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    Clinical Trial Results:
    A randomized, double-blind, parallel group, placebo controlled Phase II study to evaluate the safety and efficacy of inhaled LASAG and Placebo, applied three times daily in adult hospitalized patients with acute serious influenza

    Summary
    EudraCT number
    		 2012-004072-19
    Trial protocol
    		 DE   CZ   HU   SK   ES   LV   LT   BG  
    Global end of trial date
    15 May 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    31 Mar 2021
    First version publication date
    18 May 2016
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    New version of PDF without the scanned signatures. Done for security purposes so that no scanned signature are available in public domain.
    Summary report(s)
    		 CSR Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    Acti-INSP-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vectura GmbH
    Sponsor organisation address
    Robert-Koch-Allee 29, Gauting, Germany, 82131
    Public contact
    Project Manager Clinical Studies, Ventaleon GmbH Wohraer Str. 37 35285 Gemünden/Wohra, 0049 64535853043, karlheinz.nocker@ventaleon.com
    Scientific contact
    Chief Medical Officer Dr. Sebastian Canisius, Ventaleon GmbH Wohraer Str. 37 35285 Gemünden/Wohra, 0049 64535853048, sebastian.canisius@ventaleon.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
    17 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy and safety of inhaled D,L-lysine acetylsalicylate glycine (LASAG) plus standard of care compared to placebo plus standard of care in patients hospitalized due to acute serious influenza OR an influenza caused worsening of a primary medical condition measured by time to alleviation of influenza symptoms. Influenza symptoms are defined as: • nasal congestion • sore throat • cough • aches/myalgia • fatigue • headaches • feverishness/chills/sweats Time to alleviation is defined as the time in hours from first inhalation of LASAG until at least 5 of 7 clinical influenza symptoms are rated with 0 (not present, i.e. like before the influenza) or 1 (mild) on the influenza symptom questionnaire without any use of symptom relief medication (i.e. acetaminophen) and remained so for at least 24±2 hours.
    Protection of trial subjects
    Based on the data from preclinical and clinical testing as well as information from the routine clinical use of Acetyl-Salicylic Acid (ASA) it is highly probable that patients suffering from acute serious influenza could benefit from intake of the study medication. Potential risk of lacking efficacy is minimized by allowed usage of standard care, for all patients, according to routine practice of each participating site. All adverse events, including those previously observed during the initial clinical exposure, will be carefully monitored three times daily during the whole treatment period and daily until follow-up visit 3. Additionally, vital signs, physical examinations, O2 saturation and laboratory parameters will be recorded to maximize patient`s safety. Indicated, permitted antiviral treatment must have been started prior to first LASAG inhalation (and will then be continued). Initiation of antiviral treatment or any change in its dosing during the treatment period will lead to withdrawal of the patient. As usage of NSAIDs is not allowed, only acetaminophen must be used as influenza symptom relief medication during study treatment. Patients treated with a daily dose of ≤ 100mg Aspirin for Coronary Artery Disease (CAD) prevention may be included, but the Aspirin dose must remain unchanged during the course of the study.
    Background therapy
    		 Antiviral medications: Indicated, permitted antiviral treatment must have been started prior to first LASAG inhalation (and will then be continued). Initiation of antiviral treatment or any change in its dosing during the treatment period will lead to withdrawal of the patient. o Antiviral therapy with adamantane derivates is allowed. However, antiviral therapy with adamantane derivates is usually not effective because of widespread resistance of influenza viruses against these agents. o Antiviral therapy with neuraminidase blocking agents: If antiviral therapy is indicated to the investigator’s opinion the following neuraminidase blocking agents is allowed: Oseltamivir o Zanamivir is prohibited as it is administered via inhalation and interactions with the study drug LASAG cannot be excluded. If patients receive Oseltamivir as standard of care at the respective study site, this treatment should be continued during hospital stay according to Oseltamivir’s label for a minimum of 5 days. If standard of care at the respective site does not include Oseltamivir treatment, only symptomatic treatment may be initiated (i.e. acetaminophen) at investigators’ discretion. Antibiotic Treatment Antibiotic Treatment is not prohibited but, as usual, there must be a clear indication for its use. A prophylactic administration to avoid bacterial infection and / or pneumonia is not considered as such a clear indication and should therefore be avoided. Any antibiotic treatment needs to be documented in the patient’s records and in the eCRF.
    Evidence for comparator
    		 N/A as comparator is placebo.
    Actual start date of recruitment
    26 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Lithuania: 3
    Country: Number of subjects enrolled
    Romania: 89
    Worldwide total number of subjects
    115
    EEA total number of subjects
    115
    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)
    97
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started in the norther hemisphere in Germany (Europe), and the southern hemisphere was subsequently added.

