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    Clinical Trial Results:
    A COMPARISON OF THERAPEUTIC EQUIVALENCE BETWEEN THE TEST AND THE REFERENCE FORMULATION OF FIXED COMBINATION OF CETYLPYRIDINIUM CHLORIDE 1.0 mg/BENZYDAMINE HYDROCHLORIDE 3 mg IN SUBJECTS WITH SORE THROAT ASSOCIATED WITH UPPER RESPIRATORY TRACT INFECTIONS

    Summary
    EudraCT number
    		 2013-002970-32
    Trial protocol
    		 SI  
    Global end of trial date
    27 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2016
    First version publication date
    11 Aug 2016
    Other versions
    Summary report(s)
    		 KKL072012_ClinicalTrialResults_synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    KKL072012
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Krka d. d.
    Sponsor organisation address
    Šmarješka cesta 6, Novo mesto, Slovenia, 8501
    Public contact
    Info točka raziskave, KRKA, tovarna zdravil, d. d., Novo mesto, 00386 14751489, marko.boh@krka.biz
    Scientific contact
    Info točka raziskave, KRKA, tovarna zdravil, d. d., Novo mesto, 00386 14751489, marko.boh@krka.biz
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - to demonstrate the equivalence of the treatment effect between test and reference product in terms of the sore throat pain intensity difference at the predefined time point compared to baseline . _WIthin the main objective a superiority of the treatment effect of both test and reference treatment over placebo treatment is to be demonstrated in terms of sore throat pain intensity difference at the predefined time point compared to baseline.
    Protection of trial subjects
    Due to the placebo control but also for the cases of active treatient inactivity, an option of rescue medication was provided to each subject. In this respect , each subject received a number of Paracetamol tablets 500 mg to fit the treatment period with the recomended dosing schedule of maximal 4 x 500 mg daily. Subjects also had an option to request for rescue medication during 3 hour efficacy assessment at the clinical site.
    Background therapy
    		 No background therapy for the tested indication was allowed
    Evidence for comparator
    		 According to the legal basis of classical generic application, we performed therapeutic equivalence study to the originator reference product; classical bioequivalence study was not possible due to insufficient systemic absorbtion of the investigational medicinal product.
    Actual start date of recruitment
    18 Nov 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
    Slovenia: 1
    Country: Number of subjects enrolled
    Russian Federation: 290
    Worldwide total number of subjects
    291
    EEA total number of subjects
    1
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    290
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 There were 291 subjects screened; all of them were also enrolled. There were no drop-outs during the assessment period at Visit 1. Altogether 290 patients were enrolled in Russian Federation and one subject in Slovenia. First patient in date: 18.11.2013. Last patient out date: 27.2.2014

    Pre-assignment
    Screening details
    		 Basic screening criteria were the history of sore throat of 6 days or less, the adult age with the upper limit of completed 65 years and the ability to read and understand how to use the methodological tool for pain assessment. All subjects that were screened were also enrolled.

    Period 1
    Period 1 title
    SIngle dose assessment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    We were only able to ensure the complete blind for Tested Investigational Medicinal Product (TIMP) and placebo due to techical difficulties related to local application (long time oral dissolution). TIMP and placebo were Identical with regard to all of the features including appearance, shape, smell, and taste, as well as the size, colour and shape of the blisters. None of the IMPs were present on the national market so subjects were not familiar with the IMP's appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Subjects in this arm have been taking placebo during the entire trial duration.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Lozenge
    Routes of administration
    Oropharyngeal use
    Dosage and administration details
    In this period, the initial single dose was applied. The instructions were given to dissolve the lozenge in the mouth , by putting it on the tongue and left to be dissolved. Chewing, crushing or swallowing of the lozenge was not allowed, while the saliva could be swallowed.

    Arm title
    		 Group B
    Arm description
    		 Subjects in this arm were administered the reference medicinal product manufactured by the originator of the product.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    benzydamine hydrochloride 3 mg / cetylpyridinium chloride 1 mg
    Investigational medicinal product code
    Other name
    Gola action
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oropharyngeal use
    Dosage and administration details
    In this period, the initial single dose was applied. The instructions were given to dissolve the orodispersible tablet in the mouth , by putting it on the tongue and left to be dissolved. Chewing, crushing or swallowing of the orodispersible tablet was not allowed, while the saliva could be swallowed.

    Arm title
    		 Group C
    Arm description
    		 All the subjects in this arm were administered tested investigational medicinal product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    benzydamine hydrochloride 3 mg / cetylpyridinium chloride 1 mg
    Investigational medicinal product code
    Other name
    Septolete Total, Septabene
    Pharmaceutical forms
    Lozenge
    Routes of administration
    Oropharyngeal use
    Dosage and administration details
    In this period, the initial single dose was applied. The instructions were given to dissolve the lozenge in the mouth , by putting it on the tongue and left to be dissolved. Chewing, crushing or swallowing of the lozenge was not allowed, while the saliva could be swallowed.

