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    Clinical Trial Results:
    A Phase 4, Randomised, Placebo-Controlled, Double-Blind, Multicenter Study to Evaluate Efficacy of Isoprinosine® in Comparison With Placebo in Subjects With Confirmed Acute Respiratory Viral Infections due to Influenza A or B Virus, Respiratory Syncytial Virus, Adenovirus, or Parainfluenza Virus 1 or 3.

    Summary
    EudraCT number
    2014-001863-11
    Trial protocol
    CZ   SK  
    Global end of trial date
    03 Jun 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jun 2016
    First version publication date
    02 Jun 2016
    Other versions
    Summary report(s)
    Justification to ERROR - Subject analysis set: Safety Analasys Set/EudrraCT_Letterhead.pdf

    Trial information

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    Trial identification
    Sponsor protocol code
    EWO-ISO-2014/1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ewopharma AG
    Sponsor organisation address
    Vordergasse 43, Schaffhausen, Switzerland, CH-8200
    Public contact
    Medical Director, Ewopharma International, s.r.o., +421 2594 298 25, e.salpova@ewopharma.com
    Scientific contact
    Medical Director, Ewopharma International, s.r.o., +421 2594 298 25, e.salpova@ewopharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy of Isoprinosine compared with placebo in subjects with laboratory confirmed acute respiratory viral infections due to influenza A or B virus, respiratory syncytial virus (RSV), adenovirus, or parainfluenza virus 1 or 3.
    Protection of trial subjects
    The tablets could be crushed and dissolved in a small amount of flavoured liquid at the time of administration as a meassure to make ingestion easier. Study site staff also worked with the subject to determine acceptable times for dosing so that doses were taken approximately 8 hours apart and were consistent with the subject’s lifestyle; scheduling of dosing did not disturb the subject’s usual sleep patterns.
    Background therapy
    Subjects were allowed to take symptomatic antipyretics and analgesics as required.
    Evidence for comparator
    Randomisation and blinding were used to minimise bias in assessing subjective symptoms of influenza-like illness. The use of placebo in this study was justified because influenza-like illness is largely mild and self-limiting with no other treatments approved for acute respiratory viral infections other than influenza. Also, the use of influenza-specific antivirals (neuraminidase inhibitors or amantadine) is not a part of routine medical management of influenza-like illness in the countries in which the study was conducted.
    Actual start date of recruitment
    08 Dec 2014
    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
    Czech Republic: 159
    Country: Number of subjects enrolled
    Slovakia: 304
    Worldwide total number of subjects
    463
    EEA total number of subjects
    463
    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)
    438
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 25 study sites both in Czech Republic (14 sites) and Slovakia (11 sites). Due to the delay in enrolling first subject as a result of late flu alert (not before December 2014) it was decided to continue enrolling more subjects until 30 April 2015 so as to have maximum number of completed subjects.

    Pre-assignment
    Screening details
    Laboratory confirmed acute respiratory viral infections due to influenza A or B virus, respiratory syncytial virus, adenovirus, or parainfluenza virus 1 or 3. Had an influenza-like illness according predefined measures and had onset of influenza-like illness no more than 36 hours prior to screening. Did not meet any of exclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    480 [1]
    Number of subjects completed
    463

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    screenfailure: 15
    Reason: Number of subjects
    non-randomized: 2
    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: The number of subject who have started the pre-assignment period is bigger due that more patients had been screened before being randomized
    Period 1
    Period 1 title
    Randomisation visit, EOT, overall period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    Placebo tablets were identical in appearance to Isoprinosine tablets. Isoprinosine tablets and matching placebo tablets were provided in the identical cartons identified by a kit number such that all study site staff and subjects remained blinded throughout the study. Only personnel in IWRS and clinical supplies were unblinded. Each subject was assigned a randomisation number that was separate from the subject identification number.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Isoprinosine tablets 500-mg tablets
    Arm description
    Subjects self-administered two tablets of Isoprinosine (500 mg) orally three times daily
    Arm type
    Experimental

