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    Clinical Trial Results:
    A Phase II, global, randomized study to evaluate the efficacy and safety of Danirixin (GSK1325756) co-administered with a standard-of-care antiviral (oseltamivir), in the treatment of adults hospitalized with influenza

    Summary
    EudraCT number
    		 2016-002512-40
    Trial protocol
    		 SE   ES   NL   FR  
    Global end of trial date
    24 May 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    28 Jun 2018
    First version publication date
    04 May 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    201023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    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
    27 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of treatment with IV DNX twice daily given with oral oseltamivir compared to oral oseltamivir twice daily on time to clinical response (TTCR)
    Protection of trial subjects
    Not Applicable.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    10
    EEA total number of subjects
    2
    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)
    4
    From 65 to 84 years
    5
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized study to evaluate the efficacy and safety of Danirixin (DNX) co-administered with a standard-of-care antiviral (oseltamivir [OSV]), in the treatment of adults hospitalized with influenza. The study enrolled participants in 7 centers across 3 countries (Romania,Sweden and United States) and was terminated due to poor enrollment

    Pre-assignment
    Screening details
    		 A total of 14 participants were screened for the study, of which 4 participants were screening failures. 10 participants received study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + OSV
    Arm description
    		 Participants received matching placebo given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 milligram (mg) twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received matching placebo given as a 1-hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour.

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received open-label oral Oseltamivir 75 mg twice daily given as standard of care.

    Arm title
    		 DNX 15 mg + OSV
    Arm description
    		 Participants received DNX 15 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received open-label oral Oseltamivir 75 mg twice daily given as standard of care.

    Investigational medicinal product name
    Danirixin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received Danirixin 15 mg given as a 1-hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour.

    Arm title
    		 DNX 50 mg + OSV
    Arm description
    		 Participants received DNX 50 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danirixin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received Danirixin 50 mg given as a 1-hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour.

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received open-label oral Oseltamivir 75 mg twice daily given as standard of care.

    Number of subjects in period 1
    		Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Started
    2
    4
    4
    Completed
    2
    4
    3
    Not completed
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + OSV
    Reporting group description
    		 Participants received matching placebo given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 milligram (mg) twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Reporting group title
    DNX 15 mg + OSV
    Reporting group description
    		 Participants received DNX 15 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Reporting group title
    DNX 50 mg + OSV
    Reporting group description
    		 Participants received DNX 50 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Reporting group values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV Total
    Number of subjects
    		 2 4 4
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.0 ± 24.04 66.0 ± 8.76 63.0 ± 24.90 -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 3 6
        Male
    		 1 2 1 4
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 1 0 1 2
        Asian-Central/South Asian Heritage
    		 0 0 1 1
        White-White/Caucasian/European Heritage
    		 1 4 2 7

    End points

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    End points reporting groups
    Reporting group title
    Placebo + OSV
    Reporting group description
    		 Participants received matching placebo given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 milligram (mg) twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Reporting group title
    DNX 15 mg + OSV
    Reporting group description
    		 Participants received DNX 15 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Reporting group title
    DNX 50 mg + OSV
    Reporting group description
    		 Participants received DNX 50 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Primary: Time to Clinical Response (TTCR)

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    End point title
    		 Time to Clinical Response (TTCR) [1]
    End point description
    The clinical response was defined as Hospital discharge due to clinical improvement OR normalization of temperature; and oxygen saturation; and respiratory status/heart rate/systolic blood pressure (normalization of 2 out of these 3 parameters). The clinical response based on vital signs/ventilation status required 24-hour confirmation. Considering 2-hour assessment window, the response confirmation period was 22 hours. Kaplan Meier estimates for the median of TTCR was provided. One participant had vital sign resolution at Baseline and was counted as having a clinical response but was not included in the Kaplan Meier Estimates. Influenza Positive Population (IPP) Population comprised of all participants in the Intent to Treat Exposed (ITT-E) Population with influenza infection (positive influenza Polymerase Chain Reaction [PCR] or culture at any time point) confirmed by central lab testing. Only those participants with data available at the indicated time point were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 45 Days
    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: There are no statistical data to report.
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [2]
    3 [3]
    4 [4]
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    1.33 (0.71 to 1.95)
    4.53 (2.95 to 5.71)
    4.76 (3.66 to 5.08)
    Notes
    [2] - IPP Population
    [3] - IPP Population
    [4] - IPP Population
    No statistical analyses for this end point

