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    Clinical Trial Results:
    Therapeutic effectiveness, safety and tolerability of Tonsilotren tablets in patients (6 to 60 years old) with chronic tonsillitis. A randomized, international, multicenter, controlled clinical trial.

    Summary
    EudraCT number
    		 2012-001430-34
    Trial protocol
    		 DE   ES  
    Global end of trial date
    14 Aug 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Sep 2016
    First version publication date
    28 Jul 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Due to a lately discovered mistake in the statistical analysis, some results have slightly changed compared to the results entered into the EudraCT until now. These results need to be updated.

    Trial information

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    Trial identification
    Sponsor protocol code
    10-TT-EP-003
    Additional study identifiers
    ISRCTN number
    		 ISRCTN19016626
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Deutsche Homöopathie-Union, DHU-Arzneimittel GmbH & Co. KG
    Sponsor organisation address
    Ottostraße 24, Karlsruhe, Germany, 76227
    Public contact
    Deutsche Homöopathie-Union, DHU-Arzneimittel GmbH & Co. KG, Ottostrasse 24, D-76227 Karlsruhe, + 49(0)721 409301, info@dhu.com
    Scientific contact
    Deutsche Homöopathie-Union, DHU-Arzneimittel GmbH & Co. KG, Ottostrasse 24, D-76227 Karlsruhe, + 49(0)721 409301, info@dhu.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the therapeutic effectiveness of Tonsilotren in the treatment of chronic tonsillitis when used in addition to conventional symptomatic treatment (test group) in comparison to conventional symptomatic treatment alone (control group).
    Protection of trial subjects
    All patients were allowed to receive conventional symptomatic treatment, which were local antiseptics and/or anesthetics. Half of the patients received additionally Tonsilotren. Examinations performed consisted mainly of a physical examination, which included evaluation of chronic tonsillitis-specific symptoms at each visit and evaluation of acute complaints in the upper respiratory tract during additional visits in case the patients felt sick with acute complaints in the upper respiratory tract. The physical examination did not differ significantly from a routine physical examination and did not involve any particular risk for the patient. At the discretion of the investigator a throat swab (for a group A beta-hemolytic streptococci rapid test) could be performed. Patients were informed about the slight discomfort this test might cause via the patient informed consent.
    Background therapy
    		 As conventional symptomatic treatment all patients were allowed to receive either local antiseptics and/or local anesthetics for the throat.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    Ukraine: 171
    Worldwide total number of subjects
    256
    EEA total number of subjects
    85
    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)
    86
    Adolescents (12-17 years)
    51
    Adults (18-64 years)
    119
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited during a period of 13 months going from January 2013 until February 2014 inclusively. In Germany, patients were recruited at 5 ENT practices. In Spain, patients were recruited at 2 pediatrician and 4 general practitioners sites. In Ukraine, patients were recruited at 2 pediatrician, 1 general practitioner and 5 ENT sites.

    Pre-assignment
    Screening details
    		 A total of 494 patients were screened for participation in the study. From these 494 patients, 238 did not participate: 143 violated the inclusion/exclusion criteria, 86 declined to participate and 9 patients did not participate for other reasons. A total of 256 patients were randomized.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test group
    Arm description
    		 The test group received Tonsilotren tablets during Treatment Period I to III each for 8 weeks spread over 14 months and - if needed - conventional symptomatic treatment for chronic tonsillitis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atropinum sulfuricum D5, Hepar sulfuris D3, Kalium bichromicum D4, Silicea D2 and Mercurius bijodatus D8.
    Investigational medicinal product code
    PR1
    Other name
    Tonsilotren ®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tonsilotren was provided to the patients of the test group only. Separate blisters for children (<12 years) and adolescents / adults (≥12 years) were provided. All patients received Tonsilotren tablets during 3 treatment periods (TP I to III) each for 8 weeks: TP I and II were followed each by a 8 weeks follow-up period without Tonsilotren (FU I and II). TP III was followed by a 12 weeks FU III without Tonsilotren. During the 3 TPs, children took 3 times a day 1 tablet of Tonsilotren whereas adolescents/adults took 3 times a day 2 tablets Tonsilotren.

    Arm title
    		 Control group
    Arm description
    		 The control group was treated only with conventional symptomatic treatment if needed.
    Arm type
    		 Conventional symptomatic treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Test group Control group
    Started
    132
    124
    Visit 2 completed (Day 11±3)
    130
    121
    Visit 3 completed (Week 8±1)
    128
    120
    Visit 4 completed (Week 16±1)
    125
    120
    Visit 5 completed (Week 24±1)
    119
    117
    Visit 6 completed (Week 32±1)
    105
    103
    Visit 7 completed (Week 40±1)
    104
    101
    Visit 8 completed (Week 48±1)
    98
    94
    Visit 9 completed (Week 60±1)
    98
    94
    Completed
    98
    94
    Not completed
    34
    30
         Consent withdrawn by subject
    7
    4
         Physician decision
    1
    -
         Pregnancy
    -
    1
         Military operations in Eastern part of Ukraine
    13
    14
         Lost to follow-up
    1
    2
         Tonsillectomy or any other surgery in the throat
    1
    1
         Protocol deviation
    11
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Test group
    Reporting group description
    		 The test group received Tonsilotren tablets during Treatment Period I to III each for 8 weeks spread over 14 months and - if needed - conventional symptomatic treatment for chronic tonsillitis.

    Reporting group title
    Control group
    Reporting group description
    		 The control group was treated only with conventional symptomatic treatment if needed.

    Reporting group values
    		 Test group Control group Total
    Number of subjects
    		 132 124 256
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 45 41 86
        Adolescents (12-17 years)
    		 25 26 51
        Adults (18-64 years)
    		 62 57 119
    Age continuous
    Age has been recorded as integer number value.
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 15.5 (9.5 to 32) 16 (9 to 31) -
    Gender categorical
    Units: Subjects
        Female
    		 86 70 156
        Male
    		 46 54 100
    ATI baseline frequency
    Acute throat infections [ATIs] that occurred from 12 months prior to enrolment up to end of Treatment Period I are counted as baseline ATIs.
    Units: Subjects
        N=0
    		 1 0 1
        N=1
    		 1 2 3
        N=2
    		 25 18 43
        N=3
    		 70 57 127
        N=4
    		 26 28 54
        N=5
    		 6 15 21
        N=6
    		 3 2 5
        N=7
    		 0 1 1
        N=8
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Test group
    Reporting group description
    		 The test group received Tonsilotren tablets during Treatment Period I to III each for 8 weeks spread over 14 months and - if needed - conventional symptomatic treatment for chronic tonsillitis.

    Reporting group title
    Control group
    Reporting group description
    		 The control group was treated only with conventional symptomatic treatment if needed.

    Subject analysis set title
    Test group - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Test group patients without major protocol violations are included in the 'Test group - PP' Analysis subset.

    Subject analysis set title
    Control group - PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Control group patients without major protocol violations are included in the 'Control group - PP' Analysis subset.