    Pre-assignment
    Screening details
    		 During periods of documented influenza in the community, subjects with influenza-like illness meeting all inclusion and none of the exclusion criteria were enrolled and randomized prior to laboratory confirmation of influenza. Subjects outside of periods of documented community influenza had to have RT-PCR or RAT confirmation prior to randomization

    Pre-assignment period milestones
    Number of subjects started
    		 171 [1]
    Number of subjects completed
    		 115

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Not eligible: 56
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: We reported also the number of patients screened (171) but a certain amount was not eligible and therefore was never recruited really.
    Period 1
    Period 1 title
    Baseline (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
    		 LASAG group
    Arm description
    		 800 mg LASAG/4mL fill dose is equivalent to 400 mg ASA/4 mL fill dose. 400mg ASA/4mL fill dose results in an alveolar dose of 45mg ASA.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LASAG
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects will receive 15 doses of study medication by AKITA JET nebulizer on 5 to 6 consecutive days. Usually, three doses per day will be applied, depending on the start time of the first inhalation. Start of Treatment can then consist of either: o 3 inhalations starting with morning inhalation between 7:00 – 9:00 o 2 inhalations starting with mid-day inhalation between 12:00 – 14:00 o 1 inhalation starting with evening inhalation between 17:00 – 19:00 This is depending on the time the patient can be randomized.

    Arm title
    		 Placebo Group
    Arm description
    		 4 mL saline solution (0.9% Sodium chloride (NaCl)).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Isotonic Saline
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects will receive 15 doses of study medication by AKITA JET nebulizer on 5 to 6 consecutive days. Start of Treatment can then consist of either: o 3 inhalations starting with morning inhalation between 7:00 – 9:00 o 2 inhalations starting with mid-day inhalation between 12:00 – 14:00 o 1 inhalation starting with evening inhalation between 17:00 – 19:00 This is depending on the time the patient can be randomized.

    Arm title
    		 LASAG low dose
    Arm description
    		 400 mg LASAG/4mL fill dose is equivalent to 200 mg/4mL ASA fill dose. 200 mg/4mL ASA fill dose results in an alveolar dose of 27mg ASA.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LASAG low dose
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects will receive 15 doses of study medication by AKITA JET nebulizer on 5 to 6 consecutive days. Usually, three doses per day will be applied, depending on the start time of the first inhalation. Start of Treatment can then consist of either: o 3 inhalations starting with morning inhalation between 7:00 – 9:00 o 2 inhalations starting with mid-day inhalation between 12:00 – 14:00 o 1 inhalation starting with evening inhalation between 17:00 – 19:00 This is depending on the time the patient can be randomized.

    Number of subjects in period 1
    		LASAG group Placebo Group LASAG low dose
    Started
    57
    52
    6
    Completed
    37
    31
    4
    Not completed
    20
    21
    2
         No inhalation of study drug
    1
    1
    -
         No Influenza Infection confirmed
    11
    15
    2
         Protocol deviation
    8
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LASAG group
    Reporting group description
    		 800 mg LASAG/4mL fill dose is equivalent to 400 mg ASA/4 mL fill dose. 400mg ASA/4mL fill dose results in an alveolar dose of 45mg ASA.

    Reporting group title
    Placebo Group
    Reporting group description
    		 4 mL saline solution (0.9% Sodium chloride (NaCl)).

    Reporting group title
    LASAG low dose
    Reporting group description
    		 400 mg LASAG/4mL fill dose is equivalent to 200 mg/4mL ASA fill dose. 200 mg/4mL ASA fill dose results in an alveolar dose of 27mg ASA.