    Number of subjects in period 1
    		Group A Group B Group C
    Started
    57
    116
    118
    Completed
    57
    116
    118
    Period 2
    Period 2 title
    Therapy follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The blinding was assured similarly to Period I, i.e. Placebo had the same appearance as TIMP. Besides, none of the products was at the market of any of the participating countries at the time of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 All the subjects in this arm have been taking placebo as in the period I.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Lozenge
    Routes of administration
    Oropharyngeal use
    Dosage and administration details
    In this period, subjects were taking the IMP according to the planned Schedule ( 4 times daily each 3 hours). The instructions were given to dissolve the lozenge in the mouth , by putting it on the tongue and left to be dissolved. Chewing, crushing or swallowing of the lozenge was not allowed, while the saliva could be swallowed.

    Arm title
    		 Group B
    Arm description
    		 Subjects in this arm were administered the reference medicinal product manufactured by the originator of the product.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    benzydamine hydrochloride 3 mg / cetylpyridinium chloride 1 mg
    Investigational medicinal product code
    Other name
    Gola action
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oropharyngeal use
    Dosage and administration details
    In this period, the initial single dose was applied. The instructions were given to dissolve the orodispersible tablet in the mouth , by putting it on the tongue and left to be dissolved. Chewing, crushing or swallowing of the orodispersible tablet was not allowed, while the saliva could be swallowed.

    Arm title
    		 Group C
    Arm description
    		 All the subjects in this arm were administered tested investigational medicinal product.
    Arm type
    		 Experimental

    Investigational medicinal product name
    benzydamine hydrochloride 3 mg / cetylpyridinium chloride 1 mg
    Investigational medicinal product code
    Other name
    Septolete Total, Septabene
    Pharmaceutical forms
    Lozenge
    Routes of administration
    Oropharyngeal use
    Dosage and administration details
    In this period, subjects were taking the IMP according to the planned Schedule ( 4 times daily each 3 hours). The instructions were given to dissolve the lozenge in the mouth , by putting it on the tongue and left to be dissolved. Chewing, crushing or swallowing of the lozenge was not allowed, while the saliva could be swallowed.

    Number of subjects in period 2
    		Group A Group B Group C
    Started
    57
    116
    118
    Completed
    37
    51
    54
    Not completed
    20
    65
    64
         Complete disease resolution
    -
    62
    63
         condition completely resolved
    18
    -
    -
         Lost to follow-up
    -
    1
    -
         Protocol deviation
    1
    1
    1
         non-allowed concomitant therapy indicated
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Subjects in this arm have been taking placebo during the entire trial duration.

    Reporting group title
    Group B
    Reporting group description
    		 Subjects in this arm were administered the reference medicinal product manufactured by the originator of the product.

    Reporting group title
    Group C
    Reporting group description
    		 All the subjects in this arm were administered tested investigational medicinal product.

    Reporting group values
    		 Group A Group B Group C Total
    Number of subjects
    		 57 116 118 291
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    A descriptive statistics of the subject mean age per treatment group was calculated. The population set analysed was full analysis set. A comparative analysis of baseline characteristics did not show any differences between the treatment arms.
    Units: years
        arithmetic mean (standard deviation)
    		 39.9 ± 10.8 40.5 ± 12.23 38.5 ± 11.07 -
    Gender categorical
    The descriptive statistics for FAS analsysis has been made on the percentage of gender categories per treatment group. The comparison between the treatment groups did not show any significant differences. FAS analysis has been performed.
    Units: Subjects
        Female
    		 37 74 87 198
        Male
    		 20 42 31 93
    concomitant therapy for current URTI
    The descriptive statistics about subjects who have been taking any medication for the current upper respiratory tract infection (URTI). In all of the subjects the therapy has been withdrawn in time with respect to the protocol. The distribution among the treatment groups was relatively even.
    Units: Subjects
        concomitant therapy
    		 9 18 26 53
        no concomitant therapy
    		 48 98 92 238
    body weight
    A descriptive statistics has been made for body weight at baseline per treatment group with between group comparison. No significant differences were identified. FAS analysis has been done.
    Units: kg
        arithmetic mean (standard deviation)
    		 73.2 ± 13.81 72.8 ± 14.59 70.5 ± 13.3 -
    body temperature
    Descriptive statistics has been made for mean body temperature per treatment group with the intergroup comparison. there were no significant differences between the treatment groups in mean body temperature. FAS analysis has been done.
    Units: Celsius Degrees
        arithmetic mean (standard deviation)
    		 37.48 ± 0.33 37.48 ± 0.38 37.48 ± 0.38 -
    TPA score
    Tonsillo-pharingitis assessment ( TPA) is a method of the assessment of the upper respiratory tract infection signs. Five parameters are assessed including body temperature, oropharyngeal status and status of local lymph nodes. The examination results are transformed into score with the maximum of 10 points. A descriptive statistics on the mean TPA score and comparison between the treatment groups were done and showed no significant differences.
    Units: points
        arithmetic mean (standard deviation)
    		 5.1 ± 0.91 5.1 ± 1.05 5.2 ± 0.85 -
    Sore throat pain intensitiy
    Abreviaiton: STPI The pain intensity is measured by the pain Visual analogue scale, which is completed by the subjects and evaluated by the investigator. It also denotes basic inclusion criterion.
    Units: mm
        arithmetic mean (standard deviation)
    		 80 ± 10.28 78.2 ± 10.02 77.6 ± 9.89 -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) included all subjects who were randomised and have received minimally one dose of the study medication regardless of protocol violations or premature discontinuation status. The FAS analysis of efficacy was a supportive analysis to per protocol set analysis for the primary efficacy endpoint and was used for all secondary and tertiary efficacy endpoints analysis and safety analysis.