    Secondary: Time to Respiratory Response (TTRR)

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    End point title
    		 Time to Respiratory Response (TTRR)
    End point description
    Time to Respiratory Response was defined as meeting at least one of the following criteria, and maintained for 24 hours: return to pre-morbid oxygen requirement (participants with chronic oxygen use or ventilator support), or return to no requirement of supplemental oxygen, or respiratory rate <=24 per minute (without supplemental oxygen). Kaplan Meier estimates for the median of TTRR for each treatment group was provided. 99999 indicates data is not available, as data could not be calculated due to insufficient number of participants with events. Due to limited data, no TTRR estimate could be calculated for any of the treatment groups.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [5]
    4 [6]
    4 [7]
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    99999 (1.95 to 99999)
    99999 (1.07 to 99999)
    99999 (3.04 to 99999)
    Notes
    [5] - IPP Population
    [6] - IPP Population
    [7] - IPP Population
    No statistical analyses for this end point

    Secondary: Time to absence of fever

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    End point title
    		 Time to absence of fever
    End point description
    Time from first dose of treatment to time to afebrile status (<=36.6 degree celsius-axilla/temporal or <=37.2 degree celsius- oral, or <=37.7 degree celsius-rectal/core, tympanic) was to be evaluated. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Days
    median (full range (min-max))
        Days
    ( to )
    ( to )
    ( to )
    Notes
    [8] - IPP Population.
    [9] - IPP Population
    [10] - IPP Population
    No statistical analyses for this end point

    Secondary: Time to improved oxygen saturation

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    End point title
    		 Time to improved oxygen saturation
    End point description
    Time from first dose of treatment to time of improved oxygen saturation was to be calculated. A participant with a history of chronic hypoxia (without supplemental oxygen) satisfied normalization criteria for oxygen saturation if the value (without supplemental oxygen) is <=2 percent from participant’s historical oxygen saturation Baseline as recorded within 12 months prior to enrollment as documented in the participant’s medical records. This requirement was to be waived for participants with a history of chronic supplemental oxygen requirement who had a Baseline oxygen saturation <95 percent with supplemental oxygen, within 12 months prior to enrollment as documented in the participant’s medical records. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: Days
    median (full range (min-max))
        Days
    ( to )
    ( to )
    ( to )
    Notes
    [11] - IPP Population
    [12] - IPP Population
    [13] - IPP Population
    No statistical analyses for this end point

    Secondary: Time to improved heart rate

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    End point title
    		 Time to improved heart rate
    End point description
    Time from first dose of treatment to time of heart rate <=100 beats per minute was to be evaluated. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    Units: Days
    median (full range (min-max))
        Days
    ( to )
    ( to )
    ( to )
    Notes
    [14] - IPP Population
    [15] - IPP Population
    [16] - IPP Population
    No statistical analyses for this end point

    Secondary: Time to improved systolic blood pressure (SBP)

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    End point title
    		 Time to improved systolic blood pressure (SBP)
    End point description
    Time from first dose of treatment to time of SBP at >=90 millimeters of mercury (mmHg) was to be evaluated. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: Days
    median (full range (min-max))
        Days
    ( to )
    ( to )
    ( to )
    Notes
    [17] - IPP Population
    [18] - IPP Population
    [19] - IPP Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinical response over time

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    End point title
    		 Percentage of participants with clinical response over time
    End point description
    The clinical response was defined as Hospital discharge due to clinical improvement OR normalization of temperature; and oxygen saturation; and respiratory status/heart rate/systolic blood pressure (normalization of 2 out of these 3 parameters). The clinical response based on vital signs/ventilation status required 24-hour confirmation. Considering 2-hour assessment window, the response confirmation period was 22 hours. Percentage of participants with positive clinical response are presented.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [20]
    4 [21]
    4 [22]
    Units: Percentage of Participants
        Percentage of Participants
    100
    100
    100
    Notes
    [20] - IPP Population
    [21] - IPP Population
    [22] - IPP Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with improved respiratory status over time