    Subject analysis set title
    ATI events - Test group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    This analysis set consists of 'ATI events' rather than individual patients. All ATI Events documented between Visit 1 and Termination Visit within test group ITT patients are included in this group. [Note: There were 92 ATI events recorded for 50 test group patients.]

    Subject analysis set title
    ATI events - Control group
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    This analysis set consists of 'ATI events' rather than individual patients. All ATI Events documented between Visit 1 and Termination Visit within control group ITT patients are included in this group. [Note: There were 189 ATI events recorded for 87 control group patients.]

    Primary: Number of documented ATIs

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    End point title
    		 Number of documented ATIs
    End point description
    End point type
    Primary
    End point timeframe
    Basis are event occurrences observed beyond Visit 3 until the end of study. (Note that any ATI event occurrences prior to Visit 3 have been added to baseline ATI frequencies.)
    End point values
    		 Test group Control group Test group - PP Control group - PP
    Number of subjects analysed
    128 [1]
    120 [2]
    103
    70
    Units: ATI events
        No event
    86
    45
    67
    26
        One event
    28
    39
    25
    22
        Two events
    10
    16
    8
    9
        Three events
    0
    12
    0
    10
        Four events
    2
    3
    1
    1
        Five events
    0
    2
    0
    1
        Six events
    2
    2
    2
    1
        Seven events
    0
    1
    0
    0
    Attachments
    		 Estimated Overall Survival Curves
    Notes
    [1] - Only patients continued beyond Visit 3.
    [2] - Only patients continued beyond Visit 3.
    Statistical analysis title
    		 Modeling the time between consecutive ATIs
    Statistical analysis description
    An extension of a survival model based on the Cox proportional hazards approach was applied. Multiple ATI events per patient within observational period (if there were any) contributed to proportional means model, which included baseline ATI frequency as further covariable [which was not shown to be statistically significant]. Presented results refer to the treatment arm related effect.
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0002
    Method
    		 Proportional means model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.4496
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.297
         upper limit
    		 0.6806
    Notes
    [3] - Analysis followed an exploratory rather than confirmatory approach. Presented Hazard ratio [HR] refers to 'Hazard for test group compared to control group'.
    Statistical analysis title
    		 Modeling the time between consecutive ATIs - PP
    Statistical analysis description
    Basis: Per-protocol patients An extension of a survival model based on the Cox proportional hazards approach was applied. Multiple ATI events per patient within observational period (if there were any) contributed to proportional means model, which included baseline ATI frequency as further covariable [which was not shown to be statistically significant]. Presented results refer to the treatment arm related effect.
    Comparison groups
    Test group - PP v Control group - PP
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.001
    Method
    		 Proportional means model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.4559
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2846
         upper limit
    		 0.7306
    Notes
    [4] - Analysis followed an exploratory rather than confirmatory approach. Presented Hazard ratio [HR] refers to 'Hazard for test group compared to control group'.
    Statistical analysis title
    		 Proportions of patients with at least 1 ATI
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding binary categorization of patients with either 'No ATI event' or 'At least one ATI event' observed within considered timeframe.
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -29.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.57
         upper limit
    		 -17.81
    Notes
    [5] - Analysis followed an exploratory rather than confirmatory approach.
    [6] - The presented risk difference refers to the difference of proportions [%] of patients with at least one ATI event considering 'Test - Control'. I.e. a negative value indicates less patients with ATI in test group compared to control group.
    Statistical analysis title
    		 Proportions of patients with at least 1 ATI - PP
    Statistical analysis description
    Basis: Per-protocol patients Analysis is based on comparison of treatment arms regarding binary categorization of patients with either 'No ATI event' or 'At least one ATI event' observed within considered timeframe.
    Comparison groups
    Test group - PP v Control group - PP
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0003 [8]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -27.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.5
         upper limit
    		 -13.31
    Notes
    [7] - Analysis followed an exploratory rather than confirmatory approach.
    [8] - The presented risk difference refers to the difference of proportions [%] of patients with at least one ATI event considering 'Test - Control'. I.e. a negative value indicates less patients with ATI in test group compared to control group.
    Statistical analysis title
    		 Sensitivity model: Poisson regression
    Statistical analysis description
    Analysis of ATI event occurrences in terms of count-data has been additionally assessed via Poisson regression modelling. As a result event rates (Test=0.5946 [events/year] | Control=1.3401[events/year]) and 'estimated time to event' (Test=613.8 [days] | Control=272.4[days]), respectively, have been calculated from estimated treatment specific least squares means.
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.0003 [10]
    Method
    		 Poisson Regression [GEE]
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.4437
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2867
         upper limit
    		 0.6868
    Notes
    [9] - Analysis followed an exploratory rather than confirmatory approach. Poisson regression model was intended as a sensitivity analysis.
    [10] - Relative risk [RR] refers to 'Test/Control'. I.e. the statistically significant finding and referring RR value below '1' indicates less ATI in test group compared to control group. Thus, sensitivity analysis confirms primary analysis findings.

    Secondary: Standardized number of days with any chronic tonsillitis symptom - per diary period

