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    Clinical Trial Results:
    Phase 1/2 Study of Intratumoral G100 with or without Pembrolizumab or Rituximab in Patients with Follicular Non-Hodgkin’s Lymphoma

    Summary
    EudraCT number
    2015-005382-23
    Trial protocol
    GB   ES   FR  
    Global end of trial date
    01 Aug 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Aug 2020
    First version publication date
    12 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-3475-174 (IMDZ-G142)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02501473
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    01 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This is a Phase 1/2 open label trial of G100 in participants with low grade Non-Hodgkin's Lymphoma (NHL). G100 is composed of glucopranosyl lipid A in a stable emulsion and is a potent TLR4 (toll-like receptor-4) agonist. G100 will be administered by direct injection (intratumorally) into tumors of low grade NHL with or without standard low dose radiation therapy. Preclinical models and clinical studies in other cancers such as Merkel cell carcinoma have demonstrated that G100 administered in this manner can alter the tumor microenvironment, activate dendritic cells, T cells and other immune cells and induce systemic anti-tumor immune responses. In this trial, the safety, immunogenicity, and preliminary clinical efficacy of G100 will be examined alone or with pembrolizumab.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Feb 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    16 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Spain: 8
    Worldwide total number of subjects
    52
    EEA total number of subjects
    11
    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)
    31
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled in the study at clinical sites in the United States and Europe.

    Pre-assignment
    Screening details
    Part 5, G100 plus Rituximab, Dose Escalation: 12 to 24 participants were planned; no participant was enrolled or dosed.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 1: Local Radiation + G100 5μg/lesion
    Arm description
    Part 1: Local radiation and G100 [glucopyranosyl lipid A stable emulsion, GLA-SE] at 5μg/lesion administered intratumoral (IT) into accessible lesions for up to 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    G100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    G100 [glucopyranosyl lipid A stable emulsion, GLA-SE] at 5μg/lesion administered intratumoral (IT) into accessible lesions for up to 8 weeks.

    Investigational medicinal product name
    Local radiation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Local use
    Dosage and administration details
    Radiation of a tumor in the radiation field on Day 1.

    Arm title
    Part 1: Local Radiation + G100 10μg/lesion
    Arm description
    Part 1: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Local radiation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Local use
    Dosage and administration details
    Radiation of a tumor in the radiation field on Day 1.

    Investigational medicinal product name
    G100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Arm title
    Part 2: Local Radiation + G100 10μg/lesion
    Arm description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Local radiation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Local use
    Dosage and administration details
    Radiation of a tumor in the radiation field on Day 1.

    Investigational medicinal product name
    G100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Arm title
    Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg
    Arm description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible tumors for up to 8 weeks; pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.
    Arm type
    Experimental

    Investigational medicinal product name
    G100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

    Investigational medicinal product name
    Local radiation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Local use
    Dosage and administration details
    Radiation of a tumor in the radiation field on Day 1.

    Arm title
    Part 2: Local Radiation, G100 20μg/lesion in Large Tumors
    Arm description
    Part 2: Local radiation and G100 at 20μg/lesion administered IT into accessible large tumors (injectable lymphoma mass(es) ≥ 4 cm in total size) for up to 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Local radiation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Local use
    Dosage and administration details
    Radiation of a tumor in the radiation field on Day 1.

    Investigational medicinal product name
    G100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    G100 at 20 μg/lesion administered IT into accessible large tumors (injectable lymphoma mass(es) ≥ 4 cm in total size) for up to 8 weeks.

    Arm title
    Part 3: Local Radiation + G100 20μg/lesion
    Arm description
    Part 3: Local radiation and G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    G100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Investigational medicinal product name
    Local radiation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radionuclide generator
    Routes of administration
    Local use
    Dosage and administration details
    Radiation of a tumor in the radiation field on Day 1.