    Reporting group values
    		 LASAG group Placebo Group LASAG low dose Total
    Number of subjects
    		 57 52 6 115
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.84 ( 13.31 ) 45.85 ( 16.87 ) 53.33 ( 11.24 ) -
    Gender categorical
    Units: Subjects
        Female
    		 30 29 2 61
        Male
    		 27 23 4 54
        Not recorded
    		 0 0 0 0
    Influenza positive (RT-PCR)
    An RT-PCR was performed to determine whether a subject enrolled really had an Influenza infection. The MITT was defined as the subjects having Influenza infection.
    Units: Subjects
        Influenza positive
    		 46 38 5 89
        Influenza negative
    		 11 14 1 26
    Subject analysis sets

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set (SA) includes all subjects randomized in the trial who received at least one inhalation. Treatment groups for the SA will be defined by real treatments of patients.

    Subject analysis set title
    MITT Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified intent-to-treat (MITT) population consisted of all subjects who received at least one dose of study drug (or an inhalation of placebo) and who had influenza infection confirmed by RT-PCR.

    Subject analysis set title
    PP Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) analysis set included all subjects from the MITT population who had at least 13 inhalations of LASAG or placebo and had no major protocol deviations (identified prior to database lock and unblinding).

    Subject analysis sets values
    		 Safety Set MITT Set PP Set
    Number of subjects
    113
    81
    68
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.55 ( 15.85 )
    44.94 ( 15.46 )
    44.04 ( 14.51 )
    Gender categorical
    Units: Subjects
        Female
    59
    46
    38
        Male
    54
    35
    30
        Not recorded
    0
    0
    0
    Influenza positive (RT-PCR)
    An RT-PCR was performed to determine whether a subject enrolled really had an Influenza infection. The MITT was defined as the subjects having Influenza infection.
    Units: Subjects
        Influenza positive
    85
    81
    68
        Influenza negative
    28
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    LASAG group
    Reporting group description
    		 800 mg LASAG/4mL fill dose is equivalent to 400 mg ASA/4 mL fill dose. 400mg ASA/4mL fill dose results in an alveolar dose of 45mg ASA.

    Reporting group title
    Placebo Group
    Reporting group description
    		 4 mL saline solution (0.9% Sodium chloride (NaCl)).

    Reporting group title
    LASAG low dose
    Reporting group description
    		 400 mg LASAG/4mL fill dose is equivalent to 200 mg/4mL ASA fill dose. 200 mg/4mL ASA fill dose results in an alveolar dose of 27mg ASA.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set (SA) includes all subjects randomized in the trial who received at least one inhalation. Treatment groups for the SA will be defined by real treatments of patients.

    Subject analysis set title
    MITT Set
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified intent-to-treat (MITT) population consisted of all subjects who received at least one dose of study drug (or an inhalation of placebo) and who had influenza infection confirmed by RT-PCR.

    Subject analysis set title
    PP Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) analysis set included all subjects from the MITT population who had at least 13 inhalations of LASAG or placebo and had no major protocol deviations (identified prior to database lock and unblinding).

    Primary: Time to alleviation of clinical influenza symptoms

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    End point title
    		 Time to alleviation of clinical influenza symptoms [1]
    End point description
    The primary variable was the time to alleviation of clinical influenza symptoms which was defined as the time in hours from first inhalation of LASAG until at least 5 of 7 clinical influenza symptoms were rated with 0 (not present, i.e. like before the influenza) or 1 (mild) on the influenza symptom questionnaire without any use of symptom relief medication (i.e. acetaminophen) and remained so for at least 24±2 hours.
    End point type
    Primary
    End point timeframe
    From first inhalation of study drug until first occurrence of alleviation of symptoms defined as at least 5 of 7 clinical influenza symptoms rated with 0 or 1 without any symptom relief medication and remained so for at least 24±2 hrs.
    Notes
    [1] - 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: The arm "low dose" was discontinued prematurely. Therefore results for this arm for the endpoints are not reported.
    End point values
    		 LASAG group Placebo Group MITT Set PP Set
    Number of subjects analysed
    39
    34
    73
    67
    Units: hours
        arithmetic mean (standard deviation)
    43.03 ( 26.6 )
    42.2 ( 28.63 )
    42.64 ( 27.37 )
    43.28 ( 25.87 )
    Attachments
    		 Kaplan-Meier estimation of time to alleviation [h]
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The difference between treatment groups calculated by means of a t-Test (two-sided).
    Comparison groups
    LASAG group v Placebo Group
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.65 [3]
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.0653
         upper limit
    		 13.7213
    Variability estimate
    Standard deviation
    Dispersion value
    27.5589
    Notes
    [2] - This is the primary analysis of time to alleviation between LASAG Group and Placebo Group in the MITT analysis set.
    [3] - one-sided p-value