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    End point title
    		 Percentage of participants with improved respiratory status over time
    End point description
    The Respiratory Response was defined as meeting at least one of the following criteria, and maintained for 24 hours: return to pre-morbid oxygen requirement (participants with chronic oxygen use or ventilator support), or return to no requirement of supplemental oxygen, or respiratory rate <=24 per minute (without supplemental oxygen). Percentage of participants with improved respiratory status has been presented.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [23]
    4 [24]
    4 [25]
    Units: Percentage of Participants
        Percentage of Participants
    50
    50
    50
    Notes
    [23] - IPP Population
    [24] - IPP Population
    [25] - IPP Population
    No statistical analyses for this end point

    Secondary: Time to improvement of ventilation status

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    End point title
    		 Time to improvement of ventilation status
    End point description
    Time to improvement of ventilation status was assessed by modality, frequencies and durations of invasive and non-invasive ventilator support, duration of oxygen supplementation. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [26]
    0 [27]
    0 [28]
    Units: Days
    median (full range (min-max))
        Days
    ( to )
    ( to )
    ( to )
    Notes
    [26] - IPP Population
    [27] - IPP Population
    [28] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of days of stay in the intensive care unit (ICU)

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    End point title
    		 Number of days of stay in the intensive care unit (ICU)
    End point description
    Number of days of stay in the ICU over the treatment period and post treatment period was to be recorded. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [29]
    0 [30]
    0 [31]
    Units: Days
    median (full range (min-max))
        Days
    ( to )
    ( to )
    ( to )
    Notes
    [29] - IPP Population
    [30] - IPP Population
    [31] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants requiring ICU admission and readmission

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    End point title
    		 Number of participants requiring ICU admission and readmission
    End point description
    Number of participants requiring ICU admission during treatment period and after post treatment was to be recorded. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [32]
    0 [33]
    0 [34]
    Units: Participants
        Participants
    Notes
    [32] - IPP Population
    [33] - IPP Population
    [34] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of days of stay in the hospital

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    End point title
    		 Number of days of stay in the hospital
    End point description
    Number of days of stay in the hospital over treatment period and post treatment period was to be recorded. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [35]
    0 [36]
    0 [37]
    Units: Days
    median (full range (min-max))
        Days
    ( to )
    ( to )
    ( to )
    Notes
    [35] - IPP Population
    [36] - IPP Population
    [37] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with development of septic shock

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    End point title
    		 Number of participants with development of septic shock
    End point description
    Development of septic shock was to be assessed by occurrence of hypotension requiring vasopressive therapy and serum lactate level >2 millimeter (mm) after adequate fluid resuscitation. Number of participants with development of septic shock were planned to be presented. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [38]
    0 [39]
    0 [40]
    Units: Participants
        Participants
    Notes
    [38] - IPP Population
    [39] - IPP Population
    [40] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants used antibiotics for complications of influenza

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    End point title
    		 Number of participants used antibiotics for complications of influenza
    End point description
    Complications of influenza such as bacterial pneumonia, pneumothorax, pleural effusion, acute respiratory distress syndrome (ARDS), myositis, encephalitis, myocarditis, and associated antibiotic use was recorded. Number of participants who reqruied use of associated antibiotics for complications of influenza is presented.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [41]
    4 [42]
    4 [43]
    Units: Participants
        Participants
    1
    1
    1
    Notes
    [41] - IPP Population
    [42] - IPP Population
    [43] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with improvement in ordinal scale of clinical efficacy over time

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    End point title
    		 Number of participants with improvement in ordinal scale of clinical efficacy over time
    End point description
    Number of participants with improvement in ordinal scale of clinical efficacy over time was to be assessed by: death, mechanical vent, in the ICU, non-ICU hospitalization, and hospital discharge. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [44]
    0 [45]
    0 [46]
    Units: Participants
        Participants
    Notes
    [44] - IPP Population
    [45] - IPP Population
    [46] - IPP Population
    No statistical analyses for this end point

    Secondary: Number of participants with any non-serious adverse event (AE); any serious AE (SAE); any AEs of special interest (AESIs)

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    End point title
    		 Number of participants with any non-serious adverse event (AE); any serious AE (SAE); any AEs of special interest (AESIs)
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention or event associated with liver injury and impaired liver function were categorized as SAE. Participants who received any of the study treatment and had any AE or SAE or AESI were considered for analysis. Safety Population comprised of all participants who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 45 Days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [47]
    4
    4
    Units: Participants
        Any non-SAE
    0
    4
    4
        Any SAE
    0
    0
    2
        Any AESI
    0
    1
    1
    Notes
    [47] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in albumin and total protein

