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    Clinical Trial Results:
    A randomized, double-blind Phase III study of copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin’s lymphoma (iNHL) - CHRONOS-2

    Summary
    EudraCT number
    		 2014-000925-19
    Trial protocol
    		 AT   IE   GR   PL   IT  
    Global end of trial date
    26 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Oct 2023
    First version publication date
    20 Oct 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY80-6946 / 17322
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02369016
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety of copanlisib.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Turkey: 2
    Worldwide total number of subjects
    25
    EEA total number of subjects
    7
    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)
    17
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 20 study centers in 10 countries/regions: Brazil (2), Bulgaria (1), Greece (1), Italy (2), Poland (1), Russian Federation (5), South Africa (1), South Korea (5), Taiwan (1) and Turkey (1) between 22 September 2015 (first patient first visit) and 26 October 2022 (last patient last visit).

    Pre-assignment
    Screening details
    		 34 participants were screened. 9 participants were screening failures and 25 participants were randomized to study treatment: 17 to copanlisib and 8 to placebo. All randomized participants also received at least one dose of study treatment and were valid for safety analyses. After study unblinding 7 placebo participants switched to copanlisib.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Copanlisib (BAY80-6946, Aliqopa)
    Arm description
    		 Participants who were randomized to copanlisib until end of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib 60 mg solution for infusion
    Investigational medicinal product code
    BAY80-6946
    Other name
    Aliqopa
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Copanlisib was administered IV over approximately 1 h on Days 1, 8, and 15 of each 28-day treatment cycle (3 weeks on/1 week off).

    Arm title
    		 Placebo
    Arm description
    		 Participants who were randomized to placebo until switching from placebo to copanlisib after disease progression or after study unblinding
    Arm type
    		 Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered IV over approximately 1 h on Days 1, 8, and 15 of each 28-day treatment cycle (3 weeks on/1 week off).

    Number of subjects in period 1
    		Copanlisib (BAY80-6946, Aliqopa) Placebo
    Started
    17
    8
    Completed
    0
    0
    Not completed
    17
    8
         AE associated with clinical disease progression
    2
    1
         AE not associated with clinical diseaseprogression
    4
    1
         Progressive disease - clinical progression
    1
    4
         withdrawal by patient
    4
    -
         Progressive disease - radiological progression
    6
    2

    Baseline characteristics

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

    Reporting group values
    		 overall Total
    Number of subjects
    		 25 25
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 17
        From 65-84 years
    		 8 8
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 17 17
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants with at least one administration of the study drug were included in the Safety analysis set.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who were randomized to the treatment arms at the start of the study were included in the FAS.

    Subject analysis set title
    Switched to copanlisib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who switched from placebo to copanlisib

    Subject analysis set title
    Treated with copanlisib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were treated with copanlisib (randomized to copanlisib + switched from placebo to copanlisib)

    Subject analysis sets values
    		 Safety analysis set Full analysis set Switched to copanlisib Treated with copanlisib
    Number of subjects
    25
    25
    7
    24
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    17
    17
    4
    16
        From 65-84 years
    8
    8
    3
    8
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    8
    8
    1
    8
        Male
    17
    17
    6
    16

    End points

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    End points reporting groups
    Reporting group title
    Copanlisib (BAY80-6946, Aliqopa)
    Reporting group description
    		 Participants who were randomized to copanlisib until end of the study

    Reporting group title
    Placebo
    Reporting group description
    		 Participants who were randomized to placebo until switching from placebo to copanlisib after disease progression or after study unblinding

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants with at least one administration of the study drug were included in the Safety analysis set.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who were randomized to the treatment arms at the start of the study were included in the FAS.

    Subject analysis set title
    Switched to copanlisib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who switched from placebo to copanlisib

    Subject analysis set title
    Treated with copanlisib
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were treated with copanlisib (randomized to copanlisib + switched from placebo to copanlisib)

    Primary: Number of participants with treatment-emergent adverse events (TEAE)s

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    End point title
    		 Number of participants with treatment-emergent adverse events (TEAE)s [1]
    End point description
    Adverse event data were collected after signing the informed consent until 30 days after the last study drug administration (end of safety follow-up)
    End point type
    Primary
    End point timeframe
    up to 7 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due the limited number of patients, statistical analyses included in this study focused on descriptive statistics only. Due to the short duration of placebo treatment before switching to copanlisib and the small number of patients receiving placebo, any comparisons between copanlisib and placebo treatment are not considered meaningful.
    End point values
    		 Copanlisib (BAY80-6946, Aliqopa) Placebo Switched to copanlisib Treated with copanlisib
    Number of subjects analysed
    17
    8
    7
    24
    Units: patients
    17
    7
    7
    24
    No statistical analyses for this end point