    Secondary: Time to alleviation of clinical influenza signs

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    End point title
    		 Time to alleviation of clinical influenza signs [4]
    End point description
    End point type
    Secondary
    End point timeframe
    First inhalation until end of treatment
    Notes
    [4] - 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: The arm "low dose" was discontinued prematurely. Therefore results for this arm for the endpoints are not reported.
    End point values
    		 LASAG group Placebo Group MITT Set
    Number of subjects analysed
    39
    31
    70
    Units: hours
        arithmetic mean (standard deviation)
    26.58 ( 20.65 )
    33.58 ( 24.56 )
    29.68 ( 22.57 )
    Statistical analysis title
    		 Comparison between LASAG and Placebo
    Statistical analysis description
    Two Sided T-Test
    Comparison groups
    LASAG group v Placebo Group
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Secondary: Change in routine daily activity score

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    End point title
    		 Change in routine daily activity score [5]
    End point description
    The efficacy of LASAG and placebo was investigated in addition by routine daily activity score on a functional visual analogue scale ranging from 0 (unable to perform one’s routine daily activities at all) to 10 (fully able to perform one’s routine daily activities). This score was integrated in the influenza symptom questionnaire. Scores had to be measured by a regular ruler starting from 0 to the nearest 0.1 cm and be documented together with date and time. The baseline corrected area under these daily activity score curve (AUC) was calculated for each patient and standardized by division through the time interval of the underlying measurements. Missing values were imputed by LOCF (last observation carried forward).
    End point type
    Secondary
    End point timeframe
    Activity scores were filled out prior to each inhalation (i.e. mostly on a 3-times per day) during the treatment phase, once daily during each follow-up visit and three times daily during the daily visit after termination of treatment.
    Notes
    [5] - 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: The arm "low dose" was discontinued prematurely. Therefore results for this arm for the endpoints are not reported.
    End point values
    		 LASAG group Placebo Group
    Number of subjects analysed
    45
    36
    Units: points
        arithmetic mean (standard deviation)
    3.2 ( 1.64 )
    2.69 ( 1.46 )
    Statistical analysis title
    		 Comparison between LASAG and Placebo
    Statistical analysis description
    The improvement of the daily activity scores was analyzed by the Mann-Whitney U-test.
    Comparison groups
    LASAG group v Placebo Group
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.25
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [6] - The improvement of the daily activity scores was more pronounced in the LASAG group (mean and median of 3.2) compared with the placebo group (mean and median of 2.7). The difference between both treatment groups was small however (mean difference 0.51) and the Mann-Whitney U-test yielded a non significant p=0.25.

    Secondary: Anti-viral efficacy

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    End point title
    		 Anti-viral efficacy [7]
    End point description
    Since no quantitative values for viral load were available, a qualitative analysis of viral load prior to 8th inhalation was performed. The RT-PCR prior to 8th inhalation determined the influenza status of the patients (negative/positive). The test was performed for 76 patients of the MITT set, excluding patients #0701-001 (LASAG group, stopped after inhalation 2), #1002-005 (LASAG group, stopped after inhalation 4) and #1006-010 (LASAG group, stopped after inhalation 5). Additionally, patient #0306-001 (LASAG group) and patient #0901-001 (placebo group) were excluded because no RT-PCR data were obtained.
    End point type
    Secondary
    End point timeframe
    Number of patients with positive inflzenza RT-PCR test prior to inhalation 8
    Notes
    [7] - 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: The arm "low dose" was discontinued prematurely. Therefore results for this arm for the endpoints are not reported.
    End point values
    		 LASAG group Placebo Group
    Number of subjects analysed
    41
    35
    Units: number of pts.
    15
    15
    Statistical analysis title
    		 Comparison between LASAG and Placebo
    Statistical analysis description
    Comparison of percentage of patients who still have positive Influenza RT-PCR test prior to inhalation 8 (MITT). Per definition, all patients in MITT had a positive Influenza RT-PCR test at baseline.
    Comparison groups
    LASAG group v Placebo Group
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.58 [9]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [8] - The number of patients with negative RT-PCR at inhalation 8 was slightly larger in the LASAG group (63% LASAG vs. 57% placebo).
    [9] - The chi-squared test performed showed no statistically significant difference between LASAG and placebo group (two sided Chi-squared test: p-value=0.58).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After signing ICF until 30 days after the end of Follow-Up Visit 3, serious adverse events will be collected by Investigator and reported to Sponsor. Adverse Events will be collected until the end of Follow-Up Visit 3.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    LASAG group
    Reporting group description
    		 800 mg LASAG/4mL fill dose is equivalent to 400 mg ASA/4 mL fill dose. 400mg ASA/4mL fill dose results in an alveolar dose of 45mg ASA.