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    End point title
    		 Change from Baseline in albumin and total protein
    End point description
    Blood samples were collected to evaluate albumin and total protein at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data was not available due to insufficient number of participants.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 45 days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [48]
    4 [49]
    4 [50]
    Units: Gram per Liter (G/L)
    arithmetic mean (standard deviation)
        Albumin, Day 2, n=1,0,0
    2.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        Albumin, Day 2, sample 2, n=0,0,1
    99999 ± 99999
    99999 ± 99999
    0.0 ± 99999
        Albumin, Day 3, n=1,2,2
    0.0 ± 99999
    -5.0 ± 1.41
    -2.0 ± 2.83
        Albumin, Day 3, sample 2, n=0,1,2
    99999 ± 99999
    -9.0 ± 99999
    -4.5 ± 4.95
        Albumin, Day 4, n=0,1,2
    99999 ± 99999
    -1.0 ± 99999
    -3.0 ± 4.24
        Albumin, Day 4, sample 2, n=0,1,1
    99999 ± 99999
    -8.0 ± 99999
    -5.0 ± 99999
        Albumin, Day 5, n=1,1,3
    0.0 ± 99999
    -5.0 ± 99999
    -3.7 ± 6.03
        Albumin, Day 6, n=1,1,4
    1.0 ± 99999
    -6.0 ± 99999
    -2.8 ± 4.99
        Albumin, Day 7, n=1,1,1
    -2.0 ± 99999
    -5.0 ± 99999
    -3.0 ± 99999
        Albumin, Day 8, n=1,0,0
    0.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        Albumin, Discharge/Day 45, n=2,2,3
    2.5 ± 2.12
    -0.5 ± 0.71
    5.7 ± 6.81
        Albumin, Day 3 post last dose, n=1,3,3
    0.0 ± 99999
    -1.3 ± 1.15
    -2.3 ± 1.15
        Total Protein, Day 2, n=1,0,1
    1.0 ± 99999
    99999 ± 99999
    -1.0 ± 99999
        Total Protein, Day 3, n=1,2,2
    1.0 ± 99999
    -5.5 ± 4.95
    -3.0 ± 4.24
        Total Protein, Day 3, sample 2, n=0,1,2
    99999 ± 99999
    -13.0 ± 99999
    -4.0 ± 4.24
        Total Protein, Day 4, n=0,1,2
    99999 ± 99999
    -1.0 ± 99999
    -4.0 ± 5.66
        Total Protein, Day 4, sample 2, n=0,1,1
    99999 ± 99999
    -10.0 ± 99999
    -7.0 ± 99999
        Total Protein, Day 5, n=1,1,3
    -1.0 ± 99999
    -7.0 ± 99999
    -5.7 ± 10.97
        Total Protein, Day 6, n=1,1,4
    0.0 ± 99999
    -7.0 ± 99999
    -4.0 ± 6.98
        Total Protein, Day 7, n=1,1,1
    -3.0 ± 99999
    -5.0 ± 99999
    -2.0 ± 99999
        Total Protein, Day 8, n=1,0,0
    0.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        Total Protein, Discharge/Day 45, n=2,2,3
    0.0 ± 2.83
    -1.5 ± 2.12
    6.7 ± 11.02
        Total Protein, Day 3 post last dose, n=1,3,3
    -0.3 ± 99999
    -3.0 ± 2.00
    -3.3 ± 3.51
    Notes
    [48] - Safety Population
    [49] - Safety Population
    [50] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in white blood cell count (WBC) and absolute neutrophil count (ANC)

