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    Clinical Trial Results:
    Phase 2b, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the Efficacy and Safety of Intravenous VIS410 in Addition to Oseltamivir (Tamiflu®) Compared with Oseltamivir Alone in Hospitalized Adults with Influenza A Infection Requiring Oxygen Support

    Summary
    EudraCT number
    		 2016-004009-15
    Trial protocol
    		 ES   BG   EE   LV   BE  
    Global end of trial date
    22 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Nov 2020
    First version publication date
    13 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VIS410-203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03040141
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Visterra, Inc.
    Sponsor organisation address
    275 2nd Ave, Waltham, United States, 02451
    Public contact
    Kristi Schaefers, Visterra, Inc., 1 6174981070, clinicaltrials@visterrainc.com
    Scientific contact
    Kristi Schaefers, Visterra, Inc., 1 6174981070, clinicaltrials@visterrainc.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
    02 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the effect of 2 dose levels of VIS410 + oseltamivir on clinical outcomes as assessed by comparison of clinical status ordinal scale Day 7 scores between treatment groups, and between all VIS410 dose groups versus placebo.
    Protection of trial subjects
    An independent Data Safety Monitoring Board (DSMB) was established to review all available safety data after 30 subjects and again after approximately 70 subjects completed the Day 14 visit. Additional DSMB reviews could have occurred throughout the trial as deemed necessary by the DSMB or Sponsor to ensure subject safety and well being.
    Background therapy
    		 Administration of concomitant medications was reported in the appropriate section of the EDC system along with dates of administration and reasons for use. Subjects were allowed to receive up to 6 doses of an approved anti-influenza therapy (i.e., oral oseltamivir, inhaled zanamivir, or oral ribavirin) within the 96 hours between the onset of symptoms and VIS410/placebo dosing. These 6 doses were to be counted toward the overall 20 doses of oseltamivir which the subject could receive before and during the study. Subjects were not allowed to receive monoclonal antibody products within 3 months prior to VIS410/placebo dosing.
    Evidence for comparator
    		 Placebo-controlled, double-blind study
    Actual start date of recruitment
    02 Oct 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
    Spain: 14
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Estonia: 9
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Belarus: 1
    Country: Number of subjects enrolled
    Georgia: 1
    Country: Number of subjects enrolled
    Serbia: 14
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Thailand: 11
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    89
    EEA total number of subjects
    42
    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)
    49
    From 65 to 84 years
    33
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was initiated in 115 study centers; 34 sites enrolled at least 1 subject.

    Pre-assignment
    Screening details
    		 Samples from prospective subjects admitted to the hospital within 5 days of onset of initial symptoms who required supplemental oxygen were evaluated via a diagnostic assay to confirm influenza A infection. Flu-positive subjects were then given a full explanation of the nature of the study and written informed consent was obtained.

    Period 1
    Period 1 title
    Treatment Period & Follow up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    The study was blinded using placebo infusion to prevent bias in the assessment of effect. The investigative site personnel, the Sponsor, and their representatives involved in the monitoring or conduct of the study, and the subjects were blinded to the study drug codes. In addition, the infusion bag was covered with an opaque sleeve in the pharmacy to maintain the study blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VIS410 4000
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    VIS410 4000mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIS410 4000 mg was administered IV over 2 hours as single 200-mL infusions followed by a 25-mL (or volume equivalent to length of IV line) saline flush to ensure all the product was administered.

    Arm title
    		 VIS410 2000
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    VIS410 2000mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    VIS410 2000 mg was administered IV over 2 hours as single 200-mL infusions followed by a 25-mL (or volume equivalent to length of IV line) saline flush to ensure all the product was administered.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for VIS410
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered IV over 2 hours as single 200-mL infusions followed by a 25-mL (or volume equivalent to length of IV line) saline flush to ensure all the product was administered.

    Number of subjects in period 1
    		VIS410 4000 VIS410 2000 Placebo
    Started
    29
    30
    30
    Completed
    25
    24
    24
    Not completed
    4
    6
    6
         Adverse event, serious fatal
    1
    2
    3
         Consent withdrawn by subject
    3
    1
    1
         subject did not receive study drug
    -
    2
    2
         Subject discharged
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period & Follow up
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Period & Follow up Total
    Number of subjects
    		 89 89
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 49 49
        From 65-84 years
    		 33 33
        85 years and over
    		 7 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.2 ( 18.91 ) -
    Gender categorical
    Units: Subjects
        Female
    		 45 45
        Male
    		 44 44
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population included all subjects randomized to treatment and are grouped according to the treatment assigned

    Subject analysis set title
    MITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified ITT (MITT) population included all subjects who received IV study drug and were confirmed influenza A positive by qRT-PCR in central lab analysis of pre-dose Day 1 and/or post-dose Day 1. Subjects were grouped according to the randomly assigned treatment. All efficacy analyses including the primary efficacy analyses were performed in the MITT population.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all ITT subjects who received IV study drug. Subjects were grouped according to the actual treatment received.

    Subject analysis sets values
    		 ITT MITT Safety
    Number of subjects
    88
    85
    88
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    49
    46
    48
        From 65-84 years
    33
    32
    33
        85 years and over
    7
    7
    7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.2 ( 18.75 )
    61.2 ( 18.91 )
    61.2 ( 18.86 )
    Gender categorical
    Units: Subjects
        Female
    45
    44
    45
        Male
    44
    41
    43

    End points

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    End points reporting groups
    Reporting group title
    VIS410 4000
    Reporting group description
    		 -

    Reporting group title
    VIS410 2000
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Intent-to-Treat (ITT) population included all subjects randomized to treatment and are grouped according to the treatment assigned

    Subject analysis set title
    MITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The modified ITT (MITT) population included all subjects who received IV study drug and were confirmed influenza A positive by qRT-PCR in central lab analysis of pre-dose Day 1 and/or post-dose Day 1. Subjects were grouped according to the randomly assigned treatment. All efficacy analyses including the primary efficacy analyses were performed in the MITT population.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all ITT subjects who received IV study drug. Subjects were grouped according to the actual treatment received.

    Primary: Summary of Clinical Status Ordinal Scale

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    End point title
    		 Summary of Clinical Status Ordinal Scale
    End point description
    For use in overall summary statistical presentations, frequencies of ordinal scores at each visit were generated and evaluated by proportional odds ratio analysis, as implemented by logistic regression, including a test of the proportional odds assumption and generation of estimates of odds ratios. For this analysis, the reference response category was best (1=Discharge with full resumption of normal activities) to worst (7=Death).
    End point type
    Primary
    End point timeframe
    Day 7
    End point values
    		 VIS410 4000 VIS410 2000 Placebo
    Number of subjects analysed
    29
    28
    28
    Units: Persons
        Death
    1
    1
    1
        ICU Stay with Mechanical Ventilation
    1
    2
    1
        ICU Stay without Mechanical Ventilation
    2
    0
    0
        Non-ICU hospitalization with Supplemental O2
    5
    5
    3
        Non-ICU hospitalization without Supplemental O2
    12
    8
    10
        Discharge/partial resumption of normal activities
    7
    5
    11
        Discharge/full resumption of normal activities
    1
    7
    2
    Statistical analysis title
    		 proportional odds ratio analysis
    Comparison groups
    VIS410 4000 v VIS410 2000 v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.435 [1]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [1] - P-values and Odds Ratios reflect comparisons to placebo evaluated by proportional odds ratio analysis, as implemented by logistic regression, including a test of the proportional odds assumption

    Secondary: Time to Cessation of Oxygen Support

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    End point title
    		 Time to Cessation of Oxygen Support
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime
    End point values
    		 VIS410 4000 VIS410 2000 Placebo MITT
    Number of subjects analysed
    18
    15
    15
    85
    Units: hours
        median (inter-quartile range (Q1-Q3))
    92.5 (45.5 to 138.7)
    101.3 (26.9 to 114.6)
    79.0 (41.7 to 103.2)
    92 (26.9 to 138.7)
    Statistical analysis title
    		 Wald Chi-square statistic
    Comparison groups
    VIS410 4000 v VIS410 2000 v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.902
    Method
    		 Chi-squared corrected
    Confidence interval
    Notes
    [2] - Wald Chi-square statistic

    Secondary: Time to First Room Air Oxygen > 92%

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    End point title
    		 Time to First Room Air Oxygen > 92%
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime
    End point values
    		 VIS410 4000 VIS410 2000 Placebo MITT
    Number of subjects analysed
    27
    22
    25
    85
    Units: hours
        median (inter-quartile range (Q1-Q3))
    88.0 (24.1 to 156.4)
    74.2 (35.0 to 100.2)
    74.2 (43.5 to 120.6)
    80 (24.1 to 156.4)
    Statistical analysis title
    		 Log-Rank
    Comparison groups
    VIS410 2000 v VIS410 4000 v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8679
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to First Room Air Oxygen > 94%

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    End point title
    		 Time to First Room Air Oxygen > 94%
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime
    End point values
    		 VIS410 4000 VIS410 2000 Placebo MITT
    Number of subjects analysed
    29
    27
    28
    85
    Units: hours
        median (inter-quartile range (Q1-Q3))
    90.7 (37.0 to 162.6)
    101.3 (38.9 to 124.7)
    86.3 (50.5 to 120.6)
    90 (37 to 162.6)
    Statistical analysis title
    		 Log-Rank
    Comparison groups
    VIS410 2000 v Placebo v VIS410 4000
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8834
    Method
    		 Logrank
    Confidence interval

    Secondary: Time to Clinical Response (Resolution of Vital Signs)

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    End point title
    		 Time to Clinical Response (Resolution of Vital Signs)
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime
    End point values
    		 VIS410 4000 VIS410 2000 Placebo MITT
    Number of subjects analysed
    29
    28
    28
    85
    Units: hours
        median (inter-quartile range (Q1-Q3))
    2.6 (2.2 to 21.9)
    2.6 (2.2 to 24.0)
    2.8 (2.2 to 44.2)
    2.6 (2.2 to 44.2)
    Statistical analysis title
    		 Cox proportional hazards model Wald Chi-Square
    Comparison groups
    VIS410 4000 v VIS410 2000 v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.157
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Time to Complete Clinical Response (normalization of 5 of 5 vital signs)

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    End point title
    		 Time to Complete Clinical Response (normalization of 5 of 5 vital signs)
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime
    End point values
    		 VIS410 4000 VIS410 2000 Placebo MITT
    Number of subjects analysed
    29
    28
    28
    0 [3]
    Units: hours
        median (inter-quartile range (Q1-Q3))
    103.0 (45.4 to 170.6)
    114.6 (47.5 to 166.1)
    99.8 (63.0 to 168.5)
    ( to )
    Notes
    [3] - Values for the total MITT group were not calculated
    Statistical analysis title
    		 Log-Rank
    Comparison groups
    VIS410 4000 v VIS410 2000 v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5487
    Method
    		 Logrank
    Confidence interval