    Investigational medicinal product name
    Isoprinosine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets of Isoprinosine (500 mg) orally three times daily, seven-day dosing duration period (Day 1 to Day 7)

    Arm title
    Placebo
    Arm description
    Subjects self-administered two tablets of placebo orally three times daily
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    placebo two tablets orally three times daily, seven day administration period

    Number of subjects in period 1
    Isoprinosine tablets 500-mg tablets Placebo
    Started
    231
    232
    Completed
    226
    230
    Not completed
    5
    2
         non-compliance with the protocol
             2
             -
         Adverse event, non-fatal
             1
             1
         Consent withdrawn by subject
             2
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Isoprinosine tablets 500-mg tablets
    Reporting group description
    Subjects self-administered two tablets of Isoprinosine (500 mg) orally three times daily

    Reporting group title
    Placebo
    Reporting group description
    Subjects self-administered two tablets of placebo orally three times daily

    Reporting group values
    Isoprinosine tablets 500-mg tablets Placebo Total
    Number of subjects
    231 232 463
    Age categorical
    Study population: male or nonpregnant female subject aged 18 to 75 years
    Units: Subjects
        Adults (18-64 years)
    219 219 438
        From 65-84 years
    12 13 25
    Age continuous
    A summary of demographics and baseline information were presented by treatment group and overall. The demographic characteristics consisted of age (years), sex, fertility status (female only), baseline weight, baseline height, and baseline body mass index (BMI).
    Units: years
        median (standard deviation)
    40 ± 12.86 40 ± 13.45 -
    Gender categorical
    Male or nonpregnant female subject aged 18 to 75 years;
    Units: Subjects
        Female
    111 107 218
        Male
    120 125 245
    Subject group by age and BMI
    Non-obese/obese subjects of less or more than 50 years of age (≥ <50)
    Units: Subjects
        obese (BMI ≥30 kg/m2) subjects of less than 50 y
    29 25 54
        Non-obese (BMI <30 kg/m2)subjects of less than 50y
    136 142 278
        non-obese (BMI <30 kg/m2) subjects ≥50 y
    45 44 89
        obese (BMI ≥30 kg/m2) subjects ≥50 y
    21 21 42
    Subject analysis sets

    Subject analysis set title
    mITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    mITT analysis set consists of all subjects randomly assigned to study drug who had a positive laboratory confirmation of acute respiratory viral infection due to influenza A or B virus, respiratory syncytial virus, adenovirus, or parainfluenza virus 1 or 3. This is the analysis set used for evaluating the primary efficacy objective. 137 subjects were included in the mITT analysis set. The mITT analysis set is used as the primary efficacy analysis set.

    Subject analysis set title
    PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per-protocol analysis set consists of subjects in the mITT analysis set with an EOT assessment that received the randomised study drug, took at least 80% of the prescribed doses of study drug, and did not have any major protocol deviations.

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT analysis set consists of all subjects who were randomly assigned to receive double-blinded study drug. All analyses using the ITT set groups subjects according to randomised treatment.

    Subject analysis sets values
    mITT PP ITT
    Number of subjects
    137
    116
    463
    Age categorical
    Study population: male or nonpregnant female subject aged 18 to 75 years
    Units: Subjects
        Adults (18-64 years)
    438
        From 65-84 years
    25
    Age continuous
    A summary of demographics and baseline information were presented by treatment group and overall. The demographic characteristics consisted of age (years), sex, fertility status (female only), baseline weight, baseline height, and baseline body mass index (BMI).
    Units: years
        median (standard deviation)
    ±
    ±
    40 ± 13.15
    Gender categorical
    Male or nonpregnant female subject aged 18 to 75 years;
    Units: Subjects
        Female
    218
        Male
    245
    Subject group by age and BMI
    Non-obese/obese subjects of less or more than 50 years of age (≥ <50)
    Units: Subjects
        obese (BMI ≥30 kg/m2) subjects of less than 50 y
    54
        Non-obese (BMI <30 kg/m2)subjects of less than 50y
    278
        non-obese (BMI <30 kg/m2) subjects ≥50 y
    89
        obese (BMI ≥30 kg/m2) subjects ≥50 y
    42