    Primary: Number of participants with treatment-emergent serious adverse events

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    End point title
    		 Number of participants with treatment-emergent serious adverse events [2]
    End point description
    Serious Adverse event data were collected after signing the informed consent until 30 days after the last study drug administration (end of safety follow-up)
    End point type
    Primary
    End point timeframe
    up to 7 years
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due the limited number of patients, statistical analyses included in this study focused on descriptive statistics only. Due to the short duration of placebo treatment before switching to copanlisib and the small number of patients receiving placebo, any comparisons between copanlisib and placebo treatment are not considered meaningful.
    End point values
    		 Copanlisib (BAY80-6946, Aliqopa) Placebo Switched to copanlisib Treated with copanlisib
    Number of subjects analysed
    17
    8
    7
    24
    Units: patients
    6
    1
    5
    11
    No statistical analyses for this end point

    Primary: Participants with abnormal laboratory parameters

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    End point title
    		 Participants with abnormal laboratory parameters [3]
    End point description
    - Above threshold 10% and reported as TEAEs - - any event grade 1-4 -
    End point type
    Primary
    End point timeframe
    up to 7 years
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due the limited number of patients, statistical analyses included in this study focused on descriptive statistics only. Due to the short duration of placebo treatment before switching to copanlisib and the small number of patients receiving placebo, any comparisons between copanlisib and placebo treatment are not considered meaningful.
    End point values
    		 Copanlisib (BAY80-6946, Aliqopa) Placebo Switched to copanlisib Treated with copanlisib
    Number of subjects analysed
    17
    8
    7
    24
    Units: patients
        ANY
    9
    1
    3
    12
        Hyperglycaemia
    6
    0
    4
    10
        Neutropenia
    6
    0
    1
    7
        Neutrophil count decreased
    4
    0
    2
    6
        Anaemia
    2
    2
    4
    6
        Platelet count decreased
    3
    0
    2
    5
    No statistical analyses for this end point

    Primary: Participants with abnormal vital signs

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    End point title
    		 Participants with abnormal vital signs [4]
    End point description
    - Reported as TEAEs - worst CTCAE grade 'total' -
    End point type
    Primary
    End point timeframe
    up to 7 years
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due the limited number of patients, statistical analyses included in this study focused on descriptive statistics only. Due to the short duration of placebo treatment before switching to copanlisib and the small number of patients receiving placebo, any comparisons between copanlisib and placebo treatment are not considered meaningful.
    End point values
    		 Copanlisib (BAY80-6946, Aliqopa) Placebo Switched to copanlisib Treated with copanlisib
    Number of subjects analysed
    17
    8
    7
    24
    Units: patients
        Blood pressure increased
    2
    0
    1
    3
        Electrocardiogram QT prolonged
    1
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from the start of study drug administration until 30 days after the last study drug administraion, up to end of safety follow-up, approximately 7 years
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Randomized to copanlisib
    Reporting group description
    		 Participants who were randomized to copanlisib and continued copanlisib treatment after study unbilnding (randomized to copanlisib group)

    Reporting group title
    Randomized to placebo
    Reporting group description
    		 Participants who were randomized to placebo until switching from placebo to copanlsib after disease progression or after study unblinding

    Reporting group title
    Switched to copanlisib
    Reporting group description
    		 Participants who switched from placebo to copanlisib

    Reporting group title
    Treated with copanlisib
    Reporting group description
    		 Participants who were treated with copanlisib (randomized to copanlisib + switched from placebo to copanlisib)