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    End point title
    		 Change from Baseline in white blood cell count (WBC) and absolute neutrophil count (ANC)
    End point description
    Blood samples were collected to evaluate WBC and ANC at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data was not available due to insufficient number of participants.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 45 days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [51]
    4 [52]
    4 [53]
    Units: Giga cells per Liter (GI/L)
    arithmetic mean (standard deviation)
        WBC, Day 2, n=1,0,0
    -2.70 ± 99999
    99999 ± 99999
    99999 ± 99999
        WBC, Day 3, n=1,1,0
    -5.10 ± 99999
    -3.00 ± 99999
    99999 ± 99999
        WBC, Day 4, n=0,2,1
    99999 ± 99999
    1.15 ± 3.889
    -7.10 ± 99999
        WBC, Day 5, n=1,1,1
    -2.90 ± 99999
    -3.70 ± 99999
    -5.30 ± 99999
        WBC, Day 6, n=1,0,0
    -2.40 ± 99999
    99999 ± 99999
    99999 ± 99999
        WBC, Day 7, n=1,0,0
    -2.90 ± 99999
    99999 ± 99999
    99999 ± 99999
        WBC, Day 8, n=1,0,0
    -3.10 ± 99999
    99999 ± 99999
    99999 ± 99999
        WBC, Discharge/Day 45, n=2,3,1
    -3.55 ± 2.051
    3.97 ± 2.765
    -9.50 ± 99999
        WBC, Day 3 post last dose, n=1,4,1
    -4.60 ± 99999
    1.95 ± 2.594
    -8.00 ± 99999
        ANC, Day 2, n=1,0,0
    -3.880 ± 99999
    99999 ± 99999
    99999 ± 99999
        ANC, Day 3, n=1,1,0
    -5.640 ± 99999
    -4.070 ± 99999
    99999 ± 99999
        ANC, Day 4, n=0,2,1
    99999 ± 99999
    1.410 ± 3.2810
    -7.420 ± 99999
        ANC, Day 5, n=1,1,1
    -4.250 ± 99999
    -4.250 ± 99999
    -6.260 ± 99999
        ANC, Day 6, n=1,0,0
    -3.540 ± 99999
    99999 ± 99999
    99999 ± 99999
        ANC, Day 7, n=1,0,0
    -4.180 ± 99999
    99999 ± 99999
    99999 ± 99999
        ANC, Day 8, n=1,0,0
    -4.580 ± 99999
    99999 ± 99999
    99999 ± 99999
        ANC, Discharge/Day 45, n=2,3,1
    -4.650 ± 1.9092
    3.050 ± 2.9511
    -9.720 ± 99999
        ANC, Day 3 post last dose, n=1,4,1
    -5.680 ± 99999
    1.033 ± 2.9818
    -9.060 ± 99999
    Notes
    [51] - Safety Population
    [52] - Safety Population
    [53] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Bilirubin (T. Bilirubin), creatinine and Direct Bilirubin (D. Bilirubin)

