairment
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
    Additional description: Vision blurred
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Aphthous ulcer
    Additional description: Aphthous ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Oral pain
    Additional description: Oral pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Toothache
    Additional description: Toothache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
    Additional description: Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 7 (28.57%)
         occurrences all number
    5
    2
    Intestinal obstruction
    Additional description: Intestinal obstruction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Vomiting
    Additional description: Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 24 (29.17%)
    2 / 7 (28.57%)
         occurrences all number
    12
    2
    Abdominal pain upper
    Additional description: Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Dry mouth
    Additional description: Dry mouth
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Anal haemorrhage
    Additional description: Anal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Large intestine perforation
    Additional description: Large intestine perforation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gastritis
    Additional description: Gastritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Nausea
    Additional description: Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 24 (54.17%)
    2 / 7 (28.57%)
         occurrences all number
    27
    2
    Submaxillary gland enlargement
    Additional description: Submaxillary gland enlargement
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Haemorrhoids
    Additional description: Haemorrhoids
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Gingival pain
    Additional description: Gingival pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Swollen tongue
    Additional description: Swollen tongue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Constipation
    Additional description: Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 24 (45.83%)
    4 / 7 (57.14%)
         occurrences all number
    17
    7
    Diarrhoea
    Additional description: Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 24 (50.00%)
    3 / 7 (42.86%)
         occurrences all number
    20
    7
    Angular cheilitis
    Additional description: Angular cheilitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
    Additional description: Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 7 (0.00%)
         occurrences all number
    4
    0
    Faeces discoloured
    Additional description: Faeces discoloured
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Flatulence
    Additional description: Flatulence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Overflow diarrhoea
    Additional description: Overflow diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Abdominal discomfort
    Additional description: Abdominal discomfort
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Anal fissure
    Additional description: Anal fissure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
    Additional description: Mouth ulceration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Abdominal mass
    Additional description: Abdominal mass
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic steatosis
    Additional description: Hepatic steatosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Pain of skin
    Additional description: Pain of skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
    Additional description: Hyperhidrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Dry skin
    Additional description: Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 7 (42.86%)
         occurrences all number
    1
    3
    Erythema
    Additional description: Erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Night sweats
    Additional description: Night sweats
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Rash
    Additional description: Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 24 (20.83%)
    2 / 7 (28.57%)
         occurrences all number
    5
    2
    Skin lesion
    Additional description: Skin lesion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Blood blister
    Additional description: Blood blister
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Skin discolouration
    Additional description: Skin discolouration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Alopecia
    Additional description: Alopecia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    4
    1
    Rash pruritic
    Additional description: Rash pruritic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Skin ulcer
    Additional description: Skin ulcer
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    Rash macular
    Additional description: Rash macular
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nail discolouration
    Additional description: Nail discolouration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    Nail growth abnormal
    Additional description: Nail growth abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Nail dystrophy
    Additional description: Nail dystrophy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Pruritus
    Additional description: Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 24 (20.83%)
    0 / 7 (0.00%)
         occurrences all number
    8
    0
    Eczema
    Additional description: Eczema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Calculus urinary
    Additional description: Calculus urinary
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Groin pain
    Additional description: Groin pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Myalgia
    Additional description: Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Metatarsalgia
    Additional description: Metatarsalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Arthralgia
    Additional description: Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    5
    2
    Bone pain
    Additional description: Bone pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
    Additional description: Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    0 / 7 (0.00%)
         occurrences all number
    5
    0
    Arthritis
    Additional description: Arthritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