    Arm title
    Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Arm description
    Part 4: G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks and Pembrolizumab 200mg IV and administered Q3W for up to 2 years.
    Arm type
    Experimental

    Investigational medicinal product name
    Pembrolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

    Investigational medicinal product name
    G100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intratumoral use
    Dosage and administration details
    G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Number of subjects in period 1
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Started
    3
    3
    13
    14
    4
    14
    1
    Treated
    3
    3
    13
    13
    4
    14
    1
    Completed
    0
    0
    0
    0
    0
    0
    0
    Not completed
    3
    3
    13
    14
    4
    14
    1
         Study Terminated
    2
    3
    7
    9
    2
    10
    1
         Adverse event, serious fatal
    -
    -
    1
    1
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    3
    3
    2
    2
    -
         Reason not specified
    -
    -
    1
    1
    -
    -
    -
         Lost to follow-up
    1
    -
    1
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Local Radiation + G100 5μg/lesion
    Reporting group description
    Part 1: Local radiation and G100 [glucopyranosyl lipid A stable emulsion, GLA-SE] at 5μg/lesion administered intratumoral (IT) into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 1: Local Radiation + G100 10μg/lesion
    Reporting group description
    Part 1: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 2: Local Radiation + G100 10μg/lesion
    Reporting group description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg
    Reporting group description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible tumors for up to 8 weeks; pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

    Reporting group title
    Part 2: Local Radiation, G100 20μg/lesion in Large Tumors
    Reporting group description
    Part 2: Local radiation and G100 at 20μg/lesion administered IT into accessible large tumors (injectable lymphoma mass(es) ≥ 4 cm in total size) for up to 8 weeks.

    Reporting group title
    Part 3: Local Radiation + G100 20μg/lesion
    Reporting group description
    Part 3: Local radiation and G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Reporting group description
    Part 4: G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks and Pembrolizumab 200mg IV and administered Q3W for up to 2 years.

    Reporting group values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg Total
    Number of subjects
    3 3 13 14 4 14 1 52
    Age categorical
    There was no enrollment in Part 5.
    Units: Subjects
        In utero
    0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0 0
        Adults (18-64 years)
    2 2 6 10 3 8 0 31
        From 65-84 years
    1 1 7 4 1 6 1 21
        85 years and over
    0 0 0 0 0 0 0 0
    Age Continuous
    Age not reported for the participant in Part 4 due to risk of identification of a person. No participants were enrolled in Part 5.
    Units: years
        arithmetic mean (standard deviation)
    54.0 ± 13.45 56.3 ± 16.07 60.2 ± 10.26 57.6 ± 10.98 59.3 ± 5.85 63.9 ± 8.74 0 ± 0 -
    Sex: Female, Male
    No participants enrolled in Part 5.
    Units: Participants
        Female
    1 2 3 3 1 5 1 16
        Male
    2 1 10 11 3 9 0 36
    Race (NIH/OMB)
    No participants enrolled in Part 5.
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0 0 0 0 0
        Asian
    0 0 0 0 1 0 0 1
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0 0 0
        Black or African American
    0 0 1 0 0 1 0 2
        White
    2 3 11 13 2 12 1 44
        More than one race
    0 0 0 0 0 0 0 0
        Unknown or Not Reported
    1 0 1 1 1 1 0 5
    Ethnicity (NIH/OMB)
    No participants enrolled in Part 5.
    Units: Subjects
        Hispanic or Latino
    0 1 1 3 0 0 0 5
        Not Hispanic or Latino
    2 2 12 11 4 13 1 45
        Unknown or Not Reported
    1 0 0 0 0 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Local Radiation + G100 5μg/lesion
    Reporting group description
    Part 1: Local radiation and G100 [glucopyranosyl lipid A stable emulsion, GLA-SE] at 5μg/lesion administered intratumoral (IT) into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 1: Local Radiation + G100 10μg/lesion
    Reporting group description
    Part 1: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 2: Local Radiation + G100 10μg/lesion
    Reporting group description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg
    Reporting group description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible tumors for up to 8 weeks; pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

    Reporting group title
    Part 2: Local Radiation, G100 20μg/lesion in Large Tumors
    Reporting group description
    Part 2: Local radiation and G100 at 20μg/lesion administered IT into accessible large tumors (injectable lymphoma mass(es) ≥ 4 cm in total size) for up to 8 weeks.

