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    Clinical Trial Results:
    Investigation of the efficacy and safety of ANGOCIN® Anti-Infekt N versus placebo in adult patients with acute, uncomplicated rhinosinusits. A multi-center, randomized, double-blind, placebo-controlled, parallel-group phase IV clinical trial.

    Summary
    EudraCT number
    		 2017-002081-40
    Trial protocol
    		 DE  
    Global end of trial date
    28 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2022
    First version publication date
    06 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Repha_1431
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Repha GmbH
    Sponsor organisation address
    Alt-Godshorn 87, Langenhagen, Germany, 30855
    Public contact
    Mediconomics GmbH, CRO, Mediconomics GmbH, 049 0511 5609980, info@mediconomics.com
    Scientific contact
    Mediconomics GmbH, CRO, Mediconomics GmbH , 049 0511 5609980, info@mediconomics.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
    28 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In this parallel-group phase IV study, the aim was to investigate the use of Angocin® Anti-Infect N under routine conditions in the treatment of acute uncomplicated rhinosinusitis in adults between 18 and 75 years of age with a focus on efficacy, safety and tolerability.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of Good Clinical Practice (GCP), which has its origins in the Declaration of Helsinki, and in strict compliance with the German Drug Law (AMG) and the German Federal Data Protection Act (BDSG), in order to protect the rights, safety and well-being of patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Oct 2017
    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
    Germany: 380
    Worldwide total number of subjects
    380
    EEA total number of subjects
    380
    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)
    362
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A 14-day treatment with a total of 5 visits was planned for each patient of which 3 were face-to-face visits at the study centre and 2 visits were conducted by telephone. The study began on day 0 (visit 1) with randomisation and in the presence of acute, uncomplicated rhinosinusitis. rhinosinusitis.

    Pre-assignment
    Screening details
    		 All patients who appeared suitable for the clinical trial, taking into account the inclusion and exclusion criteria, and who had given their written consent to participate in the clinical trial were entered into the Patient Identification Log and the Patient Identification List at visit 1.

    Period 1
    Period 1 title
    Therapy Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Blinding of investigator and patient was achieved by the following measures: Verum and placebo did not differ visually. The blisters and secondary packaging did not contain any information on the name and strength of the study medication. The study medication of the two study arms was labelled with the same batch name and expiry date, traceability was ensured via the randomisation number and the manufacturing documentation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Investigational product
    Arm description
    		 Angocin Anti-Infekt N 3x4 tablets daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Angocin Anti-Infekt N
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3x4 tablets daily for a total of 14 days

    Arm title
    		 Placebo
    Arm description
    		 3x4 tablets per day for a total of 14 days
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3x4 tablets daily for a total of 14 days

    Number of subjects in period 1
    		Investigational product Placebo
    Started
    192
    188
    Completed
    179
    177
    Not completed
    13
    11
         violation of selection criteria
    -
    1
         Consent withdrawn by subject
    4
    1
         administration of antibiotics
    -
    5
         Adverse event, non-fatal
    3
    3
         antibiotics were prescribed
    5
    -
         Occurence of exclusion criterium
    -
    1
         personal reasons
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Investigational product
    Reporting group description
    		 Angocin Anti-Infekt N 3x4 tablets daily

    Reporting group title
    Placebo
    Reporting group description
    		 3x4 tablets per day for a total of 14 days

    Reporting group values
    		 Investigational product Placebo Total
    Number of subjects
    		 192 188 380
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 185 177 362
        From 65-84 years
    		 7 11 18
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 133 119 252
        Male
    		 59 69 128

    End points

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    End points reporting groups
    Reporting group title
    Investigational product
    Reporting group description
    		 Angocin Anti-Infekt N 3x4 tablets daily

    Reporting group title
    Placebo
    Reporting group description
    		 3x4 tablets per day for a total of 14 days

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population included all patients treated in the study, i.e. who took at least one tablet. The safety population was the primary analysis population for the safety evaluation. Patients were evaluated according to their actual treatment.

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS excludes patients with a presumed seasonal rhinosinusitis. The FAS was used for the assessment of the efficacy.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol population (PP population) comprised all patients of the FAS population for whom no serious protocol violations were present. Protocol violations were assessed before unblinding.

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat population (ITT population) comprised all randomised patients in the safety population for whom at least one co-primary post-baseline value was collected. According to data review, 10 patients did not have a co-primary endpoint.

    Primary: Difference in the mean symptom scores MRSSinv/MRSSpat between both treatment Groups in the course of the treatment Phase

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    End point title
    		 Difference in the mean symptom scores MRSSinv/MRSSpat between both treatment Groups in the course of the treatment Phase
    End point description
    The change of the area under the curve (AUC)with Last Observation Carried Forward (LOCF) under the mean curve Major Rhinosinusitis symptom score as assessed by the investigator (MRSSinv)/ Major Rhinosinusitis symptom score as assessed by the patient (MRSSpat) from day 6 to day 10, Calculated according to the trapezoidal method and completion of missing data according to Next Observation Carried Backward/NOCB)/LOCF was used as primary objective. AUC(SENS) denotes the respective area, if missing data was completed using NOCB, interpolation and linear regression. AUC(LOCF) and AUC(SENS) were tested in hierarchical order.
    End point type
    Primary
    End point timeframe
    Day 6 to Day 10
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118
    120
    Units: number
        least squares mean (standard error)
    15.97 ( 1.20 )
    18.58 ( 1.20 )
    Statistical analysis title
    		 Primary endpoint - day 3
    Statistical analysis description
    Primary endpoint was MRSS inv/MRSS pat documented between day 6 and day 10, computed as AUC, assessed by ANCOVA with day 3 as covariate.
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Primary endpoint - day 0
    Statistical analysis description
    Primary endpoint was MRSS inv/MRSS pat documented between day 6 and day 10, computed as AUC, assessed by ANCOVA with day 0 as covariate.
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0306
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Change of MRSSinv anterior secretion

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    End point title
    		 Change of MRSSinv anterior secretion
    End point description
    Change of anterior secretion score as assessed by the investigator between baseline (visit 1) and the visits 2,3,4 and 5 as well as in the course of the study. FAS
    End point type
    Secondary
    End point timeframe
    Visit 1 - Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118
    120
    Units: Symptom Score mean
        arithmetic mean (standard deviation)
    1.94 ( 0.54 )
    1.98 ( 0.57 )
    Statistical analysis title
    		 Wilcoxon-Mann-Whitney U-Test Anterior Secretion
    Comparison groups
    Placebo v Investigational product
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9005
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change of MRSSinv posterior secretion

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    End point title
    		 Change of MRSSinv posterior secretion
    End point description
    Change of posterior secretion score as assessed by the investigator between baseline (visit 1) and the visits 2,3,4 and 5 as well as in the course of the study. FAS
    End point type
    Secondary
    End point timeframe
    Visit 1 to Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118
    120
    Units: Symptom score mean
        arithmetic mean (standard deviation)
    1.74 ( 0.70 )
    1.78 ( 0.70 )
    Statistical analysis title
    		 Wilcoxon-Mann-Whitney U-Test Posterior Secretion
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6567
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change of MRSSinv nasal breathing obstruction

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    End point title
    		 Change of MRSSinv nasal breathing obstruction
    End point description
    Change of nasal breathing obstruction score as assessed by the investigator between baseline (visit 1) and the visits 2,3,4 and 5 as well as in the course of the study. FAS
    End point type
    Secondary
    End point timeframe
    Visit 1 to Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118
    120
    Units: Symptom score mean
        arithmetic mean (standard deviation)
    2.26 ( 0.55 )
    2.00 ( 0.57 )
    Statistical analysis title
    		 Wilcoxon-Mann-Whitney U-Test Nasal Obstruction
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9374
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change of MRSSinv headache

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    End point title
    		 Change of MRSSinv headache
    End point description
    Change of headache score as assessed by the investigator between baseline (visit 1) and the visits 2,3,4 and 5 as well as in the course of the study. FAS
    End point type
    Secondary
    End point timeframe
    Visit 1- Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118
    120
    Units: Symptom score mean
        arithmetic mean (standard deviation)
    1.64 ( 0.73 )
    1.52 ( 0.71 )
    Statistical analysis title
    		 Wilcoxon-Mann-Whitney U-Test Headache
    Comparison groups
    Placebo v Investigational product
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9556
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change of MRSSinv facial pain

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    End point title
    		 Change of MRSSinv facial pain
    End point description
    Change of anterior secretion score as assessed by the investigator between baseline (visit 1) and the visits 2,3,4 and 5 as well as in the course of the study. FAS
    End point type
    Secondary
    End point timeframe
    Visit 1 - Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118
    120
    Units: Symptom score mean
        arithmetic mean (standard deviation)
    1.74 ( 0.44 )
    1.68 ( 0.47 )
    Statistical analysis title
    		 Wilcoxon-Mann-Whitney U-Test facial swelling
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8418
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Healingscore

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    End point title
    		 Healingscore
    End point description
    The healing as a quantitative objective was defined as Major Rinosinusitis Score as defined by the patient (MRSSpat) ≤ 2. Three patients were not enclosed due to MRSSpat ≤ 2 at baseline. FAS.
    End point type
    Secondary
    End point timeframe
    Visit 3
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    116 [1]
    119 [2]
    Units: number of patients
    89
    95
    Notes
    [1] - 2 patients were disregarded from the FAS due to MRSSpat ≤ 2 at baseline
    [2] - 1 patient was disregarded from the FAS due to MRSSpat ≤ 2 at baseline
    Statistical analysis title
    		 Healing
    Statistical analysis description
    Chi squared tests of responder rates
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5634
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Time to healing

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    End point title
    		 Time to healing
    End point description
    FAS
    End point type
    Secondary
    End point timeframe
    Visit 1 to Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118
    120
    Units: days
    9
    10
    Statistical analysis title
    		 PP set
    Statistical analysis description
    Healing rates (MRRpat>2), PP set Angocin: 89/110 Placebo: 92/113
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8978 [3]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - inlcuding three patients in the investigational arm with MRRSpat <= 2 at baseline

    Secondary: Recurrence rate

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    End point title
    		 Recurrence rate
    End point description
    In the FAS, 91 patients from the investigational arm were classified as responders vs. 96 patients of the placebo arm. Recurrence is defined as values of Major Rinohosinusitis score as assessed by the patient above or equal 8.
    End point type
    Secondary
    End point timeframe
    Visit 1 - visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    91
    96
    Units: number of patients
    3
    5
    Statistical analysis title
    		 Recurrence rates
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5185
    Method
    		 Chi-squared
    Confidence interval

    Secondary: General efficacy as assessed by the investigator

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    End point title
    		 General efficacy as assessed by the investigator
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 2
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    118 [4]
    120
    Units: number of patients
        Symptoms healed
    0
    0
        Symptoms improved
    78
    84
        Symptoms unchanged
    33
    33
        Symptoms worsened
    7
    3
    Notes
    [4] - Visit 2
    Statistical analysis title
    		 General efficacy Visit 2
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4298
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: General efficacy as assessed by the investigator

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    End point title
    		 General efficacy as assessed by the investigator
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 3
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    114
    120
    Units: number of patients
        Symptoms healed
    3
    6
        Symptoms improved
    102
    94
        Symptoms unchanged
    7
    13
        Symptoms worsened
    2
    7
    Statistical analysis title
    		 General efficacy Visit 3
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1792
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: General efficacy as assessed by the investigator

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    End point title
    		 General efficacy as assessed by the investigator
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 4
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    113 [5]
    115
    Units: number of patients
        Symptoms healed
    22
    17
        Syptoms impoved
    86
    94
        Symptoms unchanged
    4
    2
        Symptoms worsened
    1
    2
    Notes
    [5] - Visit 4
    Statistical analysis title
    		 General efficacy Visit 4
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4896
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: General efficacy as assessed by the investigator

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    End point title
    		 General efficacy as assessed by the investigator
    End point description
    End point type
    Secondary
    End point timeframe
    Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    113 [6]
    120
    Units: number of patients
        Symptoms healed
    53
    61
        Symptoms improved
    55
    50
        Symptoms unchanged
    4
    1
        Symptoms worsened
    1
    3
    Notes
    [6] - Visit 5
    Statistical analysis title
    		 General efficacy Visit 5
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3527
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: SNOT-20 GAV total

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    End point title
    		 SNOT-20 GAV total
    End point description
    6 point scala of 20 main criteria of a rhinosinusitis (SNOT-20 GAV). Change of total score between baseline, visit 3 and visit 5 was assessed. FAS.
    End point type
    Secondary
    End point timeframe
    Visit 1, Visit 3 and Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    116 [7]
    120 [8]
    Units: Symptom score
    arithmetic mean (standard deviation)
        Baseline
    43.04 ( 12.26 )
    43.58 ( 13.95 )
        Visit 3
    22.47 ( 13.54 )
    26.00 ( 15.59 )
        Visit 5
    10.00 ( 13.26 )
    9.31 ( 13.74 )
    Notes
    [7] - 116 patients at baseline and visit 3, 113 at visit 5
    [8] - 120 subjects at basline and visit 3, 115 subjects at visit 5
    Statistical analysis title
    		 MMRM V3
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0542
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 MMRM V5
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8237
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: SNOT-20 GAV Nasal Symptoms

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    End point title
    		 SNOT-20 GAV Nasal Symptoms
    End point description
    6 point scala of nasal main criteria of a rhinosinusitis (SNOT-20 GAV). Change of total score between baseline, visit 3 and visit 5 was assessed. FAS
    End point type
    Secondary
    End point timeframe
    Visit 1, Visit 3 and Visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    116 [9]
    120 [10]
    Units: Symptom Score
    arithmetic mean (standard deviation)
        Baseline
    52.62 ( 14.67 )
    53.80 ( 15.01 )
        Visit 3
    29.93 ( 16.67 )
    34.63 ( 18.42 )
        Visit 5
    12.46 ( 15.89 )
    12.56 ( 16.72 )
    Notes
    [9] - 116 subjects at baseline and visit 3, 113 subjects at visit 5
    [10] - 120 subjects at baseline and visit 3, 115 subjects at visit 5
    Statistical analysis title
    		 MMRM V3
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0427
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 MMRM V5
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8364
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: SNOT-20 GAV Rhino-associated Symptoms

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    End point title
    		 SNOT-20 GAV Rhino-associated Symptoms
    End point description
    6 point scala of rhino-associated main criteria of a rhinosinusitis (SNOT-20 GAV). Change of total score between baseline, visit 3 and visit 5 was assessed. FAS.
    End point type
    Secondary
    End point timeframe
    Baseline, Visit 3 and visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    116 [11]
    120 [12]
    Units: Symptom score
    arithmetic mean (standard deviation)
        Baseline
    44.19 ( 13.74 )
    46.87 ( 15.85 )
        Visit 3
    22.14 ( 14.25 )
    27.73 ( 17.73 )
        Visit 5
    9.48 ( 13.68 )
    9.10 ( 14.87 )
    Notes
    [11] - 116 subjects at baseline, visit 3 and 113 at visit 5
    [12] - 120 subjects at baseline, visit 3 and 115 at visit 5
    Statistical analysis title
    		 MMRM V3
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0128
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 MMRM V5
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6194
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: SNOT-20 GAV general quality of life

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    End point title
    		 SNOT-20 GAV general quality of life
    End point description
    6 point scala of quality of life criteria of a rhinosinusitis (SNOT-20 GAV). Change of total score between baseline, visit 3 and visit 5 was assessed. FAS.
    End point type
    Secondary
    End point timeframe
    Baseline, visit 3 and visit 5
    End point values
    		 Investigational product Placebo
    Number of subjects analysed
    116 [13]
    120 [14]
    Units: Symptom score
    arithmetic mean (standard deviation)
        Baseline
    36.96 ( 17.60 )
    35.69 ( 18.24 )
        Visit 3
    18.49 ( 17.03 )
    20.06 ( 17.60 )
        Visit 5
    8.91 ( 13.73 )
    7.62 ( 13.88 )
    Notes
    [13] - 116 subjects at baseline and visit 3, 113 subjects at visit 5
    [14] - 120 subjects at baseline and visit 3, 115 subjects at visit 5
    Statistical analysis title
    		 MMRM V3
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2534
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 MMRM V5
    Statistical analysis description
    Difference of Least square means of Angocin and Placebo
    Comparison groups
    Investigational product v Placebo
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.8281
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [15] - Visit 5