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    End point title
    		 Standardized number of days with any chronic tonsillitis symptom - per diary period
    End point description
    Patients were asked to report their suffering of chronic tonsillitis symptoms on a weekly basis restrospectively for each day in a diary. The standardized number of days, which is the ratio of days with presence of any symptom divided by the total number of days recorderd in a diary period, was evaluated.
    End point type
    Secondary
    End point timeframe
    Following diary periods are considered (the number of patients differs between periods - depending on individual drop out [see subject disposition]): T I: V1 to V3 FU I: V3 to V4 T II: V4 to V5 FU II: V5 to V6 T III: V6 to V7 FU III: V7 to V9
    End point values
    		 Test group Control group
    Number of subjects analysed
    131 [11]
    123 [12]
    Units: proportion of total diary days
    median (inter-quartile range (Q1-Q3))
        Diary period T I
    0.214 (0.107 to 0.436)
    0.393 (0.224 to 0.615)
        Diary period FU I
    0.179 (0.092 to 0.276)
    0.328 (0.179 to 0.589)
        Diary period T II
    0.143 (0.081 to 0.229)
    0.298 (0.148 to 0.576)
        Diary period FU II
    0.113 (0.054 to 0.246)
    0.268 (0.107 to 0.582)
        Diary period T III
    0.107 (0.052 to 0.2)
    0.21 (0.1 to 0.5)
        Diary period FU III
    0.113 (0.057 to 0.2)
    0.227 (0.1 to 0.529)
    Notes
    [11] - 1 Patient excluded due to no post-baseline data. Number of patients varies between diary periods.
    [12] - 1 Patient excluded due to no post-baseline data. Number of patients varies between diary periods.
    Statistical analysis title
    		 Diary period 'T I' - days with any symptom
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented suffering from any chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period T I (Visit 1 to Visit 3) Number of patients with data in this period: 254 (Test group:131 | Control group: 123).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of location shift
    Point estimate
    -0.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.202
         upper limit
    		 -0.079
    Notes
    [13] - Analysis followed an exploratory rather than confirmatory approach.
    [14] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from any chronic tonsillitis symptoms.
    Statistical analysis title
    		 Diary period 'FU I' - days with any symptom
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented suffering from any chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period FU I (Visit 3 to Visit 4) Number of patients with data in this period: 248 (Test group:128 | Control group: 120).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.0001 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of location shift
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.212
         upper limit
    		 -0.095
    Notes
    [15] - Analysis followed an exploratory rather than confirmatory approach.
    [16] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from any chronic tonsillitis symptoms.
    Statistical analysis title
    		 Diary period 'T II' - days with any symptom
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented suffering from any chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period T II (Visit 4 to Visit 5) Number of patients with data in this period: 241 (Test group:124 | Control group: 117).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of location shift
    Point estimate
    -0.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 -0.089
    Notes
    [17] - Analysis followed an exploratory rather than confirmatory approach.
    [18] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from any chronic tonsillitis symptoms.
    Statistical analysis title
    		 Diary period 'FU II' - days with any symptom
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented suffering from any chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period FU II (Visit 5 to Visit 6) Number of patients with data in this period: 230 (Test group:115| Control group: 115).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 < 0.0001 [20]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of location shift
    Point estimate
    -0.119
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 -0.069
    Notes
    [19] - Analysis followed an exploratory rather than confirmatory approach.
    [20] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from any chronic tonsillitis symptoms.
    Statistical analysis title
    		 Diary period 'T III' - days with any symptom
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented suffering from any chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period T III (Visit 6 to Visit 7) Number of patients with data in this period: 226 (Test group:114 | Control group: 112).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 < 0.0001 [22]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of location shift
    Point estimate
    -0.102
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.164
         upper limit
    		 -0.054
    Notes
    [21] - Analysis followed an exploratory rather than confirmatory approach.
    [22] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from any chronic tonsillitis symptoms.
    Statistical analysis title
    		 Diary period 'FU III' - days with any symptom
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented suffering from any chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period FU III (Visit 7 to Visit 9) Number of patients with data in this period: 211 (Test group:107 | Control group: 104).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 < 0.0001 [24]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of location shift
    Point estimate
    -0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.181
         upper limit
    		 -0.062
    Notes
    [23] - Analysis followed an exploratory rather than confirmatory approach.
    [24] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from any chronic tonsillitis symptoms.

    Secondary: Number of documented upper respiratory tract infections [URTIs]

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    End point title
    		 Number of documented upper respiratory tract infections [URTIs]
    End point description
    End point type
    Secondary
    End point timeframe
    Basis are event occurrences observed beyond Visit 3 until the end of study. (Note that any URTI event occurrences prior to Visit 3 have been added to baseline URTI frequencies.)
    End point values
    		 Test group Control group
    Number of subjects analysed
    128 [25]
    120 [26]
    Units: URTI events
        No event
    101
    71
        One event
    21
    34
        Two events
    3
    12
        Three events
    3
    2
        Four events
    0
    1
    Notes
    [25] - Only patients continued beyond Visit 3.
    [26] - Only patients continued beyond Visit 3.
    Statistical analysis title
    		 Proportions of patients with at least 1 URTI
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding binary categorization of patients with either 'No URTI event' or 'At least one URTI event' observed within considered timeframe.
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.0008 [28]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -19.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.02
         upper limit
    		 -8.46
    Notes
    [27] - Analysis followed an exploratory rather than confirmatory approach.
    [28] - The presented risk difference refers to the difference of proportions [%] of patients with at least one URTI event considering 'Test -Control'. I.e. a negative value indicates less patients with URTI in test group compared to control group.

    Secondary: Presence / Absence of chronic tonsillitis symptoms per visit (investigators assessment)