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    End point title
    		 Change from Baseline in Total Bilirubin (T. Bilirubin), creatinine and Direct Bilirubin (D. Bilirubin)
    End point description
    Blood samples were collected to evaluate T. Bilirubin, creatinine and D. Bilirubin at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data was not available due to insufficient number of participants.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 45 days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [54]
    4 [55]
    4 [56]
    Units: Micromole per Liter (µmol/L)
    arithmetic mean (standard deviation)
        D. Bilirubin, Day 2, n=1,0,0
    -2.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        D. Bilirubin, Day 2, sample 2, n=0,0,1
    99999 ± 99999
    99999 ± 99999
    0.0 ± 99999
        D. Bilirubin, Day 3, n=1,2,2
    -2.0 ± 99999
    -2.0 ± 0.00
    0.0 ± 2.83
        D. Bilirubin, Day 3, sample 2, n=0,1,2
    99999 ± 99999
    -2.0 ± 99999
    0.0 ± 2.83
        D. Bilirubin, Day 4, n=0,1,2
    99999 ± 99999
    0.0 ± 99999
    0.0 ± 0.00
        D. Bilirubin, Day 4, sample 2, n=0,1,1
    99999 ± 99999
    -2.0 ± 99999
    -2.0 ± 99999
        D. Bilirubin, Day 5, n=1,1,3
    0.0 ± 99999
    0.0 ± 99999
    0.0 ± 2.00
        D. Bilirubin, Day 6, n=1,1,4
    0.0 ± 99999
    0.0 ± 99999
    -0.5 ± 1.91
        D. Bilirubin, Day 7, n=1,1,1
    0.0 ± 99999
    0.0 ± 99999
    2.0 ± 99999
        D. Bilirubin, Day 8, n=1,0,0
    -2.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        D. Bilirubin, Discharge/Day 45, n=2,2,3
    -3.0 ± 4.24
    -1.0 ± 1.41
    -0.7 ± 1.15
        D. Bilirubin, Day 3 post last dose, n=1,3,3
    0.0 ± 99999
    0.0 ± 0.00
    0.7 ± 2.31
        T. Bilirubin, Day 2, n=1,0,0
    0.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        T. Bilirubin, Day 2, sample 2, n=0,0,1
    99999 ± 99999
    99999 ± 99999
    -4.00 ± 99999
        T. Bilirubin, Day 3, n=1,2,2
    -2.0 ± 99999
    -2.0 ± 2.828
    -1.00 ± 1.414
        T. Bilirubin, Day 3, sample 2, n=0,1,2
    99999 ± 99999
    -6.0 ± 99999
    -2.00 ± 0.000
        T. Bilirubin, Day 4, n=0,1,2
    99999 ± 99999
    0.0 ± 99999
    -2.00 ± 2.828
        T. Bilirubin, Day 4, sample 2, n=0,1,1
    99999 ± 99999
    -6.0 ± 99999
    0.00 ± 99999
        T. Bilirubin, Day 5, n=1,1,3
    0.0 ± 99999
    -2.0 ± 99999
    0.67 ± 1.155
        T. Bilirubin, Day 6, n=1,1,4
    -2.0 ± 99999
    2.0 ± 99999
    -0.50 ± 1.000
        T. Bilirubin, Day 7, n=1,1,1
    -6.0 ± 99999
    2.0 ± 99999
    0.00 ± 99999
        T. Bilirubin, Day 8, n=1,0,0
    -6.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        T. Bilirubin, Discharge/Day 45, n=2,2,3
    -1.0 ± 1.414
    0.0 ± 2.828
    -0.67 ± 1.155
        T. Bilirubin, Day 3 post last dose, n=1,3,3
    -4.0 ± 99999
    0.0 ± 2.000
    -4.60 ± 4.503
        Creatinine, Day 2, n=2,2,4
    -7.95 ± 18.738
    -0.50 ± 5.657
    -3.35 ± 1.323
        Creatinine, Day 2, sample 2, n=1,1,2
    3.50 ± 99999
    7.90 ± 99999
    -8.40 ± 0.566
        Creatinine, Day 3, n=1,2,3
    -33.60 ± 99999
    -3.60 ± 1.273
    -4.77 ± 1.012
        Creatinine, Day 3, sample 2, n=0,2,4
    99999 ± 99999
    -9.30 ± 6.930
    1.32 ± 8.397
        Creatinine, Day 4, n=1,3,4
    -39.80 ± 99999
    -5.90 ± 6.222
    -4.20 ± 6.975
        Creatinine, Day 4, sample 2, n=0,2,3
    99999 ± 99999
    0.45 ± 15.627
    -2.40 ± 7.375
        Creatinine, Day 5, n=1,2,3
    -40.60 ± 99999
    -1.35 ± 9.405
    -2.67 ± 4.070
        Creatinine, Day 5, sample 2, n=0,1,0
    99999 ± 99999
    -15.90 ± 99999
    99999 ± 99999
        Creatinine, Day 6, n=1,1,4
    -44.20 ± 99999
    -10.60 ± 99999
    3.52 ± 4.396
        Creatinine, Day 7, n=1,1,1
    -38.00 ± 99999
    -10.60 ± 99999
    -1.80 ± 99999
        Creatinine, Day 8, n=1,0,0
    -26.50 ± 99999
    99999 ± 99999
    99999 ± 99999
        Creatinine, Discharge/Day 45, n=2,2,3
    -16.80 ± 22.486
    -3.55 ± 8.697
    6.50 ± 4.521
        Creatinine, Day 3 post last dose, n=1,3,3
    -23.00 ± 99999
    -4.47 ± 9.750
    2.93 ± 9.304
    Notes
    [54] - Safety Population
    [55] - Safety Population
    [56] - Safety Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST) and Alkaline Phosphatase (ALP)