    Additional description: Muscle spasms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 7 (14.29%)
         occurrences all number
    2
    1
    Pain in jaw
    Additional description: Pain in jaw
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Back pain
    Additional description: Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Neck pain
    Additional description: Neck pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Metapneumovirus infection
    Additional description: Metapneumovirus infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Oral candidiasis
    Additional description: Oral candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Rhinitis
    Additional description: Rhinitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Cellulitis
    Additional description: Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    COVID-19
    Additional description: COVID-19
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
    Additional description: Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
    Additional description: Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 24 (25.00%)
    1 / 7 (14.29%)
         occurrences all number
    8
    1
    Pneumocystis jirovecii pneumonia
    Additional description: Pneumocystis jirovecii pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
    Additional description: Herpes zoster
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    Oral herpes
    Additional description: Oral herpes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nail bed infection
    Additional description: Nail bed infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Influenza
    Additional description: Influenza
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Eye infection
    Additional description: Eye infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
    Additional description: Lower respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 7 (28.57%)
         occurrences all number
    1
    3
    Wound infection
    Additional description: Wound infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Nasopharyngitis
    Additional description: Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Gingivitis
    Additional description: Gingivitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Helicobacter gastritis
    Additional description: Helicobacter gastritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Neutropenic sepsis
    Additional description: Neutropenic sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypokalaemia
    Additional description: Hypokalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    Decreased appetite
    Additional description: Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 7 (14.29%)
         occurrences all number
    4
    2
    Hypoalbuminaemia
    Additional description: Hypoalbuminaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    Vitamin B12 deficiency
    Additional description: Vitamin B12 deficiency
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    Folate deficiency
    Additional description: Folate deficiency
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2017
    v1 - Addition of patient cards.
    20 Dec 2017
    v3 - Updated editions of investigator brochure for R-CHOP and Acalabrutinib. Updates to inclusion and exclusion criteria to add clarification. Tumour block hierarchy of testing clarified. List of prohibited proton pump inhibitors added as an appendix. Updated patient information sheets to detail prohibited medications.
    11 Jul 2018
    v4 - Updated editions of investigator brochure for acalabrutinib. Clarification of PET-CT requirements and permitted time windows for assessments in the protocol. Introduction of a centralised review of signed consent forms at the SCTU via nhs.net email. Introduction of a Tissue Block Screening Information Sheet and Consent Form to enable patient’s diagnostic tissue sample to be sent to HMDS in Leeds (central lab) prior to main study consent. Introduction of a Pregnant Partner Information Sheet and Consent Form. Addition of Pneumocystis jirovecii pneumonia (PCP) prophylaxis to the protocol. Amendments to the protocol and patient information sheets to meet GDPR requirements.
    13 Dec 2018
    v5 - Age restriction to exclude patients aged 65 and over introduced in line with urgent safety measure.
    04 Sep 2019
    v6 - Reversal of urgent safety measure to include patients aged 65 and over. Updated editions of investigator brochure for acalabrutinib and SmPCs for the components of R-CHOP. Removal of the optional BTK occupancy sub-study. Adverse events to be collected from date of consent. Permitted window introduced for end of treatment and follow up visits, as well as translational samples. Exclusion criteria updated to state patients taking a proton pump inhibitor should be switched to a short-acting H2-receptor antagonist or antacid prior to study entry. Supportive care updated to state GCSF support and infective prophylaxis are mandatory. Dose modification section updated in line with GCSF becoming mandatory. Contraception requirements clarified and a definition of women of childbearing potential added to the protocol. Overdose definition changed and reporting requirements clarified. Warnings and precautions related to acalabrutinib added. Suspected transmission of an infection agent via the study drug and potential drug induced liver injury added to safety reporting requirements. Pregnancy reporting requirements updated and pregnant partners information sheet and consent form amended to apply to both pregnant participants and partners of pregnant participants. Data sharing statement added. Clarification added that bidimensional measurements are expected for CT scans. Discrepancies between text and schedule of observations corrected for baseline blood tests. End of study date updated.
    16 Dec 2020
    v9 - Addition of Event-Free Survival and Time To Treatment Failure as secondary endpoints. Clarification of statistical analysis populations.

    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.
    N/A

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33093947
    For support, Contact us.
    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.

    European Medicines Agency © 1995-Sun May 25 11:06:46 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA