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    Clinical Trial Results:
    Efficacy and safety of acetylcysteine for the treatment of acute uncomplicated rhinosinusitis: a prospective, randomized, double-blind, placebo-controlled trial

    Summary
    EudraCT number
    		 2019-000060-20
    Trial protocol
    		 DE   BG  
    Global end of trial date
    20 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Nov 2021
    First version publication date
    05 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2018-08-EFT-1 / C1018001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04123405
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    20 Apr 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to assess the efficacy of three different total daily doses of the investigational medicinal product containing 600 mg acetylcysteine per effervescent tablet compared to placebo for the treatment of acute uncomplicated rhinosinusitis. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Oct 2020
    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
    Bulgaria: 284
    Country: Number of subjects enrolled
    Germany: 55
    Country: Number of subjects enrolled
    Moldova, Republic of: 334
    Country: Number of subjects enrolled
    Russian Federation: 271
    Worldwide total number of subjects
    944
    EEA total number of subjects
    339
    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)
    17
    Adults (18-64 years)
    879
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled from 42 clinical centers located in Bulgaria, Germany, Moldova and Russia.

    Pre-assignment
    Screening details
    		 Participants were randomized in 1:1:1:1 ratio

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A: 600 mg acetylcysteine
    Arm description
    		 one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    acetylcysteine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Arm title
    		 Group B: 1200 mg acetylcysteine
    Arm description
    		 two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    acetylcysteine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Arm title
    		 Group C: 2400 mg acetylcysteine
    Arm description
    		 four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    acetylcysteine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily)

    Arm title
    		 Group D: Placebo
    Arm description
    		 four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Effervescent tablet
    Routes of administration
    Oral use
    Dosage and administration details
    four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Number of subjects in period 1
    		Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Started
    235
    238
    238
    233
    Full Analysis set
    235
    236
    238
    230
    Safety Set
    235
    238
    238
    233
    Completed
    231
    231
    235
    225
    Not completed
    4
    7
    3
    8
         Exclusion criteria met
    1
    2
    -
    2
         Contact to subject lost
    -
    -
    -
    1
         Consent withdrawn by subject
    1
    3
    -
    2
         Adverse event, non-fatal
    1
    2
    3
    3
         screening failure
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A: 600 mg acetylcysteine
    Reporting group description
    		 one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group B: 1200 mg acetylcysteine
    Reporting group description
    		 two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group C: 2400 mg acetylcysteine
    Reporting group description
    		 four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group D: Placebo
    Reporting group description
    		 four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily).

    Reporting group values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo Total
    Number of subjects
    		 235 238 238 233 944
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 6 5 3 3 17
        Adults (18-64 years)
    		 219 222 224 214 879
        From 65-84 years
    		 10 11 11 16 48
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 41.0 ( 13.8 ) 40.7 ( 13.6 ) 41.3 ( 13.1 ) 41.1 ( 14.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 128 142 145 141 556
        Male
    		 107 96 93 92 388
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 230 235 232 231 928
        Asian
    		 4 2 5 2 13
        Unknown
    		 1 1 1 0 3

    End points

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    End points reporting groups
    Reporting group title
    Group A: 600 mg acetylcysteine
    Reporting group description
    		 one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group B: 1200 mg acetylcysteine
    Reporting group description
    		 two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group C: 2400 mg acetylcysteine
    Reporting group description
    		 four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group D: Placebo
    Reporting group description
    		 four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily).

    Primary: Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period, Full Analysis Set

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    End point title
    		 Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period, Full Analysis Set [1]
    End point description
    The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this endpoint
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    235
    236
    238
    230
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -4.8213 ( 1.98247 )
    -4.7394 ( 1.99090 )
    -4.7758 ( 1.96938 )
    -5.0180 ( 1.98262 )
    No statistical analyses for this end point

    Primary: Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period, Per-Protocol Set

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    End point title
    		 Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period, Per-Protocol Set [2]
    End point description
    The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed for this endpoint
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    213
    215
    212
    207
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -4.9085 ( 1.92431 )
    -4.8688 ( 1.84448 )
    -4.8002 ( 1.90569 )
    -5.1256 ( 1.95072 )
    No statistical analyses for this end point

    Secondary: Time to onset of action, Full Analysis Set

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    End point title
    		 Time to onset of action, Full Analysis Set [3]
    End point description
    Time to onset of action was defined as first day of active treatment on which MSS showed statistically significant (p value<0.05) improvement from placebo. There was no statistically significant improvement of the drug from placebo on any day
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
    Notes
    [3] - 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: There was no statistically significant improvement of the drug from placebo on any day
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine
    Number of subjects analysed
    235
    236
    238
    Units: Days
    999
    999
    999
    No statistical analyses for this end point

    Secondary: Time to onset of action, Per-Protocol Set

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    End point title
    		 Time to onset of action, Per-Protocol Set [4]
    End point description
    Time to onset of action was defined as first day of active treatment on which MSS showed statistically significant (p value<0.05) improvement from placebo. There was no statistically significant improvement of the drug from placebo on any day
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
    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: There was no statistically significant improvement of the drug from placebo on any day
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine
    Number of subjects analysed
    213
    215
    212
    Units: Days
    999
    999
    999
    No statistical analyses for this end point

    Secondary: Major Symptom Score (MSS) development over the course of the study, Full Analysis Set

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    End point title
    		 Major Symptom Score (MSS) development over the course of the study, Full Analysis Set
    End point description
    The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    235
    236
    238
    230
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 1 (Baseline)
    9.634 ( 1.1181 )
    9.640 ( 1.0647 )
    9.702 ( 1.0101 )
    9.683 ( 1.0652 )
        Day 2
    9.021 ( 2.0348 )
    9.004 ( 1.9883 )
    9.038 ( 2.1235 )
    9.074 ( 1.9866 )
        Day 3
    8.485 ( 2.3376 )
    8.513 ( 2.2303 )
    8.416 ( 2.4390 )
    8.609 ( 2.1298 )
        Day 4
    7.821 ( 2.4482 )
    7.695 ( 2.5130 )
    7.723 ( 2.7156 )
    7.761 ( 2.5058 )
        Day 5
    6.983 ( 2.7284 )
    6.979 ( 2.5706 )
    7.013 ( 2.7490 )
    6.917 ( 2.6312 )
        Day 6
    6.323 ( 2.7807 )
    6.203 ( 2.8719 )
    6.315 ( 2.7980 )
    6.039 ( 2.7838 )
        Day 7
    5.528 ( 2.9747 )
    5.538 ( 2.7449 )
    5.576 ( 2.8508 )
    5.126 ( 2.7096 )
        Day 8
    4.766 ( 2.8631 )
    4.750 ( 2.6755 )
    4.891 ( 2.7598 )
    4.387 ( 2.6004 )
        Day 9
    4.204 ( 2.8149 )
    4.322 ( 2.7254 )
    4.445 ( 2.7381 )
    3.839 ( 2.5924 )
        Day 10
    3.634 ( 2.6815 )
    3.763 ( 2.6391 )
    3.845 ( 2.6634 )
    3.404 ( 2.6805 )
        Day 11
    3.051 ( 2.5229 )
    3.284 ( 2.6658 )
    3.256 ( 2.5716 )
    2.843 ( 2.6469 )
        Day 12
    2.609 ( 2.5200 )
    2.754 ( 2.5680 )
    2.756 ( 2.3795 )
    2.413 ( 2.5608 )
        Day 13
    2.038 ( 2.4202 )
    2.246 ( 2.5296 )
    2.218 ( 2.4293 )
    1.943 ( 2.4174 )
        Day 14
    1.583 ( 2.3289 )
    1.941 ( 2.5375 )
    1.836 ( 2.3300 )
    1.596 ( 2.3637 )
        Day 15
    1.332 ( 2.1485 )
    1.614 ( 2.4459 )
    1.634 ( 2.3178 )
    1.352 ( 2.1882 )
    No statistical analyses for this end point

    Secondary: Major Symptom Score (MSS) development over the course of the study, Per-protocol Set

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    End point title
    		 Major Symptom Score (MSS) development over the course of the study, Per-protocol Set
    End point description
    The MSS combines the 5 most relevant symptoms of rhinosinusitis based on expert clinician recommendations (rhinorrhea/ anterior discharge, postnasal drip, nasal congestion, headache, and facial pain/pressure). The patient rated the severity of each of the five symptoms of the MSS using a four-point rating scale of increasing severity (0 = none/not present, 1 = mild, 2 = moderate, 3 = severe). The MSS is then the sum of single ratings with a possible range from 0 to 15. Mean change from baseline in the daily Major Symptom Score (MSS) over the entire treatment period was calculated as the average total score from Day 2 to 15 compared to Baseline (Day 1). Negative change from baseline means improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    213
    215
    212
    207
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 1 (Baseline)
    9.657 ( 1.1201 )
    9.628 ( 1.0595 )
    9.698 ( 1.0319 )
    9.676 ( 1.0823 )
        Day 2
    9.080 ( 2.0160 )
    8.935 ( 2.0268 )
    9.127 ( 2.0089 )
    9.068 ( 2.0278 )
        Day 3
    8.545 ( 2.2890 )
    8.395 ( 2.2583 )
    8.528 ( 2.2591 )
    8.594 ( 2.1921 )
        Day 4
    7.803 ( 2.4779 )
    7.577 ( 2.5472 )
    7.816 ( 2.5849 )
    7.739 ( 2.5750 )
        Day 5
    6.962 ( 2.7401 )
    6.874 ( 2.5865 )
    7.061 ( 2.6522 )
    6.821 ( 2.6717 )
        Day 6
    6.315 ( 2.7914 )
    6.093 ( 2.8809 )
    6.349 ( 2.7000 )
    5.937 ( 2.8354 )
        Day 7
    5.479 ( 2.9550 )
    5.400 ( 2.7151 )
    5.604 ( 2.7800 )
    4.981 ( 2.7163 )
        Day 8
    4.685 ( 2.8250 )
    4.605 ( 2.6399 )
    4.892 ( 2.7421 )
    4.237 ( 2.5914 )
        Day 9
    4.117 ( 2.7558 )
    4.181 ( 2.6773 )
    4.382 ( 2.6734 )
    3.652 ( 2.5495 )
        Day 10
    3.521 ( 2.6127 )
    3.628 ( 2.5174 )
    3.741 ( 2.5507 )
    3.222 ( 2.6197 )
        Day 11
    2.934 ( 2.4039 )
    3.144 ( 2.5214 )
    3.146 ( 2.4538 )
    2.705 ( 2.6042 )
        Day 12
    2.493 ( 2.3485 )
    2.572 ( 2.3785 )
    2.608 ( 2.2228 )
    2.300 ( 2.4902 )
        Day 13
    1.897 ( 2.2146 )
    2.065 ( 2.2949 )
    2.085 ( 2.2013 )
    1.816 ( 2.3077 )
        Day 14
    1.432 ( 2.0812 )
    1.749 ( 2.2779 )
    1.708 ( 2.1128 )
    1.444 ( 2.2198 )
        Day 15
    1.221 ( 1.9530 )
    1.409 ( 2.1312 )
    1.524 ( 2.0846 )
    1.193 ( 1.9636 )
    No statistical analyses for this end point

    Secondary: Sino-Nasal Outcome Test (SNOT-22) by visit, Full Analysis set

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    End point title
    		 Sino-Nasal Outcome Test (SNOT-22) by visit, Full Analysis set
    End point description
    SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    235
    236
    238
    230
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 1 (Baseline)
    37.8 ( 16.89 )
    36.3 ( 15.82 )
    36.7 ( 16.21 )
    36.3 ( 17.00 )
        Day 7
    23.6 ( 15.01 )
    21.2 ( 13.14 )
    22.3 ( 13.95 )
    21.1 ( 13.56 )
        Day 14
    7.2 ( 10.80 )
    6.9 ( 11.15 )
    7.0 ( 10.07 )
    6.5 ( 10.28 )
    No statistical analyses for this end point

    Secondary: Sino-Nasal Outcome Test (SNOT-22) by visit, Per Protocol Set

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    End point title
    		 Sino-Nasal Outcome Test (SNOT-22) by visit, Per Protocol Set
    End point description
    SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    213
    215
    212
    207
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 1 (Baseline)
    37.7 ( 16.64 )
    36.7 ( 15.89 )
    36.4 ( 15.86 )
    36.2 ( 16.88 )
        Day 7
    23.3 ( 14.92 )
    21.2 ( 13.32 )
    22.2 ( 14.27 )
    21.0 ( 13.78 )
        Day 14
    6.9 ( 10.49 )
    7.1 ( 11.43 )
    6.8 ( 9.67 )
    6.6 ( 10.50 )
    No statistical analyses for this end point

    Secondary: Sino-Nasal Outcome Test (SNOT-22) by change to baseline, Full Analysis Set

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    End point title
    		 Sino-Nasal Outcome Test (SNOT-22) by change to baseline, Full Analysis Set
    End point description
    SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL. A negative change from baseline in SNOT-22 is considered a favorable outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    235
    236
    238
    230
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 7
    -35.8 ( 33.25 )
    -38.2 ( 37.48 )
    -36.7 ( 34.61 )
    -39.6 ( 30.42 )
        Day 14
    -79.3 ( 31.27 )
    -78.9 ( 31.11 )
    -78.6 ( 30.53 )
    -81.5 ( 26.54 )
    No statistical analyses for this end point

    Secondary: Sino-Nasal Outcome Test (SNOT-22) by change to baseline, Per Protocol Set

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    End point title
    		 Sino-Nasal Outcome Test (SNOT-22) by change to baseline, Per Protocol Set
    End point description
    SNOT-22 Questionnaire is a disease specific Health-Related Quality of Life (HRQoL) measure that comprises a list of 22 symptoms and social or emotional consequences of the nasal disorder. Every participant is asked to rate how severe each problem had been on a scale from 0 (no problem) to 5 (problem as bad as it can be). The total score is the sum of the scores for all 22 items, ranging from 0 to 110, with a lower score indicating better HRQoL. A negative change from baseline in SNOT-22 is considered a favorable outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 7 and Day 14
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    213
    215
    212
    207
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Day 7
    -36.4 ( 32.64 )
    -39.5 ( 36.68 )
    -36.7 ( 33.44 )
    -39.6 ( 30.60 )
        Day 14
    -79.8 ( 30.90 )
    -78.6 ( 31.77 )
    -79.1 ( 30.16 )
    -81.0 ( 27.10 )
    No statistical analyses for this end point

    Secondary: Number of responders and non-responders to treatment, Full Analysis Set

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    End point title
    		 Number of responders and non-responders to treatment, Full Analysis Set
    End point description
    Number of responders and non-responders to treatment based on the assessment of overall response to treatment by the investigator were reported.
    End point type
    Secondary
    End point timeframe
    Day 4, 7, 10 and 15
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    235
    236
    238
    230
    Units: Participants
        Day 4|Responders
    148
    152
    151
    150
        Day 7|Responders
    209
    206
    212
    209
        Day 10|Responders
    225
    225
    230
    219
        Day 15|Responders
    230
    226
    230
    224
        Day 4|Non-responders
    85
    83
    86
    79
        Day 7|Non-responders
    23
    29
    15
    18
        Day 10|Non-responders
    6
    7
    5
    6
        Day 15|Non-responders
    4
    6
    8
    4
    No statistical analyses for this end point

    Secondary: Number of responders and non-responders to treatment, Per-Protocol Set