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    End point title
    		 Presence / Absence of chronic tonsillitis symptoms per visit (investigators assessment)
    End point description
    During the study, the following 7 chronic tonsillitis-specific symptoms were evaluated by the investigator by checking the presence and intensity (3-items scale: absent, mild, severe) at each regular study visit (Visit 1 [Baseline Visit] to Visit 9): • Difficulties in swallowing / sore throat; • Bad breath and / or taste in mouth (halitosis); • Hyperemia of the anterior palatine arches; • Edema of angle where the anterior and posterior palatine arches join each other; • Caseous purulent plug and / or purulent exudates in the tonsillar crypts; • Friable tonsils or indurated tonsils or scarred adhesions between the tonsils and the palatine arches; • Enlarged submandibular lymph nodes. Presented "number of present symptoms at visit" does not refer to the symptom intensities but sums up the number of symptoms recorded to be present within a patient.
    End point type
    Secondary
    End point timeframe
    All regular study visits. Note: Data presented for "Visit 9" refers to either regular Visit 9 (Week 60±1) or early Termination Visit.
    End point values
    		 Test group Control group
    Number of subjects analysed
    131 [29]
    123 [30]
    Units: Number of present symptoms at visit
        Visit 1: No symptoms
    0
    0
        Visit 1: 1 symptom
    0
    0
        Visit 1: 2 symptoms
    0
    0
        Visit 1: 3 symptoms
    3
    2
        Visit 1: 4 symptoms
    12
    12
        Visit 1: 5 symptoms
    22
    29
        Visit 1: 6 symptoms
    36
    30
        Visit 1: 7 symptoms
    57
    50
        Visit 2: No symptoms
    1
    0
        Visit 2: 1 symptom
    3
    1
        Visit 2: 2 symptoms
    7
    3
        Visit 2: 3 symptoms
    11
    12
        Visit 2: 4 symptoms
    13
    13
        Visit 2: 5 symptoms
    43
    26
        Visit 2: 6 symptoms
    25
    23
        Visit 2: 7 symptoms
    27
    43
        Visit 3: No symptoms
    2
    1
        Visit 3: 1 symptom
    9
    6
        Visit 3: 2 symptoms
    13
    5
        Visit 3: 3 symptoms
    32
    14
        Visit 3: 4 symptoms
    23
    10
        Visit 3: 5 symptoms
    16
    19
        Visit 3: 6 symptoms
    14
    17
        Visit 3: 7 symptoms
    19
    48
        Visit 4: No symptoms
    2
    1
        Visit 4: 1 symptom
    11
    4
        Visit 4: 2 symptoms
    16
    2
        Visit 4: 3 symptoms
    27
    19
        Visit 4: 4 symptoms
    21
    15
        Visit 4: 5 symptoms
    16
    16
        Visit 4: 6 symptoms
    13
    10
        Visit 4: 7 symptoms
    19
    53
        Visit 5: No symptoms
    3
    0
        Visit 5: 1 symptom
    11
    4
        Visit 5: 2 symptoms
    43
    13
        Visit 5: 3 symptoms
    26
    10
        Visit 5: 4 symptoms
    16
    18
        Visit 5: 5 symptoms
    10
    14
        Visit 5: 6 symptoms
    5
    14
        Visit 5: 7 symptoms
    5
    44
        Visit 6: No symptoms
    4
    0
        Visit 6: 1 symptom
    7
    0
        Visit 6: 2 symptoms
    29
    10
        Visit 6: 3 symptoms
    23
    12
        Visit 6: 4 symptoms
    14
    13
        Visit 6: 5 symptoms
    7
    22
        Visit 6: 6 symptoms
    7
    12
        Visit 6: 7 symptoms
    14
    34
        Visit 7: No symptoms
    25
    3
        Visit 7: 1 symptom
    8
    3
        Visit 7: 2 symptoms
    29
    10
        Visit 7: 3 symptoms
    13
    12
        Visit 7: 4 symptoms
    9
    14
        Visit 7: 5 symptoms
    14
    15
        Visit 7: 6 symptoms
    3
    18
        Visit 7: 7 symptoms
    3
    26
        Visit 8: No symptoms
    23
    1
        Visit 8: 1 symptom
    8
    1
        Visit 8: 2 symptoms
    22
    6
        Visit 8: 3 symptoms
    14
    9
        Visit 8: 4 symptoms
    10
    9
        Visit 8: 5 symptoms
    12
    17
        Visit 8: 6 symptoms
    7
    21
        Visit 8: 7 symptoms
    2
    30
        Visit 9: No symptoms
    21
    3
        Visit 9: 1 symptom
    23
    4
        Visit 9: 2 symptoms
    32
    13
        Visit 9: 3 symptoms
    20
    10
        Visit 9: 4 symptoms
    15
    28
        Visit 9: 5 symptoms
    10
    7
        Visit 9: 6 symptoms
    5
    15
        Visit 9: 7 symptoms
    5
    43
    Notes
    [29] - 1 Patient excluded due to no post-baseline data. Number of patients varies between visits.
    [30] - 1 Patient excluded due to no post-baseline data. Number of patients varies between visits.
    Statistical analysis title
    		 Visit 1: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 1 records Number considered patients with symptom assessment data at this visit: 253 (Test group: 130 | Control group: 123).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.463 [32]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [31] - Analysis followed an exploratory rather than confirmatory approach.
    [32] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. No statistically significant could be detected at current visit.
    Statistical analysis title
    		 Visit 2: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 2 records Number considered patients with symptom assessment data at this visit: 251 (Test group: 130 | Control group: 121).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.0214 [34]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0
    Notes
    [33] - Analysis followed an exploratory rather than confirmatory approach.
    [34] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.
    Statistical analysis title
    		 Visit 3: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 3 records Number considered patients with symptom assessment data at this visit: 248 (Test group: 128 | Control group: 120).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 -1
    Notes
    [35] - Analysis followed an exploratory rather than confirmatory approach.
    [36] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.
    Statistical analysis title
    		 Visit 4: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 4 records Number considered patients with symptom assessment data at this visit: 245 (Test group: 125 | Control group: 120).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 < 0.0001 [38]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 -1
    Notes
    [37] - Analysis followed an exploratory rather than confirmatory approach.
    [38] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.
    Statistical analysis title
    		 Visit 5: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 5 records Number considered patients with symptom assessment data at this visit: 236 (Test group: 119 | Control group: 117).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 < 0.0001 [40]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 -2
    Notes
    [39] - Analysis followed an exploratory rather than confirmatory approach.
    [40] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.
    Statistical analysis title
    		 Visit 6: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 6 records Number considered patients with symptom assessment data at this visit: 208 (Test group: 105 | Control group: 103).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 < 0.0001 [42]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 -1
    Notes
    [41] - Analysis followed an exploratory rather than confirmatory approach.
    [42] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.
    Statistical analysis title
    		 Visit 7: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 7 records Number considered patients with symptom assessment data at this visit: 205 (Test group: 104 | Control group: 101).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    P-value
    		 < 0.0001 [44]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 -2
    Notes
    [43] - Analysis followed an exploratory rather than confirmatory approach.
    [44] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.
    Statistical analysis title
    		 Visit 8: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 8 records Number considered patients with symptom assessment data at this visit: 192 (Test group: 98| Control group: 94).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 < 0.0001 [46]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 -2
    Notes
    [45] - Analysis followed an exploratory rather than confirmatory approach.
    [46] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.
    Statistical analysis title
    		 Visit 9: Number of present symptoms
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of present symptoms at visit as determined by the treating physician. Basis: Visit 9 records [Regular visit (Week 60±1) or early Termination Visit] Number considered patients with symptom assessment data at this visit: 254 (Test group: 131| Control group: 123).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [47]
    P-value
    		 < 0.0001 [48]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 -2
    Notes
    [47] - Analysis followed an exploratory rather than confirmatory approach.
    [48] - The presented location shift refers to the difference in number of present symptoms 'Test -Control'. A p-value <0.05 indicates statistically significant differences. There is a lower number of present symptoms in test group compared to control group.

    Secondary: ATI treated with antibiotics

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    End point title
    		 ATI treated with antibiotics
    End point description
    Within observed ATI events, distinction has been made with respect to 'treatment with antibiotics'. Basis for this analysis are (i) recorded ATI events as well as (ii) patients with at least one ATI event. [Note: In case of multiple ATI Events per patient, a patient has been counted as 'treated with antibiotics' (due to ATI), if there was at least one of his/her ATIs treated with antibiotics.]
    End point type
    Secondary
    End point timeframe
    Whole study period (i.e. from Day 0 until Termination Visit).
    End point values
    		 Test group Control group ATI events - Test group ATI events - Control group
    Number of subjects analysed
    50 [49]
    87 [50]
    92
    189
    Units: Patients | Events
        Treated with antibiotics
    26
    59
    34
    110
        No antibiotic treatment applied
    24
    28
    58
    79
    Notes
    [49] - Only patients with at least one ATI event are considered.
    [50] - Only patients with at least one ATI event are considered.
    Statistical analysis title
    		 ATI events treated with antibiotics
    Statistical analysis description
    Analysis is based on comparison of treatment arms' ATI events regarding binary categorization of events with either 'No antibiotic treatment applied" or 'Antibiotic treatment'.
    Comparison groups
    ATI events - Test group v ATI events - Control group
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 other [51]
    P-value
    		 = 0.0008 [52]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -21.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.36
         upper limit
    		 -9.13
    Notes
    [51] - Analysis followed an exploratory rather than confirmatory approach.
    [52] - Risk difference refers to the difference of proportions [%] of ATI events "treated with antibiotics" considering the direction 'Test -Control'. I.e. a negative value indicates less events treated with antibiotics in test compared to control group.
    Statistical analysis title
    		 Patients with ATI treated with antibiotics
    Statistical analysis description
    Analysis is based on comparison of patients with at least one ATI event. The proportions of patients with 'at least one ATI with antibiotic treatment' and 'All ATI events not treated with antibiotics" are compared between treatment arms.
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other [53]
    P-value
    		 = 0.0663 [54]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -15.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.79
         upper limit
    		 1.16
    Notes
    [53] - Analysis followed an exploratory rather than confirmatory approach.
    [54] - Presented risk difference refers to the difference of proportions [%] of "patient with at least 1 ATI treated with antibiotics" 'Test -Control'. The difference is not statistically significant at alpha=0.05 level.