    End points

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    End points reporting groups
    Reporting group title
    Isoprinosine tablets 500-mg tablets
    Reporting group description
    Subjects self-administered two tablets of Isoprinosine (500 mg) orally three times daily

    Reporting group title
    Placebo
    Reporting group description
    Subjects self-administered two tablets of placebo orally three times daily

    Subject analysis set title
    mITT
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    mITT analysis set consists of all subjects randomly assigned to study drug who had a positive laboratory confirmation of acute respiratory viral infection due to influenza A or B virus, respiratory syncytial virus, adenovirus, or parainfluenza virus 1 or 3. This is the analysis set used for evaluating the primary efficacy objective. 137 subjects were included in the mITT analysis set. The mITT analysis set is used as the primary efficacy analysis set.

    Subject analysis set title
    PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Per-protocol analysis set consists of subjects in the mITT analysis set with an EOT assessment that received the randomised study drug, took at least 80% of the prescribed doses of study drug, and did not have any major protocol deviations.

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT analysis set consists of all subjects who were randomly assigned to receive double-blinded study drug. All analyses using the ITT set groups subjects according to randomised treatment.

    Primary: the time to resolution of all influenza-like symptoms presented at baseline to none

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    End point title
    the time to resolution of all influenza-like symptoms presented at baseline to none
    End point description
    The time to resolution was calculated as the total number of days from randomisation to first instance where all influenza-like symptoms had a score of 0 (date of resolution of all influenza like symptoms minus date of randomisation + 1). The subject used the daily diary card to document the symptoms on each day and continued beyond the EOT visit up to and including the follow-up visit on Day 21. The first day where it was observed that all symptoms had a score of 0 was flagged for analysis.
    End point type
    Primary
    End point timeframe
    Subjects will record the presence of influenza like illness respiratory and constitutional symptoms once daily in the evening using the 4 point scale on subject diary cards total number of days from randomisation up to and including the follow up.
    End point values
    Isoprinosine tablets 500-mg tablets Placebo mITT ITT
    Number of subjects analysed
    71
    66
    116
    463
    Units: days
        Time to Resolution of all Influenza-like Symptoms
    8
    8
    8
    8
    Statistical analysis title
    SAP Version 1.0
    Statistical analysis description
    Summary information on the number of subjects with resolution of symptoms, the number of censored subjects, median and quartile survival time and the corresponding value for the log rank test were presented. Treatment effect was estimated by calculating the hazard ratio (HR) and its 95% CI from an unstratified proportional hazards model. The assumption of proportional hazards underlying the log-rank test was investigated.
    Comparison groups
    Isoprinosine tablets 500-mg tablets v Placebo
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.324 [2]
    Method
    Chi-squared
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.175
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.806
         upper limit
    1.714
    Variability estimate
    Standard deviation
    Notes
    [1] - Continuous data were described using descriptive statistics (i.e. n, mean, standard deviation [SD], median, minimum, and maximum). Categorical data were described using the subject count and percentage in each category. All statistical tests were 2-sided hypothesis tests performed using a 5% level of significance, leading to 95% (2-sided) confidence intervals (CIs).
    [2] - If a P value was less than 0.001, it was reported as ‘<0.001’. If a value was greater than 0.999, it was reported as ‘>0.999’.