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    End point title
    		 Change from Baseline in Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST) and Alkaline Phosphatase (ALP)
    End point description
    Blood samples were collected to evaluate ALT, AST and ALP at indicated time points. Values at Day 1 were considered as Baseline values. Change from Baseline at each visit was calculated by subtracting Baseline value from post-dose visit value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates data was not available due to insufficient number of participants.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 45 days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [57]
    4 [58]
    4 [59]
    Units: International unit per Liter (IU/L)
    arithmetic mean (standard deviation)
        ALT, Day 2, n=1,0,0
    10.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        ALT, Day 2, sample 2, n=0,0,1
    99999 ± 99999
    99999 ± 99999
    -1.0 ± 99999
        ALT, Day 3, n=1,2,2
    4.0 ± 99999
    3.0 ± 1.41
    2.0 ± 5.66
        ALT, Day 3, sample 2, n=0,1,2
    99999 ± 99999
    -1.0 ± 99999
    -1.0 ± 5.66
        ALT, Day 4, n=0,1,2
    99999 ± 99999
    -18.0 ± 99999
    -3.5 ± 2.12
        ALT, Day 4, sample 2, n=0,1,1
    99999 ± 99999
    1.0 ± 99999
    10.0 ± 99999
        ALT, Day 5, n=1,1,3
    0.0 ± 99999
    -2.0 ± 99999
    -0.3 ± 3.79
        ALT, Day 6, n=1,1,4
    -1.0 ± 99999
    -37.0 ± 99999
    -2.3 ± 3.86
        ALT, Day 7, n=1,1,1
    -2.0 ± 99999
    -42.0 ± 99999
    -6.0 ± 99999
        ALT, Day 8, n=1,0,0
    -1.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        ALT, Discharge/Day 45, n=2,2,3
    -6.0 ± 4.24
    -30.0 ± 35.36
    0.7 ± 2.08
        ALT, Day 3 post last dose, n=1,3,3
    2.0 ± 99999
    -17.0 ± 19.08
    -4.0 ± 3.61
        AST, Day 2, n=1,0,0
    14.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        AST, Day 2, sample 2, n=0,0,1
    99999 ± 99999
    99999 ± 99999
    -4.0 ± 99999
        AST, Day 3, n=1,2,2
    11.0 ± 99999
    6.0 ± 8.49
    -2.0 ± 2.83
        AST, Day 3, sample 2, n=0,1,2
    99999 ± 99999
    8.0 ± 99999
    -1.5 ± 4.95
        AST, Day 4, n=0,1,2
    99999 ± 99999
    -29.0 ± 99999
    -8.0 ± 2.83
        AST, Day 4, sample 2, n=0,1,1
    99999 ± 99999
    16.0 ± 99999
    0.0 ± 99999
        AST, Day 5, n=1,1,3
    -10.0 ± 99999
    -9.0 ± 99999
    -7.3 ± 2.08
        AST, Day 6, n=1,1,4
    -12.0 ± 99999
    -46.0 ± 99999
    -5.8 ± 7.32
        AST, Day 7, n=1,1,1
    -11.0 ± 99999
    -51.0 ± 99999
    -11.0 ± 99999
        AST, Day 8, n=1,0,0
    -12.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        AST, Discharge/Day 45, n=2,2,3
    -12.0 ± 11.31
    -27.5 ± 30.41
    -3.0 ± 5.57
        AST, Day 3 post last dose, n=1,3,3
    -10.0 ± 99999
    -21.7 ± 23.76
    -10.7 ± 5.86
        ALP, Day 2, n=1,0,0
    8.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        ALP, Day 2,sample 2, n=0,0,1
    99999 ± 99999
    99999 ± 99999
    -3.0 ± 99999
        ALP, Day 3, n=1,2,2
    2.0 ± 99999
    -6.0 ± 8.49
    -8.0 ± 2.83
        ALP, Day 3, sample 2, n=0,1,2
    99999 ± 99999
    -23.0 ± 99999
    -14.0 ± 7.07
        ALP, Day 4, n=0,1,2
    99999 ± 99999
    -25.0 ± 99999
    -5.5 ± 0.71
        ALP, Day 4, sample 2, n=0,1,1
    99999 ± 99999
    -22.0 ± 99999
    -4.0 ± 99999
        ALP, Day 5, n=1,1,3
    6.0 ± 99999
    -8.0 ± 99999
    -11.0 ± 7.81
        ALP, Day 6, n=1,1,4
    5.0 ± 99999
    -51.0 ± 99999
    -9.5 ± 8.19
        ALP, Day 7, n=1,1,1
    2.0 ± 99999
    -50.0 ± 99999
    17.0 ± 99999
        ALP, Day 8, n=1,0,0
    3.0 ± 99999
    99999 ± 99999
    99999 ± 99999
        ALP, Discharge/Day 45, n=2,2,3
    10.0 ± 0.00
    -25.5 ± 30.41
    2.0 ± 9.64
        ALP, Day 3 post last dose, n=1,3,3
    1.0 ± 99999
    -19.7 ± 22.03
    -9.3 ± 7.51
    Notes
    [57] - Safety Population
    [58] - Safety Population
    [59] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with clinically significant abnormality in electrocardiogram (ECG)