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    End point title
    		 Number of responders and non-responders to treatment, Per-Protocol Set
    End point description
    Number of responders and non-responders to treatment based on the assessment of overall response to treatment by the investigator were reported.
    End point type
    Secondary
    End point timeframe
    Day 4, 7, 10 and 15
    End point values
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Number of subjects analysed
    213
    215
    212
    207
    Units: Participants
        Day 4|Responders
    138
    140
    132
    134
        Day 7|Responders
    192
    190
    191
    192
        Day 10|Responders
    207
    210
    209
    202
        Day 15|Responders
    211
    210
    206
    205
        Day 4|Non-responders
    75
    75
    80
    73
        Day 7|Non-responders
    21
    25
    21
    15
        Day 10|Non-responders
    6
    5
    3
    5
        Day 15|Non-responders
    2
    5
    6
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment up to maximum duration of 22 days.
    Adverse event reporting additional description
    Any signs or symptoms were collected from first dose of study treatment up to maximum duration of 22 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Group A: 600 mg acetylcysteine
    Reporting group description
    		 one tablet test product plus three tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group B: 1200 mg acetylcysteine
    Reporting group description
    		 two tablets test product plus two tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group C: 2400 mg acetylcysteine
    Reporting group description
    		 four tablets test product per day (taken as two tablets dissolved in a glass of water, twice daily)

    Reporting group title
    Group D: Placebo
    Reporting group description
    		 four tablets placebo per day (taken as two tablets dissolved in a glass of water, twice daily).

    Serious adverse events
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group A: 600 mg acetylcysteine Group B: 1200 mg acetylcysteine Group C: 2400 mg acetylcysteine Group D: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 235 (3.83%)
    15 / 238 (6.30%)
    15 / 238 (6.30%)
    8 / 233 (3.43%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         occurrences all number
    0
    0
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    1 / 233 (0.43%)
         occurrences all number
    0
    0
    1
    1
    Human chorionic gonadotropin increased
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertensive crisis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 238 (0.42%)
    2 / 238 (0.84%)
    1 / 233 (0.43%)
         occurrences all number
    2
    1
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 235 (0.00%)
    2 / 238 (0.84%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 235 (0.43%)
    2 / 238 (0.84%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 235 (0.00%)
    3 / 238 (1.26%)
    2 / 238 (0.84%)
    0 / 233 (0.00%)
         occurrences all number
    0
    3
    2
    0
    Nausea
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    1 / 233 (0.43%)
         occurrences all number
    1
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal crusting
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         occurrences all number
    0
    0
    0
    1
    Nasal obstruction
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    1 / 233 (0.43%)
         occurrences all number
    1
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 238 (0.42%)
    1 / 238 (0.42%)
    1 / 233 (0.43%)
         occurrences all number
    1
    1
    1
    1
    COVID-19
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otitis media bacterial
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    0 / 238 (0.00%)
    1 / 233 (0.43%)
         occurrences all number
    0
    0
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 238 (0.00%)
    1 / 238 (0.42%)
    0 / 233 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis bacterial
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 238 (0.42%)
    0 / 238 (0.00%)
    0 / 233 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Aug 2019
    This amendment was country specific and was valid for Germany only. The amendment was not used in the present trial as it was replaced by the GLOBAL Amendment 5.0 (Version 1.0, dated 14-Aug-2020).
    10 Sep 2019
    This amendment was country specific and was valid for Bulgaria and Moldova only. The amendment was not used in the present trial as it was replaced by the GLOBAL Amendment 5.0 (Version 1.0, dated 14-Aug-2020).
    15 Oct 2019
    This amendment was country specific and was valid for Russia only. The amendment was not used in the present trial as it was replaced by the GLOBAL Amendment 5.0 (Version 1.0, dated 14-Aug-2020).
    01 Nov 2019
    Amendment 4.0 (Version 1.0, dated 01-Nov-2019) to study protocol This amendment was country specific and was valid for Moldova only. The amendment was not used in the present trial as it was replaced by the GLOBAL Amendment 5.0 (Version 1.0, dated 14-Aug-2020).
    14 Aug 2020
    By this amendment the changes in sponsor’s project management were introduced with effective date 19-Aug-2020.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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