    Secondary: ATI treated with analgesics

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    End point title
    		 ATI treated with analgesics
    End point description
    Within observed ATI events, distinction has been made with respect to 'treatment with analgesics'. Basis for this analysis are (i) recorded ATI events as well as (ii) patients with at least one ATI event. [Note: In case of multiple ATI events per patient, a patient has been counted as 'treated with analgesics' (due to ATI), if there was at least one of his/her ATIs treated with analgesics.]
    End point type
    Secondary
    End point timeframe
    Whole study period (i.e. from Day 0 until Termination Visit).
    End point values
    		 Test group Control group ATI events - Test group ATI events - Control group
    Number of subjects analysed
    50 [55]
    87 [56]
    92
    189
    Units: Patients | Events
        Treated with analgesics
    34
    67
    57
    125
        No analgesic treatment applied
    16
    20
    35
    64
    Notes
    [55] - Only patients with at least one ATI event are considered.
    [56] - Only patients with at least one ATI event are considered.
    Statistical analysis title
    		 ATI events treated with analgesics
    Statistical analysis description
    Analysis is based on comparison of treatment arms' ATI events regarding binary categorization of events with either 'No analgesic treatment applied" or 'Analgesic treatment'.
    Comparison groups
    ATI events - Test group v ATI events - Control group
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 other [57]
    P-value
    		 = 0.4911 [58]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.18
         upper limit
    		 7.82
    Notes
    [57] - Analysis followed an exploratory rather than confirmatory approach.
    [58] - Presented risk difference refers to the difference of proportions [%] of ATI events "treated with analgesics" considering the direction 'Test -Control'. No statistically significant difference was detected.
    Statistical analysis title
    		 Patients with ATI treated with analgesics
    Statistical analysis description
    Analysis is based on comparison of patients with at least one ATI event. The proportions of patients with 'at least one ATI with analgesic treatment' and 'All ATI events not treated with analgesics" are compared between treatment arms.
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 other [59]
    P-value
    		 = 0.2486 [60]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.68
         upper limit
    		 6.65
    Notes
    [59] - Analysis followed an exploratory rather than confirmatory approach.
    [60] - Presented risk difference refers to the difference of proportions [%] of "patient with at least 1 ATI treated with analgesics" 'Test -Control'. The difference is not statistically significant at alpha=0.05 level.

    Secondary: Number of days with consumption of analgesics due to ATI

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    End point title
    		 Number of days with consumption of analgesics due to ATI
    End point description
    Within observed ATI events, distinction has been made with respect to 'treatment with analgesics' (see secondary endpoint "ATI treated with analgesics"). The number of days with consumption of analgesics has been evaluated, based on the documented start and end dates of documented analgesics consumption within ATI event occurrence.
    End point type
    Secondary
    End point timeframe
    Whole study period (i.e. from Day 0 until Termination Visit).
    End point values
    		 ATI events - Test group ATI events - Control group
    Number of subjects analysed
    57 [61]
    125 [62]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    5 (3 to 6)
    5 (4 to 7)
    Notes
    [61] - Only "treated" events are considered.
    [62] - Only "treated" events are considered.
    Statistical analysis title
    		 Days with consumption of analgesics due to ATI
    Statistical analysis description
    The number of days treated with analgesics due to ATI has been compared between test and control group ATI event occurrences, where only ATI events treated with analgesics have been considered (Test group: 57 | Control group: 125).
    Comparison groups
    ATI events - Control group v ATI events - Test group
    Number of subjects included in analysis
    182
    Analysis specification
    Pre-specified
    Analysis type
    		 other [63]
    P-value
    		 = 0.4802 [64]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of location shift
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0
    Notes
    [63] - Analysis followed an exploratory rather than confirmatory approach.
    [64] - The presented location shift refers to the difference 'Test -Control'. No statistically significant differences between treatment arms could be detected.

    Secondary: Standardized number of days with impact on performance of normal daily activity

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    End point title
    		 Standardized number of days with impact on performance of normal daily activity
    End point description
    Patients were asked to report impact on performance of normal daily activities by chronic tonsillitis symptoms on a weekly basis restrospectively for each day in a diary. The standardized number of days, which is the ratio of days with impact on normal daily activitiy divided by the total number of days recorderd in a diary period, was evaluated.
    End point type
    Secondary
    End point timeframe
    Following diary periods are considered (the number of patients differs between periods - depending on individual drop out [see subject disposition]): T I: V1 to V3 FU I: V3 to V4 T II: V4 to V5 FU II: V5 to V6 T III: V6 to V7 FU III: V7 to V9
    End point values
    		 Test group Control group
    Number of subjects analysed
    131 [65]
    123 [66]
    Units: proportion of total diary days
    median (inter-quartile range (Q1-Q3))
        Diary period T I
    0.018 (0 to 0.054)
    0.082 (0.018 to 0.179)
        Diary period FU I
    0 (0 to 0.036)
    0.055 (0 to 0.135)
        Diary period T II
    0 (0 to 0.018)
    0.018 (0 to 0.143)
        Diary period FU II
    0 (0 to 0.018)
    0 (0 to 0.096)
        Diary period T III
    0 (0 to 0)
    0 (0 to 0.088)
        Diary period FU III
    0 (0 to 0.021)
    0.022 (0 to 0.1)
    Notes
    [65] - 1 Patient excluded due to no post-baseline data. Number of patients varies between diary periods.
    [66] - 1 Patient excluded due to no post-baseline data. Number of patients varies between diary periods.
    Statistical analysis title
    		 Period 'T I' - days with impact on daily activity
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented impact on daily activity due to chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period T I (Visit 1 to Visit 3) Number of patients with data in this period: 254 (Test group: 131 | Control group: 123).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [67]
    P-value
    		 < 0.0001 [68]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -0.052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.071
         upper limit
    		 -0.021
    Notes
    [67] - Analysis followed an exploratory rather than confirmatory approach.
    [68] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from impact on daily activities due to symptoms.
    Statistical analysis title
    		 Period 'FU I' - days with impact on daily activity
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented impact on daily activity due to chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period FU I (Visit 3 to Visit 4) Number of patients with data in this period: 248 (Test group: 128 | Control group: 120).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [69]
    P-value
    		 < 0.0001 [70]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -0.036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.054
         upper limit
    		 -0.017
    Notes
    [69] - Analysis followed an exploratory rather than confirmatory approach.
    [70] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from impact on daily activities due to symptoms.
    Statistical analysis title
    		 Period 'T II' - days with impact on daily activity
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented impact on daily activity due to chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period T II (Visit 4 to Visit 5) Number of patients with data in this period: 241 (Test group: 124 | Control group: 117).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [71]
    P-value
    		 < 0.0001 [72]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -0.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.033
         upper limit
    		 0
    Notes
    [71] - Analysis followed an exploratory rather than confirmatory approach.
    [72] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from impact on daily activities due to symptoms.
    Statistical analysis title
    		 Period 'FU II'- days with impact on daily activity
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented impact on daily activity due to chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period FU II (Visit 5 to Visit 6) Number of patients with data in this period: 230 (Test group: 115 | Control group: 115).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [73]
    P-value
    		 = 0.0007 [74]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0003
         upper limit
    		 0
    Notes
    [73] - Analysis followed an exploratory rather than confirmatory approach.
    [74] - The statistically significant finding and referring Wilcoxon mean scores (Test=102.4 | Control=128.6) values indicate patients in test group less frequently suffering from impact on daily activities due to symptoms, although location shift is "0".
    Statistical analysis title
    		 Period 'T III'- days with impact on daily activity
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented impact on daily activity due to chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period T III (Visit 6 to Visit 7) Number of patients with data in this period: 226 (Test group: 114 | Control group: 112).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [75]
    P-value
    		 < 0.0001 [76]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [75] - Analysis followed an exploratory rather than confirmatory approach.
    [76] - The statistically significant finding and referring Wilcoxon mean scores (Test=97.2 | Control=130.1) values indicate patients in test group less frequently suffering from impact on daily activities due to symptoms, although location shift is "0".
    Statistical analysis title
    		 Period 'FU III'-days with impact on daily activity
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the fraction of days with documented impact on daily activity due to chronic tonsillitis symptoms as obtained from patients' diaries. Basis: Diary period FU III (Visit 7 to Visit 9) Number of patients with data in this period: 211 (Test group: 107 | Control group: 104).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [77]
    P-value
    		 < 0.0001 [78]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Hodges Lehman estimate of Location Shift
    Point estimate
    -0.007
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.027
         upper limit
    		 0
    Notes
    [77] - Analysis followed an exploratory rather than confirmatory approach.
    [78] - The presented location shift refers to the difference 'Test -Control'. I.e. the statistically significant finding and referring negative value indicate patients in test group less frequently suffering from impact on daily activities due to symptoms.