    Reporting group title
    Part 3: Local Radiation + G100 20μg/lesion
    Reporting group description
    Part 3: Local radiation and G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Reporting group description
    Part 4: G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks and Pembrolizumab 200mg IV and administered Q3W for up to 2 years.

    Primary: Number of Participants with an Adverse Event (AE)

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    End point title
    Number of Participants with an Adverse Event (AE) [1]
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation.
    End point type
    Primary
    End point timeframe
    Up to approximately 42 months
    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: No statistical analysis was planned or performed for this endpoint.
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    13
    13
    4
    14
    1
    Units: Participants
    3
    3
    13
    13
    4
    14
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued Study Drug Due to an Adverse Event

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    End point title
    Number of Participants Who Discontinued Study Drug Due to an Adverse Event [2]
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation.
    End point type
    Primary
    End point timeframe
    Up to approximately 105 weeks
    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: No statistical analysis was planned or performed for this endpoint.
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    13
    13
    4
    14
    1
    Units: Participants
    0
    0
    0
    2
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR) by Immune-related Response Criteria (irRC)

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    End point title
    Overall Response Rate (ORR) by Immune-related Response Criteria (irRC)
    End point description
    Overall response rate was defined as participants with best overall response of immune-related complete response (irCR) or immune-related partial response (irPR). irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new lesions add to tumor size calculations are not determinants of progressive disease by themselves. An irCR is the disappearance of all lesions, and no new lesions; an irPR is a ≥50% drop in tumour burden from baseline; and immune related Progressive Disease (irPD) is a ≥25% increase in tumour burden from the lowest level recorded. Everything else is considered immune-related Stable Disease (irSD). Tumor staging using bi-dimensional measurements was performed by CT or MRI. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    13
    13
    4
    14
    1
    Units: Participants
        Complete Response (irCR)
    0
    0
    0
    0
    0
    0
    0
        Partial Response (irPR)
    1
    2
    3
    6
    1
    6
    0
        Stable Disease (irSD)
    2
    1
    8
    6
    3
    7
    1
        Progressive Disease (irPD)
    0
    0
    2
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Using Immune-related Response Criteria (irRC)

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    End point title
    Clinical Benefit Rate (CBR) Using Immune-related Response Criteria (irRC)
    End point description
    Clinical benefit rate (CBR) was defined as the number and percent of participants with best overall response of Immune related Response Criteria (irRC); complete response, partial response or stable disease (irCR+irPR+irSD). irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new lesions add to tumor size calculations and are not determinants of progressive disease by themselves. irCR is the disappearance of all lesions, and no new lesions; irPR is a ≥50% drop in tumor burden from baseline; and immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Everything else is considered irSD. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    13
    13
    4
    14
    1
    Units: Percent of participants
        number (confidence interval 95%)
    100 (29.2 to 100)
    100 (29.2 to 100)
    84.6 (54.6 to 98.1)
    92.3 (64.0 to 99.8)
    100 (39.8 to 100)
    92.9 (66.1 to 99.8)
    100 (2.5 to 100)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Using International Working Group (IWG) Criteria

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    End point title
    Clinical Benefit Rate (CBR) Using International Working Group (IWG) Criteria
    End point description
    Clinical benefit rate (CBR) was all participants with best overall response of complete response, partial response or stable disease (CR+PR+SD). The IWG criteria (Cheson et al 2014) for a CR is a complete radiologic response (target nodes/nodal masses must regress to ≤ 1.5 cm in longest transverse diameter (LDi), no extralymphatic sites of disease, and no new tumors. A PR is a ≥ 50% decrease in SPD (sum of the product of the perpendicular diameters for multiple tumors) of up to 6 target measurable nodes and extranodal sites, spleen must have regressed by > 50% in length beyond normal, and no new tumors. Stable disease is a < 50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites; no criteria for progressive disease are met, and no new tumors. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    13
    13
    4
    14
    1
    Units: Percentage of participants
        number (confidence interval 95%)
    100 (29.2 to 100)
    100 (29.2 to 100)
    84.6 (54.6 to 98.1)
    92.3 (64.0 to 99.8)
    100 (39.8 to 100)
    78.6 (49.2 to 95.3)
    100 (2.5 to 100)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) by Immune-related Response Criteria (irRC)