    Primary: the time to resolution of all influenza-like symptoms

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    End point title
    the time to resolution of all influenza-like symptoms
    End point description
    Primary endpoint was analysed for the ITT analysis set for the subgroups based on BMI (BMI <30 kg/m2, BMI ≥30 kg/m2). Primary endpoint was displayed by the combination of subgroup of interest and age group, where age group was <50 years and ≥ 50 years.
    End point type
    Primary
    End point timeframe
    Subjects will record the presence of influenza like illness respiratory and constitutional symptoms once daily in the evening using the 4 point scale on subject diary cards total number of days from randomisation up to and including the follow up.
    End point values
    Isoprinosine tablets 500-mg tablets Placebo ITT
    Number of subjects analysed
    136
    142
    278
    Units: days
    median (confidence interval 95%)
        Age Group: <50 BMI <30
    8 (7 to 10)
    8 (7 to 12)
    8 (7 to 12)
    Statistical analysis title
    SAP Version 1.0
    Statistical analysis description
    The analysis was conducted on the ITT analysis set and consisted of an unstratified log-rank test to compare the time to resolution of all influenza-like symptoms presented at baseline to none between Isoprinosine and placebo. Any ties in the data were handled by the discrete method.
    Comparison groups
    Isoprinosine tablets 500-mg tablets v Placebo
    Number of subjects included in analysis
    278
    Analysis specification
    Post-hoc
    Analysis type
    superiority [3]
    P-value
    = 0.018
    Method
    Chi-squared
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.307
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.01
         upper limit
    1.691
    Variability estimate
    Standard deviation
    Notes
    [3] - Treatment effect was estimated by calculating the hazard ratio (HR) and its 95% CI from an unstratified proportional hazards model.

    Primary: the time to resolution of all influenza-like symptoms

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    End point title
    the time to resolution of all influenza-like symptoms
    End point description
    Primary endpoint was analysed for the ITT analysis set for the subgroups based on BMI (BMI <30 kg/m2, BMI ≥30 kg/m2). Primary endpoint was displayed by the combination of subgroup of interest and age group, where age group was <50 years and ≥ 50 years.
    End point type
    Primary
    End point timeframe
    Subjects will record the presence of influenza like illness respiratory and constitutional symptoms once daily in the evening using the 4 point scale on subject diary cards total number of days from randomisation up to and including the follow up.
    End point values
    Isoprinosine tablets 500-mg tablets Placebo ITT
    Number of subjects analysed
    29
    25
    54
    Units: days
    median (confidence interval 95%)
        Age Group: <50 BMI ≥30
    8 (7 to 16)
    7 (7 to 9)
    7.5 (7 to 16)
    Statistical analysis title
    SAP Version 1.0
    Statistical analysis description
    The analysis was conducted on the ITT analysis set and consisted of an unstratified log-rank test to compare the time to resolution of all influenza-like symptoms presented at baseline to none between Isoprinosine and placebo. Any ties in the data were handled by the discrete method.
    Comparison groups
    Isoprinosine tablets 500-mg tablets v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Post-hoc
    Analysis type
    superiority [4]
    P-value
    = 0.37
    Method
    Chi-squared
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.782
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.429
         upper limit
    1.426
    Variability estimate
    Standard deviation
    Notes
    [4] - Treatment effect was estimated by calculating the hazard ratio (HR) and its 95% CI from an unstratified proportional hazards model.

    Primary: the time to resolution of all influenza-like symptoms

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    End point title
    the time to resolution of all influenza-like symptoms
    End point description
    Primary endpoint was analysed for the ITT analysis set for the subgroups based on BMI (BMI <30 kg/m2, BMI ≥30 kg/m2). Primary endpoint was displayed by the combination of subgroup of interest and age group, where age group was <50 years and ≥ 50 years.
    End point type
    Primary
    End point timeframe
    Subjects will record the presence of influenza like illness respiratory and constitutional symptoms once daily in the evening using the 4 point scale on subject diary cards total number of days from randomisation up to and including the follow up.
    End point values
    Isoprinosine tablets 500-mg tablets Placebo ITT
    Number of subjects analysed
    45
    44
    89
    Units: days
    median (confidence interval 95%)
        Age Group: ≥50 BMI <30
    8 (8 to 11)
    8 (7 to 10)
    8 (8 to 11)
    Statistical analysis title
    SAP Version 1.0
    Statistical analysis description
    The analysis was conducted on the ITT analysis set and consisted of an unstratified log-rank test to compare the time to resolution of all influenza-like symptoms presented at baseline to none between Isoprinosine and placebo. Any ties in the data were handled by the discrete method.
    Comparison groups
    Placebo v Isoprinosine tablets 500-mg tablets
    Number of subjects included in analysis
    89
    Analysis specification
    Post-hoc
    Analysis type
    superiority [5]
    P-value
    = 0.383
    Method
    Chi-squared
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.838
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.534
         upper limit
    1.316
    Variability estimate
    Standard deviation
    Notes
    [5] - Treatment effect was estimated by calculating the hazard ratio (HR) and its 95% CI from an unstratified proportional hazards model.