    Secondary: Patient’s quality of life

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    End point title
    		 Patient’s quality of life
    End point description
    Quality of life was assessed by the patient at each regular visit except Visit 2 using a 5-point rating scale (items: "Very good", "Good", "Moderate", "Poor" and "Very poor"). Presented evaluation is related to binary categorization of patients' assessments into categories "At least good" (i.e. summarizing answers: "very good" and "good") and "Moderate or worse" (i.e. summarizing answers: "moderate ", "poor" and "very poor").
    End point type
    Secondary
    End point timeframe
    All regular study visits (except Visit 2). Note: Data presented for "Visit 9" refers to either regular Visit 9 (Week 60±1) or early Termination Visit
    End point values
    		 Test group Control group
    Number of subjects analysed
    131 [79]
    123 [80]
    Units: Patients
        Visit 1: Very good or good
    20
    18
        Visit 1: Moderate or poor or very poor
    110
    105
        Visit 3: Very good or good
    103
    36
        Visit 3: Moderate or poor or very poor
    25
    84
        Visit 4: Very good or good
    108
    36
        Visit 4: Moderate or poor or very poor
    17
    84
        Visit 5: Very good or good
    109
    35
        Visit 5: Moderate or poor or very poor
    10
    82
        Visit 6: Very good or good
    99
    51
        Visit 6: Moderate or poor or very poor
    6
    52
        Visit 7: Very good or good
    98
    48
        Visit 7: Moderate or poor or very poor
    6
    53
        Visit 8: Very good or good
    95
    40
        Visit 8: Moderate or poor or very poor
    3
    54
        Visit 9: Very good or good
    123
    46
        Visit 9: Moderate or poor or very poor
    8
    77
    Notes
    [79] - 1 Patient excluded due to no post-baseline data. Number of patients varies between visits.
    [80] - 1 Patient excluded due to no post-baseline data. Number of patients varies between visits.
    Statistical analysis title
    		 Visit 1: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 1 records Number considered patients with symptom assessment data at this visit: 253 (Test group: 130 | Control group: 123).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [81]
    P-value
    		 = 0.8674 [82]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.05
         upper limit
    		 9.55
    Notes
    [81] - Analysis followed an exploratory rather than confirmatory approach.
    [82] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. No statistically significant difference was detected for current visit.
    Statistical analysis title
    		 Visit 3: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 3 records Number considered patients with symptom assessment data at this visit: 248 (Test group: 128 | Control group: 120).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [83]
    P-value
    		 < 0.0001 [84]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    50.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 39.77
         upper limit
    		 61.16
    Notes
    [83] - Analysis followed an exploratory rather than confirmatory approach.
    [84] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. I.e. a positive value indicates more patients with "very good" or "good" QoL in test group compared to control group.
    Statistical analysis title
    		 Visit 4: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 4 records Number considered patients with symptom assessment data at this visit: 245 (Test group: 125 | Control group: 120).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [85]
    P-value
    		 < 0.0001 [86]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    56.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46.23
         upper limit
    		 66.57
    Notes
    [85] - Analysis followed an exploratory rather than confirmatory approach.
    [86] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. I.e. a positive value indicates more patients with "very good" or "good" QoL in test group compared to control group.
    Statistical analysis title
    		 Visit 5: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 5 records Number considered patients with symptom assessment data at this visit: 236 (Test group: 119 | Control group: 117).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [87]
    P-value
    		 < 0.0001 [88]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    61.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 52
         upper limit
    		 71.36
    Notes
    [87] - Analysis followed an exploratory rather than confirmatory approach.
    [88] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. I.e. a positive value indicates more patients with "very good" or "good" QoL in test group compared to control group.
    Statistical analysis title
    		 Visit 6: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 6 records Number considered patients with symptom assessment data at this visit: 208 (Test group: 105 | Control group: 103).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [89]
    P-value
    		 < 0.0001 [90]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    44.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 34.14
         upper limit
    		 55.4
    Notes
    [89] - Analysis followed an exploratory rather than confirmatory approach.
    [90] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. I.e. a positive value indicates more patients with "very good" or "good" QoL in test group compared to control group.
    Statistical analysis title
    		 Visit 7: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 7 records Number considered patients with symptom assessment data at this visit: 205 (Test group: 104 | Control group: 101).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [91]
    P-value
    		 < 0.0001 [92]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    46.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 35.99
         upper limit
    		 57.43
    Notes
    [91] - Analysis followed an exploratory rather than confirmatory approach.
    [92] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. I.e. a positive value indicates more patients with "very good" or "good" QoL in test group compared to control group.
    Statistical analysis title
    		 Visit 8: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 8 records Number considered patients with symptom assessment data at this visit: 192 (Test Group: 98 | Control Group: 94).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [93]
    P-value
    		 < 0.0001 [94]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    54.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 43.82
         upper limit
    		 64.95
    Notes
    [93] - Analysis followed an exploratory rather than confirmatory approach.
    [94] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. I.e. a positive value indicates more patients with "very good" or "good" QoL in test group compared to control group.
    Statistical analysis title
    		 Visit 9: quality of life
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the number of patients rating their quality of life [QoL] being "At least good". Basis: Visit 9 records [Regular visit (Week 60±1) or early Termination Visit] Number considered patients with symptom assessment data at this visit: 254 (Test group: 131 | Control group: 123).
    Comparison groups
    Test group v Control group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [95]
    P-value
    		 < 0.0001 [96]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    56.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 47.01
         upper limit
    		 65.98
    Notes
    [95] - Analysis followed an exploratory rather than confirmatory approach.
    [96] - The presented risk difference refers to the difference of proportions [%] of patients with "At least good" self-rating of QoL. I.e. a positive value indicates more patients with "very good" or "good" QoL in test group compared to control group.