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    End point title
    Duration of Response (DOR) by Immune-related Response Criteria (irRC)
    End point description
    Duration of response (DOR) was defined as the time interval between the date of the earliest qualifying confirmed/unconfirmed response using irRC and the date of disease progression (PD) or death for any cause, whichever occurs first. DOR in months was calculated as: (date of PD or death minus date of first confirmed/unconfirmed irCR/CR or irPR/PR + 1)/30.4375. DOR analysis included only participants with confirmed/unconfirmed response of irCR/irPR using irRC. Immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Median DOR with the corresponding two-sided 95% CI was estimated using the Kaplan-Meier method in each treatment group. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation and had a confirmed/unconfirmed response of irCR/irPR using irRC.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    1
    1
    3 [3]
    4
    1 [4]
    5
    0 [5]
    Units: Months
        median (full range (min-max))
    1.8 (1.8 to 1.8)
    15.6 (15.6 to 15.6)
    9999 (9999 to 9999)
    18.4 (3.8 to 27.2)
    9999 (9999 to 9999)
    5.6 (2.8 to 16.1)
    ( to )
    Notes
    [3] - "9999" - Median DOR was not reached by the time of last disease assessment.
    [4] - "9999" - Median DOR min./max. was not reached by the time of last disease assessment.
    [5] - No DOR data was available for this participant.
    No statistical analyses for this end point

    Secondary: Duration of Clinical Benefit by Immune-related Response Criteria (irRC)

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    End point title
    Duration of Clinical Benefit by Immune-related Response Criteria (irRC)
    End point description
    Duration of clinical benefit was defined as the time interval between the date of the earliest qualifying confirmed/unconfirmed best response using irRC and the date of progressive disease (PD) or death for any cause, whichever occurred first. Duration of clinical benefit in months was calculated as: (date of PD or death – date of first confirmed/unconfirmed irCR/irPR or irSD + 1)/30.4375. Duration of clinical benefit included only participants with confirmed/unconfirmed response of irCR/irPR or irSD using irRC. Participants without progression, symptomatic deterioration, or death were censored at the date of the last tumor assessment. Median duration of clinical benefit and 95% CI were estimated using the Kaplan Meier method. The analysis population included all enrolled participants who received at least 1 injection of G100 after standard local radiation and had a confirmed/unconfirmed response of irCR/irPR or irSD using irRC.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    11
    12
    4
    13
    0 [6]
    Units: Months
        median (full range (min-max))
    2.5 (1.8 to 3.4)
    20.8 (0.0 to 26.0)
    6.9 (0.0 to 16.2)
    9.2 (2.8 to 27.2)
    7.2 (0.0 to 20.1)
    4.3 (0.0 to 20.0)
    ( to )
    Notes
    [6] - No Duration of Clinical Benefit data was available for this participant.
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) by Immune-related Response Criteria (irRC)