    Secondary: FLU-PRO Total Symptom Score

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    End point title
    		 FLU-PRO Total Symptom Score
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1- Day 14
    End point values
    		 VIS410 4000 VIS410 2000 Placebo
    Number of subjects analysed
    29
    28
    28
    Units: unit(s)
    arithmetic mean (standard deviation)
        Baseline/Day 1
    1.27 ( 0.605 )
    1.22 ( 0.827 )
    1.37 ( 0.641 )
        Day 2
    0.75 ( 0.494 )
    0.77 ( 0.552 )
    0.96 ( 0.658 )
        Day 3
    0.64 ( 0.369 )
    0.63 ( 0.528 )
    0.69 ( 0.499 )
        Day 4
    0.44 ( 0.264 )
    0.41 ( 0.480 )
    0.46 ( 0.291 )
        Day 5
    0.38 ( 0.234 )
    0.36 ( 0.448 )
    0.44 ( 0.427 )
        Day 6
    0.35 ( 0.239 )
    0.32 ( 0.313 )
    0.42 ( 0.399 )
        Day 7
    0.30 ( 0.268 )
    0.35 ( 0.390 )
    0.39 ( 0.441 )
        Day 8
    0.25 ( 0.198 )
    0.27 ( 0.292 )
    0.37 ( 0.416 )
        Day 9
    0.23 ( 0.172 )
    0.27 ( 0.276 )
    0.24 ( 0.324 )
        Day 10
    0.37 ( 0.514 )
    0.26 ( 0.287 )
    0.31 ( 0.402 )
        Day 11
    0.38 ( 0.639 )
    0.26 ( 0.250 )
    0.29 ( 0.433 )
        Day 12
    0.34 ( 0.602 )
    0.22 ( 0.262 )
    0.21 ( 0.275 )
        Day 13
    0.36 ( 0.658 )
    0.19 ( 0.233 )
    0.23 ( 0.307 )
        Day 14
    0.19 ( 0.193 )
    0.17 ( 0.182 )
    0.17 ( 0.228 )
    Statistical analysis title
    		 ANCOVA
    Comparison groups
    VIS410 4000 v Placebo v VIS410 2000
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.05 [4]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [4] - No statistically significant differences were noted between the VIS410 groups and placebo or between the VIS410 treatment groups

    Secondary: Improvement in signs and symptoms: VAS

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    End point title
    		 Improvement in signs and symptoms: VAS
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1- Day 14
    End point values
    		 VIS410 4000 VIS410 2000 Placebo MITT
    Number of subjects analysed
    29
    28
    28
    0 [5]
    Units: score
    arithmetic mean (standard deviation)
        Day 1
    3.1 ( 1.89 )
    2.4 ( 1.97 )
    2.5 ( 1.90 )
    ( )
        Day 2
    3.6 ( 2.06 )
    3.9 ( 2.52 )
    3.4 ( 2.46 )
    ( )
        Day 3
    4.3 ( 2.04 )
    4.5 ( 2.69 )
    4.6 ( 2.53 )
    ( )
        Day 4
    4.9 ( 2.06 )
    5.4 ( 2.81 )
    5.5 ( 2.37 )
    ( )
        Day 5
    6.0 ( 2.18 )
    5.7 ( 2.89 )
    5.6 ( 1.84 )
    ( )
        Day 6
    6.3 ( 2.14 )
    5.7 ( 3.56 )
    6.2 ( 2.35 )
    ( )
        Day 7
    7.1 ( 1.78 )
    6.7 ( 2.93 )
    6.6 ( 2.36 )
    ( )
        Day 8
    7.2 ( 1.73 )
    7.0 ( 2.91 )
    6.9 ( 2.64 )
    ( )
        Day 9
    7.0 ( 1.63 )
    6.5 ( 2.83 )
    6.9 ( 2.33 )
    ( )
        Day 10
    6.7 ( 2.33 )
    6.5 ( 2.67 )
    6.5 ( 2.50 )
    ( )
        Day 11
    7.1 ( 1.76 )
    6.6 ( 2.30 )
    7.1 ( 2.66 )
    ( )
        Day 12
    7.5 ( 1.63 )
    7.0 ( 2.28 )
    6.3 ( 2.40 )
    ( )
        Day 13
    6.8 ( 2.17 )
    7.7 ( 1.51 )
    7.1 ( 2.59 )
    ( )
        Day 14
    7.9 ( 2.18 )
    7.3 ( 2.16 )
    7.2 ( 2.99 )
    ( )
    Notes
    [5] - Values for the total MITT population were not calculated
    Statistical analysis title
    		 ANOVA using ranked values
    Comparison groups
    VIS410 4000 v Placebo v VIS410 2000
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval
    Notes
    [6] - no treatment effect differences in VAS scores were detected

    Secondary: Ventilator Support

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    End point title
    		 Ventilator Support
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime
    End point values
    		 VIS410 4000 VIS410 2000 Placebo MITT
    Number of subjects analysed
    4
    3
    1
    85
    Units: Days
        median (inter-quartile range (Q1-Q3))
    2.5 (2.0 to 10)
    10 (4 to 10)
    3 (3 to 3)
    5 (2 to 10)
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization: Total Number of Days in Hospital/ICU