    Secondary: Treatment Outcome according to integrative medicine outcome scale [IMOS]

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    End point title
    		 Treatment Outcome according to integrative medicine outcome scale [IMOS]
    End point description
    Global judgement of the treatment outcome by IMOS (5-point rating scale) was done by both the investigator and the patient each separately in comparison to Visit 1 at each regular post-baseline visit except for Visit 2. IMOS items are "Complete recovery", "Major improvement", "Slight to moderate improvement", "No change" and "Deterioration". Presented evaluation is related to binary categorization of patients' assessments into categories "At least major improvement" (i.e. summarizing answers: "Complete recovery" and "Major improvement") and "Less than major improvement" (i.e. summarizing the remaining three categories). Distinction is made between patients' and investigators' IMOS ratings.
    End point type
    Secondary
    End point timeframe
    All regular post-baseline study visits (except Visit 2). Note: Data presented for "Visit 9" refers to either regular Visit 9 (Week 60±1) or early Termination Visit.
    End point values
    		 Test group Control group
    Number of subjects analysed
    131 [97]
    123 [98]
    Units: Patients
        Visit 3: At least major improvement [Patient]
    88
    9
        Visit 3: Less than major improvement [Patient]
    40
    109
        Visit 4: At least major improvement [Patient]
    82
    7
        Visit 4: Less than major improvement [Patient]
    43
    113
        Visit 5: At least major improvement [Patient]
    95
    18
        Visit 5: Less than major improvement [Patient]
    24
    99
        Visit 6: At least major improvement [Patient]
    82
    15
        Visit 6: Less than major improvement [Patient]
    23
    88
        Visit 7: At least major improvement [Patient]
    89
    14
        Visit 7: Less than major improvement [Patient]
    15
    87
        Visit 8: At least major improvement [Patient]
    82
    15
        Visit 8: Less than major improvement [Patient]
    16
    79
        Visit 9: At least major improvement [Patient]
    110
    14
        Visit 9: Less than major improvement [Patient]
    18
    108
        Visit 3: At least major improvement [Investigator]
    80
    8
        Visit 3: Less than major improvement [Investigator
    48
    110
        Visit 4: At least major improvement [Investigator]
    81
    6
        Visit 4: Less than major improvement [Investigator
    44
    114
        Visit 5: At least major improvement [Investigator]
    95
    18
        Visit 5: Less than major improvement [Investigator
    24
    99
        Visit 6: At least major improvement [Investigator]
    82
    11
        Visit 6: Less than major improvement [Investigator
    23
    92
        Visit 7: At least major improvement [Investigator]
    91
    11
        Visit 7: Less than major improvement [Investigator
    13
    90
        Visit 8: At least major improvement [Investigator]
    84
    11
        Visit 8: Less than major improvement [Investigator
    14
    83
        Visit 9: At least major improvement [Investigator]
    110
    8
        Visit 9: Less than major improvement [Investigator
    18
    114
    Notes
    [97] - 1 Patient excluded due to no post-baseline data. Number of patients varies between visits.
    [98] - 1 Patient excluded due to no post-baseline data. Number of patients varies between visits.
    Statistical analysis title
    		 Visit 3: IMOS [Patients' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 3 records Number considered patients with IMOS assessment data at this visit: 246 (Test group: 128 | Control group: 118)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [99]
    P-value
    		 < 0.0001 [100]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    61.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 51.77
         upper limit
    		 70.47
    Notes
    [99] - Analysis followed an exploratory rather than confirmatory approach.
    [100] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 4: IMOS [Patients' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 4 records Number considered patients with IMOS assessment data at this visit: 245 (Test group: 125 | Control group: 120)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [101]
    P-value
    		 < 0.0001 [102]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    59.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 50.44
         upper limit
    		 69.09
    Notes
    [101] - Analysis followed an exploratory rather than confirmatory approach.
    [102] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 5: IMOS [Patients' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 5 records Number considered patients with IMOS assessment data at this visit: 236 (Test group: 119 | Control group: 117)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [103]
    P-value
    		 < 0.0001 [104]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    64.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 54.72
         upper limit
    		 74.18
    Notes
    [103] - Analysis followed an exploratory rather than confirmatory approach.
    [104] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 6: IMOS [Patients' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 6 records Number considered patients with IMOS assessment data at this visit: 208 (Test group: 105 | Control group: 103)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [105]
    P-value
    		 < 0.0001 [106]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    63.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.09
         upper limit
    		 73.97
    Notes
    [105] - Analysis followed an exploratory rather than confirmatory approach.
    [106] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 7: IMOS [Patients' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 7 records Number considered patients with IMOS assessment data at this visit: 205 (Test group: 104 | Control group: 101)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [107]
    P-value
    		 < 0.0001 [108]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    71.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 62.18
         upper limit
    		 81.26
    Notes
    [107] - Analysis followed an exploratory rather than confirmatory approach.
    [108] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 8: IMOS [Patients' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 8 records Number considered patients with IMOS assessment data at this visit: 192 (Test group: 98 | Control group: 94)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [109]
    P-value
    		 < 0.0001 [110]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    67.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 57.31
         upper limit
    		 78.13
    Notes
    [109] - Analysis followed an exploratory rather than confirmatory approach.
    [110] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 9: IMOS [Patients' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 9 records (either regular Visit 9 (Week 60±1) or early Termination Visit) Number considered patients with IMOS assessment data at this visit: 250 (Test group: 128 | Control group: 122)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [111]
    P-value
    		 < 0.0001 [112]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    74.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 66.2
         upper limit
    		 82.72
    Notes
    [111] - Analysis followed an exploratory rather than confirmatory approach.
    [112] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 3: IMOS [Investigators' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 3 records Number considered patients with IMOS assessment data at this visit: 246 (Test group: 128 | Control group: 118)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [113]
    P-value
    		 < 0.0001 [114]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    55.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46.19
         upper limit
    		 65.26
    Notes
    [113] - Analysis followed an exploratory rather than confirmatory approach.
    [114] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 4: IMOS [Investigators' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 4 records Number considered patients with IMOS assessment data at this visit: 245 (Test group: 125 | Control group: 120)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [115]
    P-value
    		 < 0.0001 [116]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    59.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 50.56
         upper limit
    		 69.04
    Notes
    [115] - Analysis followed an exploratory rather than confirmatory approach.
    [116] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 5: IMOS [Investigators' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 5 records Number considered patients with IMOS assessment data at this visit: 236 (Test group: 119 | Control group: 117)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [117]
    P-value
    		 < 0.0001 [118]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    64.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 54.72
         upper limit
    		 74.18
    Notes
    [117] - Analysis followed an exploratory rather than confirmatory approach.
    [118] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 6: IMOS [Investigators' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 6 records Number considered patients with IMOS assessment data at this visit: 208 (Test group: 105 | Control group: 103)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [119]
    P-value
    		 < 0.0001 [120]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    67.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 57.51
         upper limit
    		 77.32
    Notes
    [119] - Analysis followed an exploratory rather than confirmatory approach.
    [120] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 7: IMOS [Investigators' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 7 records Number considered patients with IMOS assessment data at this visit: 205 (Test group: 104 | Control group: 101)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [121]
    P-value
    		 < 0.0001 [122]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    76.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 67.82
         upper limit
    		 85.4
    Notes
    [121] - Analysis followed an exploratory rather than confirmatory approach.
    [122] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 8: IMOS [Investigators' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 8 records Number considered patients with IMOS assessment data at this visit: 192 (Test group: 98 | Control group: 94)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [123]
    P-value
    		 < 0.0001 [124]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 64.51
         upper limit
    		 83.51
    Notes
    [123] - Analysis followed an exploratory rather than confirmatory approach.
    [124] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.
    Statistical analysis title
    		 Visit 9: IMOS [Investigators' assessments]
    Statistical analysis description
    Analysis is based on comparison of treatment arms regarding the proportion of patients with IMOS "At least major improvement" rating. Basis: Visit 9 records (either regular Visit 9 (Week 60±1) or early Termination Visit) Number considered patients with IMOS assessment data at this visit: 250 (Test group: 128 | Control group: 122)
    Comparison groups
    Control group v Test group
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    		 other [125]
    P-value
    		 < 0.0001 [126]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    79.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 71.93
         upper limit
    		 86.83
    Notes
    [125] - Analysis followed an exploratory rather than confirmatory approach.
    [126] - The presented risk difference refers to the difference of proportions [%] of patients with "At least least major improvement" IMOS rating. I.e. a positive value indicates more patients with better outcome category in test group compared to control.