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    End point title
    Progression-free Survival (PFS) by Immune-related Response Criteria (irRC)
    End point description
    PFS was defined as time from date of first study treatment to date of first disease progression (a ≥25% increase in tumor burden from the lowest level recorded) by irRC criteria, symptomatic deterioration, or death due to any cause, whichever occurred first. Participants without progression, symptomatic deterioration, or death were censored at the date of the last tumor assessment. Progression-free survival in months is calculated as: (date of first progression, symptomatic deterioration, or death [any reason] – date of first dose +1)/30.4375. The irRC modification required a PD confirmation no less than 4 weeks from first documentation of PD. Summary of PFS including median, 95% CI was estimated using the Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    13
    13
    4
    14
    1 [7]
    Units: Months
        median (full range (min-max))
    4.9 (3.7 to 5.3)
    22.6 (1.9 to 27.7)
    7.4 (1.7 to 33.7)
    11.1 (1.9 to 32.5)
    9.8 (1.9 to 21.9)
    7.7 (1.4 to 22.6)
    9999 (9999 to 9999)
    Notes
    [7] - "9999" - median PFS was not reached (no disease progression or death).
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall Survival (OS) was defined as the time from date of first study treatment to death due to any cause. Overall survival in months was calculated as: ([date of death – date of first dose] +1)/30.4375. Participants who were alive at the end of study were censored at the last date the participant was known to be alive or data analysis cutoff date, whichever was earlier. Summary of OS including median, 95% CI was estimated using the Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3 [8]
    3 [9]
    13 [10]
    13 [11]
    4 [12]
    14 [13]
    1 [14]
    Units: Months
        median (full range (min-max))
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [8] - "9999" - median OS was not reached (insufficient number of deaths).
    [9] - "9999" - median OS was not reached (insufficient number of deaths).
    [10] - "9999" - median OS was not reached (insufficient number of deaths).
    [11] - "9999" - median OS was not reached (insufficient number of deaths).
    [12] - "9999" - median OS was not reached (insufficient number of deaths).
    [13] - "9999" - median OS was not reached (insufficient number of deaths).
    [14] - "9999" - median OS was not reached (insufficient number of deaths).
    No statistical analyses for this end point

    Secondary: Overall Tumor Response Based on irRC Abscopal Sites

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    End point title
    Overall Tumor Response Based on irRC Abscopal Sites
    End point description
    Abscopal tumor responses were assessed in non-treated, distal tumor sites. Immune-related Response Criteria irRC requires confirmatory restaging to determine if tumor size increase is due to true progression instead of immune inflammation and that new lesions add to tumor size calculations are not determinants of progressive disease. An immune-related Complete Response (irCR) is the disappearance of all lesions, and no new lesions; an immune-related Partial Response (irPR) is a ≥50% drop in tumour burden from baseline; and immune related Progressive Disease (irPD) is a ≥25% increase in tumour burden from the lowest level recorded. Everything else was considered immune-related Stable Disease (irSD). Tumor staging by CT or MRI was performed. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    3
    13
    13
    4
    14
    1
    Units: Participants
        Complete Response (irCR)
    0
    0
    0
    0
    0
    0
    0
        Partial Response (irPR)
    0
    1
    4
    3
    0
    3
    0
        Stable Disease (irSD)
    1
    2
    4
    8
    3
    9
    1
        Progressive Disease (irPD)
    1
    0
    4
    2
    1
    2
    0
    No statistical analyses for this end point

    Secondary: Time to Response for Complete Response and Partial Response Participants

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    End point title
    Time to Response for Complete Response and Partial Response Participants
    End point description
    Time to Response for CR and PR participants was defined as time from date of first study treatment to the date of CR or PR response first documented. Complete Response (irCR) is the disappearance of all lesions, and no new lesions; an immune-related Partial Response (irPR) is a ≥50% drop in tumor burden from baseline. Time to response in months was calculated as: (date of first CR or PR minus date of first dose +1)/30.4375. Summary of Time to Response including median and range was estimated using Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    1
    2
    3
    6
    1
    6
    0 [15]
    Units: Months
        median (full range (min-max))
    1.9 (1.9 to 1.9)
    1.9 (1.9 to 1.9)
    2.3 (1.7 to 18.1)
    4.1 (2.2 to 14.1)
    2.6 (2.6 to 2.6)
    5.2 (1.9 to 7.3)
    ( to )
    Notes
    [15] - No Time to Response data was available for this participant.
    No statistical analyses for this end point

    Secondary: Time to Next Treatment (TTNT)