    Reporting group title
    Placebo Group
    Reporting group description
    		 4 mL saline solution (0.9% Sodium chloride (NaCl)).

    Reporting group title
    LASAG low dose
    Reporting group description
    		 400 mg LASAG/4mL fill dose is equivalent to 200 mg/4mL ASA fill dose. 200 mg/4mL ASA fill dose results in an alveolar dose of 27mg ASA.

    Serious adverse events
    		 LASAG group Placebo Group LASAG low dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Respiratory tract infection nosokomial
    Additional description: Event was a respiratory nosocomial infection. It was considered as SAE due to a prolongation of hospitalization. This event occurred in the placebo group.
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 51 (1.96%)
    0 / 6 (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: 5%
    Non-serious adverse events
    		 LASAG group Placebo Group LASAG low dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 56 (41.07%)
    21 / 51 (41.18%)
    5 / 6 (83.33%)
    Vascular disorders
    Hypotension/Hypertension
         subjects affected / exposed
    2 / 56 (3.57%)
    4 / 51 (7.84%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    General disorders and administration site conditions
    Influenza Symptoms
         subjects affected / exposed
    0 / 56 (0.00%)
    3 / 51 (5.88%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea/Epistaxis/Pneumonia
         subjects affected / exposed
    10 / 56 (17.86%)
    4 / 51 (7.84%)
    2 / 6 (33.33%)
         occurrences all number
    10
    4
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 51 (1.96%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Investigations
    Different Investigations
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 51 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 51 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 56 (5.36%)
    4 / 51 (7.84%)
    2 / 6 (33.33%)
         occurrences all number
    3
    4
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 51 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea/Nausea/Gastritis
         subjects affected / exposed
    10 / 56 (17.86%)
    8 / 51 (15.69%)
    1 / 6 (16.67%)
         occurrences all number
    14
    9
    1
    Skin and subcutaneous tissue disorders
    Exanthema
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 51 (3.92%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Renal and urinary disorders
    Renal insufficiency
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 51 (1.96%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Respiratory Tract Infections
         subjects affected / exposed
    7 / 56 (12.50%)
    12 / 51 (23.53%)
    1 / 6 (16.67%)
         occurrences all number
    7
    12
    1
    Metabolism and nutrition disorders
    Abnormal Lab Values
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 51 (3.92%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2014
    The protocol has been amended due to an administrative change. The sponsor Activaero GmbH with its principal place of business at Wohraer Strasse 37, 35285 Gemuenden/Wohra, Germany, has been acquired by the company Vectura Group plc (UK). As a result of this acquisition Activaero GmbH has been re-named to Vectura GmbH. The protocol is amended to discontinue the investigation of the LASAG low dose arm (i.e. 400mg LASAG /4 mL, three times daily). An additional amendment to the protocol is performed with regard to a change in the inclusion criterion 9 (see below). However, due to the fact that LASAG’s antiviral effect is affecting the host cell and not the virus cell itself, the effectiveness with regard to virus reduction can still be assumed even after 72 hours (=3 days) of symptom onset. This hypothesis was supported in preclinical efficacy models which demonstrated that LASAG was efficacious in animal models with established infection (Activaero GmbH, IB 2012). For this reason the inclusion criterion 9 is changed so that a patient reported onset of illness less than 120 hours (=5 days) before first study drug application is eligible.

    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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