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The investigator had to report all serious adverse events (SAEs) immediately, but no later than within 24 hours of becoming aware of them and submit a detailed written report (SAE report form)
    Adverse event reporting additional description
    Serious AEs that occurred after completion of the trial and could be linked to the study were also reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Investigational product
    Reporting group description
    		 All patients from the safety-set having been allocated investigational product. The safety set consisted of all patients, who had taken at least on tablet of study medication.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Investigational product Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Visual field defect
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Investigational product Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 192 (21.88%)
    34 / 188 (18.09%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Hypertonia
         subjects affected / exposed
    2 / 192 (1.04%)
    0 / 188 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 192 (0.00%)
    4 / 188 (2.13%)
         occurrences all number
    0
    5
    Facial pain
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Discomfort
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Paranasal sinus discomfort
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 188 (0.53%)
         occurrences all number
    1
    1
    Dyspnoea
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 188 (0.53%)
         occurrences all number
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 192 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    2
    Cough
         subjects affected / exposed
    3 / 192 (1.56%)
    3 / 188 (1.60%)
         occurrences all number
    3
    3
    productive cough
         subjects affected / exposed
    1 / 192 (0.52%)
    2 / 188 (1.06%)
         occurrences all number
    1
    2
    Nasal congestion
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 188 (0.53%)
         occurrences all number
    1
    1
    Sneezing
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 192 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 192 (0.52%)
    2 / 188 (1.06%)
         occurrences all number
    1
    2
    Sinus pain
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Body temperature increased
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 192 (7.81%)
    14 / 188 (7.45%)
         occurrences all number
    16
    16
    Migraine
         subjects affected / exposed
    3 / 192 (1.56%)
    1 / 188 (0.53%)
         occurrences all number
    3
    1
    Dizziness
         subjects affected / exposed
    2 / 192 (1.04%)
    2 / 188 (1.06%)
         occurrences all number
    2
    2
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Ear discomfort
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 188 (0.53%)
         occurrences all number
    1
    1
    Ear pain
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Tinnitus
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 188 (0.53%)
         occurrences all number
    1
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Dark circles under eyes
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 188 (0.53%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    2 / 192 (1.04%)
    1 / 188 (0.53%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    3 / 192 (1.56%)
    1 / 188 (0.53%)
         occurrences all number
    3
    1
    Dyspepsia
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 192 (1.04%)
    0 / 188 (0.00%)
         occurrences all number
    2
    0
    Flatulence
         subjects affected / exposed
    2 / 192 (1.04%)
    1 / 188 (0.53%)
         occurrences all number
    2
    1
    Oral pain
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 192 (1.04%)
    0 / 188 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Defaecation urgency
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    4 / 192 (2.08%)
    0 / 188 (0.00%)
         occurrences all number
    4
    0
    toothache
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Erythema
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Neurodermatitis
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 192 (0.00%)
    2 / 188 (1.06%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 192 (0.52%)
    2 / 188 (1.06%)
         occurrences all number
    1
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    2 / 192 (1.04%)
    1 / 188 (0.53%)
         occurrences all number
    2
    1
    Angular cheilitis
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 192 (1.04%)
    1 / 188 (0.53%)
         occurrences all number
    2
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 188 (0.53%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 188 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    2 / 192 (1.04%)
    0 / 188 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2017
    Addition of study centers, changes in study related documents
    27 Nov 2017
    Addition of study centers
    28 Feb 2018
    Inter alia change of QPPV, editorial changes, addition of certificates of analyses in the IMPD. The date of the submission of the amentmend is provided, here.
    07 Mar 2018
    Addition of study centers

    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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