    Serious adverse events
    		 Randomized to copanlisib Randomized to placebo Switched to copanlisib Treated with copanlisib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 17 (35.29%)
    1 / 8 (12.50%)
    5 / 7 (71.43%)
    11 / 24 (45.83%)
         number of deaths (all causes)
    2
    1
    2
    4
         number of deaths resulting from adverse events
    0
    0
    2
    2
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomized to copanlisib Randomized to placebo Switched to copanlisib Treated with copanlisib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    7 / 8 (87.50%)
    7 / 7 (100.00%)
    24 / 24 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cancer pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
    5 / 24 (20.83%)
         occurrences all number
    32
    1
    19
    51
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    General disorders and administration site conditions
    Extravasation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    2
    2
    Fatigue
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 24 (8.33%)
         occurrences all number
    3
    0
    1
    4
    Pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Injection site irritation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
    3 / 7 (42.86%)
    5 / 24 (20.83%)
         occurrences all number
    6
    0
    4
    10
    General physical health deterioration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Immunodeficiency common variable
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
    5 / 24 (20.83%)
         occurrences all number
    3
    1
    4
    7
    Catarrh
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Organising pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Sinus pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    2
    0
    0
    2
    Productive cough
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 8 (25.00%)
    1 / 7 (14.29%)
    2 / 24 (8.33%)
         occurrences all number
    5
    3
    1
    6
    Lung disorder
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    3 / 24 (12.50%)
         occurrences all number
    1
    0
    2
    3
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Restlessness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Insomnia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    3 / 24 (12.50%)
         occurrences all number
    2
    0
    1
    3
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    3 / 24 (12.50%)
         occurrences all number
    12
    0
    7
    19
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    5 / 24 (20.83%)
         occurrences all number
    5
    0
    4
    9
    Neutrophil count decreased
         subjects affected / exposed
    4 / 17 (23.53%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    6 / 24 (25.00%)
         occurrences all number
    9
    0
    4
    13
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Weight increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    3 / 24 (12.50%)
         occurrences all number
    4
    1
    1
    5
    Lipase increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Accidental overdose
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    6
    3
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    4 / 24 (16.67%)
         occurrences all number
    5
    0
    1
    6
    Dizziness
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    8
    1
    0
    8
    Ataxia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle contractions involuntary
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    4
    0
    0
    4
    Somnolence
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 24 (8.33%)
         occurrences all number
    1
    0
    1
    2
    Neuralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Tremor
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    6 / 17 (35.29%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    7 / 24 (29.17%)
         occurrences all number
    14
    0
    4
    18
    Thrombocytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    3 / 24 (12.50%)
         occurrences all number
    1
    0
    2
    3
    Lymphopenia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    11
    0
    0
    11
    Anaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 8 (25.00%)
    4 / 7 (57.14%)
    6 / 24 (25.00%)
         occurrences all number
    2
    2
    11
    13
    Hyperviscosity syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    0
    1
    Ear and labyrinth disorders
    External ear inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    2 / 24 (8.33%)
         occurrences all number
    1
    1
    1
    2
    Abdominal pain
         subjects affected / exposed
    2 / 17 (11.76%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Anal fissure
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dental caries
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    4 / 24 (16.67%)
         occurrences all number
    12
    0
    6
    18
    Dyspepsia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    2
    2
    Gastric ulcer
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    2
    0
    0
    2
    Gastritis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Gastrointestinal pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Gingival pain
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    3 / 24 (12.50%)
         occurrences all number
    2
    0
    1
    3
    Haemorrhoids
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Stomatitis
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    5 / 24 (20.83%)
         occurrences all number
    5
    0
    2
    7
    Proctalgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Nausea
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    6
    1
    0
    6
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Dry skin
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Dermatitis bullous
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Dermatitis atopic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Paraneoplastic rash
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    3
    0
    0
    3
    Skin ulcer
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    1
    1
    Skin reaction
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    1
    1
    Joint contracture
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Muscular weakness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    3
    0
    0
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Cellulitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 24 (8.33%)
         occurrences all number
    1
    0
    1
    2
    Herpes simplex
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    3 / 24 (12.50%)
         occurrences all number
    1
    0
    2
    3
    Periodontitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Scrub typhus
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 24 (8.33%)
         occurrences all number
    3
    0
    2
    5
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    3 / 7 (42.86%)
    4 / 24 (16.67%)
         occurrences all number
    1
    0
    4
    5
    Urinary tract infection
         subjects affected / exposed
    3 / 17 (17.65%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    3
    1
    0
    3
    Oral infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Alveolar osteitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Herpes zoster reactivation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    3
    1
    0
    3
    Hypermagnesaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    6 / 17 (35.29%)
    0 / 8 (0.00%)
    4 / 7 (57.14%)
    10 / 24 (41.67%)
         occurrences all number
    107
    0
    59
    166
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Cachexia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    2 / 7 (28.57%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    3
    3
    Hypomagnesaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 24 (8.33%)
         occurrences all number
    2
    0
    1
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    3
    3
    Lactic acidosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    1
    1
    Decreased appetite
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    3 / 24 (12.50%)
         occurrences all number
    2
    1
    1
    3
    Dyslipidaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Nov 2014
    • Several inclusion/exclusion and withdrawal criteria were modified. • The study target population for efficacy analysis was changed from iNHL to FL patients. • Randomization ratio was changed from 1:1 to 2:1 and prior treatment with PI3K inhibitors was added as a new stratification factor. • Time to improvement in disease-related symptoms physical (subscale) (DRS-P) and secondary PFS (PFS2) were added as efficacy variables.
    16 Feb 2016
    • Several inclusion/exclusion criteria were modified. • Guidance for the management of noninfectious pneumonitis (NIP), glucose and BP increases were updated.
    21 Jul 2016
    • Several inclusion/exclusion criteria were modified. • Withdrawal criteria of study treatment due to cytomegalovirus (CMV) infection was added. • Guidance for monitoring and prophylaxis of opportunistic infections was added.
    31 Mar 2017
    Changes were made following the sponsor’s decision to stop enrollment due to a lack of feasibility to complete this study in a reasonable time frame: • Study design was modified from a randomized, double-blind, placebo-controlled study to an open-label, single arm study. • Statistical analyses and efficacy endpoints were revised. Primary efficacy endpoint was changed from PFS to objective response rate and several secondary efficacy endpoints were removed. • Central imaging review was removed, and bone marrow biopsy was changed to local standard of care.
    01 Dec 2017
    The study design was further modified due to the limited number of participants to be included in the analyses: • Primary endpoint was changed to safety and other study objectives were removed. • Active and survival follow-up periods were removed. • Several withdrawal criteria were modified. • Timing of statistical analysis and guidance for tumor assessments were changed.

    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.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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