    Primary: the time to resolution of all influenza-like symptoms

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    End point title
    the time to resolution of all influenza-like symptoms
    End point description
    Primary endpoint was analysed for the ITT analysis set for the subgroups based on BMI (BMI <30 kg/m2, BMI ≥30 kg/m2). Primary endpoint was displayed by the combination of subgroup of interest and age group, where age group was <50 years and ≥ 50 years.
    End point type
    Primary
    End point timeframe
    Subjects will record the presence of influenza like illness respiratory and constitutional symptoms once daily in the evening using the 4 point scale on subject diary cards total number of days from randomisation up to and including the follow up.
    End point values
    Isoprinosine tablets 500-mg tablets Placebo ITT
    Number of subjects analysed
    21
    21
    42
    Units: days
    median (confidence interval 95%)
        Age Group: ≥50 BMI ≥30
    10 (8 to 12)
    8 (8 to 11)
    9 (8 to 16)
    Statistical analysis title
    SAP Version 1.0
    Statistical analysis description
    The analysis was conducted on the ITT analysis set and consisted of an unstratified log-rank test to compare the time to resolution of all influenza-like symptoms presented at baseline to none between Isoprinosine and placebo. Any ties in the data were handled by the discrete method.
    Comparison groups
    Placebo v Isoprinosine tablets 500-mg tablets
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    superiority [6]
    P-value
    = 0.37
    Method
    Chi-squared
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.782
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.429
         upper limit
    1.426
    Variability estimate
    Standard deviation
    Notes
    [6] - Treatment effect was estimated by calculating the hazard ratio (HR) and its 95% CI from an unstratified proportional hazards model.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed from the time the subject signs the informed consent until exit from the study (day 21 +/- 3 days)
    Adverse event reporting additional description
    Safety assessments included monitoring AEs, serious AEs (SAEs), and AEs leading to treatment interruption or discontinuation. The number of subjects included in Safety Analysis Set is corresponding with the number of subjects who were given at least one dose of study treatment – 464 subjects.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Isoprinosine treatment group
    Reporting group description
    All percentages were based on the number of subjects on the actual treatment in the ITT analysis set for isoprinosine treatment group.

    Reporting group title
    Placebo treatment group
    Reporting group description
    All percentages were based on the number of subjects on the actual treatment in the ITT analysis set for placebo treatment group.