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    End point title
    		 Number of participants with clinically significant abnormality in electrocardiogram (ECG)
    End point description
    Single 12-lead ECGs were obtained at Baseline and on the day of last dose during the study using an ECG machine that automatically calculates the heart rate (HR) and measures PR, QRS, QT, and QT duration corrected for heart rate (QTc). Number of participants with clinically significant abnormality in ECG are presented.
    End point type
    Secondary
    End point timeframe
    Up to 6 days
    End point values
    		 Placebo + OSV DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    2 [60]
    4 [61]
    4 [62]
    Units: Participants
        Participants
    0
    0
    1
    Notes
    [60] - Safety Population
    [61] - Safety Population
    [62] - Safety Population
    No statistical analyses for this end point

    Secondary: Maximum observed plasma concentration (Cmax) of intravenous (IV) DNX

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    End point title
    		 Maximum observed plasma concentration (Cmax) of intravenous (IV) DNX [63]
    End point description
    Cmax of IV DNX was to be derived from the Pharmacokinetics (PK) samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. PK Population comprised of all participants who underwent blood PK sampling during the study and from whom one or more blood concentration was determined. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed due to limited sample size.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [64]
    0 [65]
    Units: Nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Nanogram per milliliter (ng/mL)
    ±
    ±
    Notes
    [64] - PK Population
    [65] - PK Population
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC [0-t]) of IV DNX

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    End point title
    		 Area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC [0-t]) of IV DNX [66]
    End point description
    AUC (0-t) of IV DNX was to be derived from the PK samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed due to limited sample size.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [67]
    0 [68]
    Units: Hour*nanogram per milliliter(hour*ng/mL)
    geometric mean (geometric coefficient of variation)
        Hour*nanogram per milliliter(hour*ng/mL)
    ±
    ±
    Notes
    [67] - PK Population
    [68] - PK Population
    No statistical analyses for this end point

    Secondary: Time to reach Cmax (Tmax) of IV DNX

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    End point title
    		 Time to reach Cmax (Tmax) of IV DNX [69]
    End point description
    Tmax of IV DNX was to be derived from the PK samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed due to limited PK parameters available.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose
    Notes
    [69] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [70]
    0 [71]
    Units: Hour
    median (full range (min-max))
        Hour
    ( to )
    ( to )
    Notes
    [70] - PK Population
    [71] - PK Population
    No statistical analyses for this end point

    Secondary: Average concentration (Cavg) of IV DNX

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    End point title
    		 Average concentration (Cavg) of IV DNX [72]
    End point description
    Cavg of IV DNX was to be derived from the PK samples collected at Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose. As the study was terminated, only a selected set of originally planned analysis were performed and hence this endpoint was not analyzed due to limited sample size.
    End point type
    Secondary
    End point timeframe
    Day 1 pre-dose, Day 3 at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours post-dose and Day 5 pre-dose
    Notes
    [72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period.
    End point values
    		 DNX 15 mg + OSV DNX 50 mg + OSV
    Number of subjects analysed
    0 [73]
    0 [74]
    Units: ng/mL
    arithmetic mean (standard deviation)
        ng/mL
    ±
    ±
    Notes
    [73] - PK Population
    [74] - PK Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment SAEs and non-serious AEs were collected from the start of the study treatment up to Day 45.
    Adverse event reporting additional description
    On treatment SAEs and non-serious AEs were reported for the Safety Population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo + OSV
    Reporting group description
    		 Participants received matching placebo given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Reporting group title
    DNX 50 mg + OSV
    Reporting group description
    		 Participants received DNX 50 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Reporting group title
    DNX 15 mg + OSV
    Reporting group description
    		 Participants received DNX 15 mg given as a 1 hour infusion twice daily for up to 5 days. Infusion was administered at a constant rate over approximately 1 hour +- 10 minutes and approximately 12 hours apart +- 1 hour. All participants also received open-label oral OSV 75 mg twice daily given as standard of care. The investigator could elect to continue treatment with OSV after 5 days of study treatment.

    Serious adverse events
    		 Placebo + OSV DNX 50 mg + OSV DNX 15 mg + OSV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo + OSV DNX 50 mg + OSV DNX 15 mg + OSV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Monocytosis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Atelectasis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Fungal infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Interpretation of data is limited by the few participants enrolled prior to termination of the study due to poor recruitment.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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