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    End point title
    		 Healthcare Resource Utilization: Total Number of Days in Hospital/ICU
    End point description
    End point type
    Secondary
    End point timeframe
    Anytime
    End point values
    		 VIS410 4000 VIS410 2000 Placebo
    Number of subjects analysed
    29
    28
    28
    Units: Days
        arithmetic mean (standard deviation)
    11.4 ( 8.60 )
    9.6 ( 7.02 )
    9.6 ( 6.38 )
    No statistical analyses for this end point

    Secondary: Virologic response: changes in nasopharyngeal influenza titers by culture

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    End point title
    		 Virologic response: changes in nasopharyngeal influenza titers by culture
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 7
    End point values
    		 VIS410 4000 VIS410 2000 Placebo
    Number of subjects analysed
    29
    28
    28
    Units: Number of negative subjects
        Day 1 predose
    7
    6
    11
        Day 1 postdose
    7
    6
    9
        Day 3
    23
    24
    19
        Day 5
    25
    26
    28
        Day 7
    28
    27
    27
    Statistical analysis title
    		 logistic regression
    Statistical analysis description
    For use in overall summary statistical presentations, frequencies of ordinal scores at each visit were generated and evaluated by proportional odds ratio analysis, as implemented by logistic regression, including a test of the proportional odds assumption and generation of estimates of odds ratios. For this analysis, the reference response category was best (1=Discharge with full resumption of normal activities) to worst (7=Death).
    Comparison groups
    VIS410 4000 v VIS410 2000 v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.05
    Method
    		 proportional odds ratio
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [7] - Results were not statistically significant.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Day 56
    Adverse event reporting additional description
    "Non serious" adverse events includes both serious and nonserious events occurring greater than or equal to 5% of subjects. All serious adverse events are reported. Six deaths were reported in the study (Table 14.3.1.10); 3 subjects who received VIS410 (1 who received 4000 mg and 2 who received received 2000mg); None were related to study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    VIS410 4000
    Reporting group description
    		 -

    Reporting group title
    VIS410 2000
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 VIS410 4000 VIS410 2000 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 29 (20.69%)
    4 / 29 (13.79%)
    6 / 30 (20.00%)
         number of deaths (all causes)
    1
    2
    3
         number of deaths resulting from adverse events
    1
    2
    3
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    cardiac failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (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
    Neurological decompensation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
    Additional description: Single subject; concurrent with Pneumonia and Sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (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
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic encephalopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VIS410 4000 VIS410 2000 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 29 (55.17%)
    17 / 29 (58.62%)
    10 / 30 (33.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 29 (6.90%)
    3 / 30 (10.00%)
         occurrences all number
    2
    2
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 29 (13.79%)
    0 / 30 (0.00%)
         occurrences all number
    5
    4
    0
    Dyspepsia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0
    Nausea
         subjects affected / exposed
    4 / 29 (13.79%)
    2 / 29 (6.90%)
    1 / 30 (3.33%)
         occurrences all number
    4
    2
    1
    Vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    2
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 29 (10.34%)
    2 / 30 (6.67%)
         occurrences all number
    1
    3
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 29 (3.45%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 29 (10.34%)
    1 / 30 (3.33%)
         occurrences all number
    0
    3
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 29 (3.45%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2017
    Sample size adjustment; reduced to 120 subjects.
    19 Apr 2018
    • Reduction in number of sites. • Decreasing sample size from 390 to 120 subjects to enable completion in 2 influenza seasons; therefore, second DSMB review not required. • Clarification added to ensure all study product administered. Some sites used infusion lines with hold-up volumes of greater than 25 mL. • Utility of ordinal scale observed in prior trials of this size. • Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) added to complete the assays being performed. • Primary objective changed. • Time to cessation of oxygen support changed from primary endpoint to secondary. Some subjects may be on oxygen with SpO2 > 92% at baseline. • Added ordinal scale parameters to be assessed. • Removed interim analysis as sample size decreased to 120 subjects; final analysis to be performed upon completion of enrollment. • Statistical analysis changed due to the decrease in sample size.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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