    Serious adverse events
    Isoprinosine treatment group Placebo treatment group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pleuropneumonia
    Additional description: Study Day 5, the subject experienced a severe serious adverse event of pleuropneumonia. Study drug permanently discontinued.The investigator assessed the serious adverse event of pleuropneumonia to be unrelated to study drug.
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 48
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    vertebrogenic pain syndrome
    Additional description: Subject in the Isoprinosine treatment group experienced severe treatment-emergent SAEs of rhinopharyngitis and vertebrogenic pain syndrome that led to the permanent discontinuation of study drug, and the subject discontinued from the study.
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         occurrences causally related to treatment / all
    0 / 39
    0 / 48
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Isoprinosine treatment group Placebo treatment group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 229 (17.03%)
    48 / 235 (20.43%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Hypotension
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    General disorders and administration site conditions
    Influenza-like symptoms
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Fever
         subjects affected / exposed
    2 / 229 (0.87%)
    3 / 235 (1.28%)
         occurrences all number
    39
    48
    Mucous discharge
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Pain menstrual
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Premenstrual pain
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Respiratory, thoracic and mediastinal disorders
    Bronchoconstriction
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Cough
         subjects affected / exposed
    0 / 229 (0.00%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Hemoptysis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Irritative cough
         subjects affected / exposed
    1 / 229 (0.44%)
    3 / 235 (1.28%)
         occurrences all number
    39
    48
    Nasal mucosal swelling
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Nasal obstruction
         subjects affected / exposed
    3 / 229 (1.31%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Shortness of breath
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 229 (0.87%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Eye disorders
    Eyelid rash
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Ear and labyrinth disorders
    Earache
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Motion sickness
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Tinnitus
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Sensation of pressure in ear
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Vertigo
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 229 (0.44%)
    5 / 235 (2.13%)
         occurrences all number
    39
    48
    Dyspepsia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Diarrhoea
         subjects affected / exposed
    1 / 229 (0.44%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Nausea
         subjects affected / exposed
    1 / 229 (0.44%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Pyrosis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Stomatitis aphthous
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Rectal bleeding
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Vomiting
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Efflorescence
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Skin rash
         subjects affected / exposed
    0 / 229 (0.00%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Musculoskeletal and connective tissue disorders
    Cervicocranial syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Joint pain
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Muscle pain
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Muscle cramps
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Vertebrogenic pain syndrome
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Infections and infestations
    Paronychia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Pharyngitis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Pneumonia
         subjects affected / exposed
    1 / 229 (0.44%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 229 (0.00%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Rhinitis
         subjects affected / exposed
    1 / 229 (0.44%)
    2 / 235 (0.85%)
         occurrences all number
    39
    48
    Rhinopharyngitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Rhinosinusitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48
    Sinusitis
         subjects affected / exposed
    0 / 229 (0.00%)
    3 / 235 (1.28%)
         occurrences all number
    39
    48
    Superinfection bacterial
         subjects affected / exposed
    0 / 229 (0.00%)
    3 / 235 (1.28%)
         occurrences all number
    39
    48
    Tonsillitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 235 (0.00%)
         occurrences all number
    39
    48
    Tracheitis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 235 (0.43%)
         occurrences all number
    39
    48

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2014
    Protocol amendment Version 1 dated 29 May 2014.: Inclusion criterion 1: Upper age limit was changed from 55 years to 75 years.; Inclusion criterion 2: Influenza-like illness definition was expanded to include self-measured axillary temperature of ≥37.5°C; Recording of daily activities assessment on additional diary cards after the EOT visit was included in case of subjects issued with additional diary cards at the EOT visit; Clarification was added for recording oral temperature, influenza-like symptoms, and ability to perform activities of daily living after the EOT visit on additional diary cards in case of subjects presenting with fever, a score of 1 or more on influenza-like symptoms assessment scale, or a score of 1 or more on daily activities assessment scale at the EOT visit. Clarification was also added regarding the resolution criteria for these 3 parameters after the EOT visit.; Body weight and height were moved from ‘demographics and other baseline characteristics’ section to ‘Vital sign measurements’ section for consistency with the schedule of events.; A section for influenza-like symptoms assessment on Day 1 prior to randomisation was added for clarity.; The section for ‘review of concomitant medications’ was updated to include prior medications as well.; Adverse event assessment was changed to only to be assessed from the time the subject signs the informed consent form (ICF) until exit from the study.; Serious adverse event assessment was amended such that those that occurred after the subject exited the study need not be reported.; Serious adverse event reporting text was amended to include electronic data capture (EDC) system and fax line number was corrected.

    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.
    The impact of the lack of significant influenza outbreak adversely affected the statistical power and reduced the power of the study and the results of the study were impacted by epidemiologic considerations.
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