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    End point title
    Time to Next Treatment (TTNT)
    End point description
    Time to next treatment was defined as the time from the date of first study treatment to the start date of subsequent therapy after PD. Immune-related Progressive Disease (irPD) is a ≥25% increase in tumor burden from the lowest level recorded. Participants who did not receive subsequent therapy after PD were censored at the date of last contact or death. Summary of time to next treatment including median and range was estimated using the Kaplan-Meier method. The analysis population included all enrolled participants without major protocol deviations, who received at least 1 injection of G100, and had baseline and at least 1 post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 42 months
    End point values
    Part 1: Local Radiation + G100 5μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20μg/lesion in Large Tumors Part 3: Local Radiation + G100 20μg/lesion Part 4: G100 20μg/lesion and Pembrolizumab 200mg
    Number of subjects analysed
    3
    1 [16]
    8
    6 [17]
    1 [18]
    6 [19]
    0 [20]
    Units: Months
        median (full range (min-max))
    5.4 (4.1 to 6.6)
    9999 (9999 to 9999)
    12.7 (1.9 to 33.7)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    ( to )
    Notes
    [16] - "9999" - median TTNT was not reached (insufficient number of treatments by time of last assessment).
    [17] - "9999" - median was not reached (insufficient number of treatments by time of last assessment).
    [18] - "9999" - median TTNT was not reached (insufficient number of treatments by time of last assessment).
    [19] - "9999" - median TTNT was not reached (insufficient number of treatments by time of last assessment).
    [20] - This participant did not have irPD data.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 42 months
    Adverse event reporting additional description
    The analysis population included all treated participants. Medical Dictionary for Regulatory Activities (MedDRA) terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" not related to study treatment were excluded as AEs as considered due to cancer progression. No participant was enrolled or dosed in Part 5.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Part 2: Local Radiation + G100 10μg/lesion
    Reporting group description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 1: Local Radiation + G100 10μg/lesion
    Reporting group description
    Part 1 + Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 1: Local Radiation + G100 5μg/lesion
    Reporting group description
    Part 1: Local radiation and G100 [glucopyranosyl lipid A stable emulsion, GLA-SE] at 5μg/lesion administered intratumoral (IT) into accessible lesions for up to 8 weeks.

    Reporting group title
    Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg
    Reporting group description
    Part 2: Local radiation and G100 at 10μg/lesion administered IT into accessible tumors for up to 8 weeks; pembrolizumab 200mg intravenously (IV) administered every 3 weeks (Q3W) IV for up to 2 years.

    Reporting group title
    Part 2: Local Radiation, G100 20 μg/lesion in Large Tumors
    Reporting group description
    Part 2: Local radiation and G100 at 20 μg/lesion administered IT into accessible large tumors (injectable lymphoma mass(es) ≥ 4 cm in total size) for up to 8 weeks.

    Reporting group title
    Part 4: G100 20μg/lesion and pembrolizumab 200mg
    Reporting group description
    Part 4: G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks and pembrolizumab 200mg IV and administered Q3W for up to 2 years.

    Reporting group title
    Part 3: Local Radiation + G100 20μg/lesion
    Reporting group description
    Part 3: Local radiation and G100 at 20μg/lesion administered IT into accessible lesions for up to 8 weeks.