    Secondary: Global Assessment of Tolerability by Investigator and Patient

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    End point title
    		 Global Assessment of Tolerability by Investigator and Patient [127]
    End point description
    Assessment of tolerability of treatment has been done for test group patients after each of the three active treatment periods. Assessment has been done separately by patients and physicians on a 5-point verbal rating scale (items: "Very good", "Good", "Moderate", "Poor" and "Very poor"). Presented evaluation is related to binary categorization of assessments into categories "At least good" (i.e. summarizing "Very good" and "Good") and "Moderate or worse" (i.e. summarizing answers: "Moderate ", "Poor" and "Very poor").
    End point type
    Secondary
    End point timeframe
    Visit 3 (Week 8 [+/- 1 week]) Visit 5 (Week 24 [+/- 1 week]) Visit 7 (Week 40 [+/- 1 week]) Early Termination Visit (if applicable)
    Notes
    [127] - 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: Endpoint was only evaluated for test group and therefore only descriptive statistics for test group is presented for this endpoint.
    End point values
    		 Test group
    Number of subjects analysed
    132 [128]
    Units: Patients
        Visit 3: At least good [Patient]
    126
        Visit 3: Moderate or worse [Patient]
    2
        Visit 5: At least good [Patient]
    118
        Visit 5: Moderate or worse [Patient]
    0
        Visit 7: At least good [Patient]
    100
        Visit 7: Moderate or worse [Patient]
    0
        Early Term.Visit: At least good [Patient]
    3
        Early Term.Visit: Moderate or worse [Patient]
    1
        Visit 3: At least good [Investigator]
    126
        Visit 3: Moderate or worse [Investigator]
    2
        Visit 5: At least good [Investigator]
    118
        Visit 5: Moderate or worse [Investigator]
    0
        Visit 7: At least good [Investigator]
    100
        Visit 7: Moderate or worse [Investigator]
    0
        Early Term.Visit: At least good [Investigator]
    2
        Early Term.Visit: Moderate or worse [Investigator]
    2
    Notes
    [128] - Number of patients varies between visits.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Whole study period.
    Adverse event reporting additional description
    As ATI and URTI occurrences were expected in the evaluated population and were part of efficacy analysis they were not regarded in the AE / SAE evaluation. Therefore events coded as J02, J03, J00, J06, J09, J10 and J11 (according to ICD-10) are not presented within the adverse event evaluation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Test Group
    Reporting group description
    		 The test group received Tonsilotren tablets during Treatment Period I to III each for 8 weeks and - if needed - conventional symptomatic treatment for chronic tonsillitis.

    Reporting group title
    Control group
    Reporting group description
    		 The control group was treated only with conventional symptomatic treatment if needed.

    Serious adverse events
    		 Test Group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 132 (3.03%)
    3 / 124 (2.42%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 124 (0.81%)
         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: 3%
    Non-serious adverse events
    		 Test Group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 132 (40.91%)
    59 / 124 (47.58%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 132 (11.36%)
    13 / 124 (10.48%)
         occurrences all number
    55
    22
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    6 / 132 (4.55%)
    2 / 124 (1.61%)
         occurrences all number
    8
    2
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    1 / 132 (0.76%)
    5 / 124 (4.03%)
         occurrences all number
    1
    8
    Cough
         subjects affected / exposed
    3 / 132 (2.27%)
    4 / 124 (3.23%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 132 (3.79%)
    1 / 124 (0.81%)
         occurrences all number
    9
    2
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    8 / 132 (6.06%)
    12 / 124 (9.68%)
         occurrences all number
    9
    14
    Bronchitis
         subjects affected / exposed
    3 / 132 (2.27%)
    9 / 124 (7.26%)
         occurrences all number
    3
    9
    Otitis externa
         subjects affected / exposed
    5 / 132 (3.79%)
    1 / 124 (0.81%)
         occurrences all number
    12
    1
    Sinusitis
         subjects affected / exposed
    0 / 132 (0.00%)
    5 / 124 (4.03%)
         occurrences all number
    0
    7
    Laryngitis
         subjects affected / exposed
    0 / 132 (0.00%)
    4 / 124 (3.23%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2012
    This amendment was implemented in Germany because of following German’s ethics committee’s (EC) request: 1. Sequential recruitment of patients: first 80 adult patients had to be recruited. Minors could only be recruited after the data of 80 adults who had passed the first 2 treatment cycles were presented to the German EC. This step was not required though as only 54 patients (adults) were recruited in total in Germany. 2. Specification of the study centers qualification: restriction to ear-nose-throat specialists.

    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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    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
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