    Serious adverse events
    Part 2: Local Radiation + G100 10μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 1: Local Radiation + G100 5μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20 μg/lesion in Large Tumors Part 4: G100 20μg/lesion and pembrolizumab 200mg Part 3: Local Radiation + G100 20μg/lesion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    1
    0
    0
    1
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Multiple fractures
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 2: Local Radiation + G100 10μg/lesion Part 1: Local Radiation + G100 10μg/lesion Part 1: Local Radiation + G100 5μg/lesion Part 2: Local Radiation + G100 10μg/lesion+Pembrolizumab 200mg Part 2: Local Radiation, G100 20 μg/lesion in Large Tumors Part 4: G100 20μg/lesion and pembrolizumab 200mg Part 3: Local Radiation + G100 20μg/lesion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    13 / 13 (100.00%)
    4 / 4 (100.00%)
    1 / 1 (100.00%)
    14 / 14 (100.00%)
    Vascular disorders
    Diastolic hypertension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Embolism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Flushing
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    0
    4
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Systolic hypertension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Varicose vein
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Administration site pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    7
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    3
    Fatigue
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    4 / 13 (30.77%)
    2 / 4 (50.00%)
    1 / 1 (100.00%)
    3 / 14 (21.43%)
         occurrences all number
    0
    2
    1
    4
    2
    1
    3
    Feeling hot
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    2
    Infusion site swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Injection site bruising
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    Injection site discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Injection site pain
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    5
    0
    0
    1
    0
    0
    3
    Injection site reaction
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    5
    1
    0
    4
    0
    0
    8
    Injection site swelling
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    3
    Peripheral swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Libido decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Epididymal cyst
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Oedema genital
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Testicular atrophy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Testis discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Vulvovaginal inflammation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Expired product administered
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    Radiation associated pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Radiation skin injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    1
    0
    5
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    Blast cell count increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    5
    2
    0
    0
    Blood bilirubin decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    5
    Blood creatinine decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    3
    Blood glucose increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Breath sounds abnormal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Haemoglobin increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    3
    1
    0
    0
    1
    0
    6
    Neutrophil count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    2
    Platelet count decreased
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    4
    1
    0
    1
    0
    0
    1
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Myocardial fibrosis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    0
    5
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    0
    4
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    4 / 13 (30.77%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Throat irritation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 13 (15.38%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    1
    3
    4
    0
    0
    Blood loss anaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Leukopenia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Lymph node pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    1
    0
    3
    0
    0
    3
    Dysgeusia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Nystagmus
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Eyelid ptosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 13 (15.38%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    2
    0
    1
    4
    3
    0
    2
    Colitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    2
    0
    0
    4
    0
    0
    2
    Dyspepsia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Hiatus hernia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    6 / 13 (46.15%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    3 / 14 (21.43%)
         occurrences all number
    2
    0
    0
    7
    2
    0
    4
    Rectal tenesmus
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hydronephrosis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    1 / 1 (100.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Night sweats
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    0
    Rash
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    5
    0
    0
    0
    Rash papular
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Skin discolouration
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin reaction
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Skin texture abnormal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Back pain
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    1
    Bone pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Gouty arthritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    3
    Pain in extremity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    2 / 4 (50.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    2
    0
    0
    Plantar fasciitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    3
    0
    0
    5
    0
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    2 / 14 (14.29%)
         occurrences all number
    0
    0
    0
    0
    7
    0
    2
    Hyperlipidaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    0
    0
    Infections and infestations
    Candida infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Helicobacter duodenitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    0
    0
    Oesophagitis bacterial
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    0 / 14 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 4 (25.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    5
    0
    0
    2
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
    0 / 1 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2015
    AM1 - This amendment added a treatment arm to Part 2 Patient Expansion to examine the sequential addition of anti-PD1 antibody pembrolizumab to intratumoral G100.
    05 Jan 2017
    AM3 - Added Part 3 G100 20μg Dose Expansion arm to allow for up to 25 participants at the 20μg dose using the same tumor size entrance criteria as the other non-Large Tumor arms.
    31 Jul 2018
    AM4 - Added Part 4, a new dose escalation and expansion arm to examine G100 20μg in combination with pembrolizumab in relapsed or refractory follicular lymphoma without radiation therapy in single and multiple tumor lesions. Added Part 5, a new dose escalation and expansion to examine the safety and preliminary clinical efficacy of G100 in combination with rituximab in follicular lymphoma.
    31 Aug 2018
    AM4A - Revised the Inclusion criteria for Part 4 to only include participants with relapsed or refractory disease after ≥3 prior therapies. Part 5 was revised to limit the intratumoral G100 treatment to a single tumor mass during Patient Expansion.
    15 Nov 2018
    AM4B - An exploratory objective of evaluating Pharmacokinetics and Pharmacodynamic properties of G100 and appropriate sample collection were added. Dose limiting toxicity criteria for Parts 4 and 5 were added.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Jun 2019
    The trial was terminated (Halted Prematurely) for business reasons.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Part 5, G100 plus Rituximab, Dose Escalation: 12 to 24 participants were planned; no participant was enrolled or dosed. The trial was terminated (Halted Prematurely) for business reasons.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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