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol (PP) set was defined as all randomized subjects entirely consistent with the protocol who received the initial IMP dose and had all assessments for all efficacy endpoints during the 3-hour measurement procedure at Visit 1. The major protocol violations for which subjects would be excluded from the PP set will represent violations that may impact the efficacy endpoints for which equivalence comparisons are being made. The decision towhich subjects to exclude from the PP set was made prior to breaking the blind. PP set was used for the primary endpoint analysis.

    Subject analysis sets values
    		 Full analysis set Per protocol set
    Number of subjects
    291
    288
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    A descriptive statistics of the subject mean age per treatment group was calculated. The population set analysed was full analysis set. A comparative analysis of baseline characteristics did not show any differences between the treatment arms.
    Units: years
        arithmetic mean (standard deviation)
    39.6 ± 11.49
    39.5 ± 11.51
    Gender categorical
    The descriptive statistics for FAS analsysis has been made on the percentage of gender categories per treatment group. The comparison between the treatment groups did not show any significant differences. FAS analysis has been performed.
    Units: Subjects
        Female
    198
    195
        Male
    93
    93
    concomitant therapy for current URTI
    The descriptive statistics about subjects who have been taking any medication for the current upper respiratory tract infection (URTI). In all of the subjects the therapy has been withdrawn in time with respect to the protocol. The distribution among the treatment groups was relatively even.
    Units: Subjects
        concomitant therapy
    53
        no concomitant therapy
    239
    body weight
    A descriptive statistics has been made for body weight at baseline per treatment group with between group comparison. No significant differences were identified. FAS analysis has been done.
    Units: kg
        arithmetic mean (standard deviation)
    71.9 ± 13.9
    72.1 ± 13.9
    body temperature
    Descriptive statistics has been made for mean body temperature per treatment group with the intergroup comparison. there were no significant differences between the treatment groups in mean body temperature. FAS analysis has been done.
    Units: Celsius Degrees
        arithmetic mean (standard deviation)
    37.48 ± 0.37
    37.49 ± 0.36
    TPA score
    Tonsillo-pharingitis assessment ( TPA) is a method of the assessment of the upper respiratory tract infection signs. Five parameters are assessed including body temperature, oropharyngeal status and status of local lymph nodes. The examination results are transformed into score with the maximum of 10 points. A descriptive statistics on the mean TPA score and comparison between the treatment groups were done and showed no significant differences.
    Units: points
        arithmetic mean (standard deviation)
    5.1 ± 0.94
    5.1 ± 0.95
    Sore throat pain intensitiy
    Abreviaiton: STPI The pain intensity is measured by the pain Visual analogue scale, which is completed by the subjects and evaluated by the investigator. It also denotes basic inclusion criterion.
    Units: mm
        arithmetic mean (standard deviation)
    78.3 ± 10.02
    78.5 ± 9.93

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Subjects in this arm have been taking placebo during the entire trial duration.

    Reporting group title
    Group B
    Reporting group description
    		 Subjects in this arm were administered the reference medicinal product manufactured by the originator of the product.

    Reporting group title
    Group C
    Reporting group description
    		 All the subjects in this arm were administered tested investigational medicinal product.
    Reporting group title
    Group A
    Reporting group description
    		 All the subjects in this arm have been taking placebo as in the period I.

    Reporting group title
    Group B
    Reporting group description
    		 Subjects in this arm were administered the reference medicinal product manufactured by the originator of the product.

    Reporting group title
    Group C
    Reporting group description
    		 All the subjects in this arm were administered tested investigational medicinal product.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) included all subjects who were randomised and have received minimally one dose of the study medication regardless of protocol violations or premature discontinuation status. The FAS analysis of efficacy was a supportive analysis to per protocol set analysis for the primary efficacy endpoint and was used for all secondary and tertiary efficacy endpoints analysis and safety analysis.

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per protocol (PP) set was defined as all randomized subjects entirely consistent with the protocol who received the initial IMP dose and had all assessments for all efficacy endpoints during the 3-hour measurement procedure at Visit 1. The major protocol violations for which subjects would be excluded from the PP set will represent violations that may impact the efficacy endpoints for which equivalence comparisons are being made. The decision towhich subjects to exclude from the PP set was made prior to breaking the blind. PP set was used for the primary endpoint analysis.

    Primary: Difference in sore throat pain intensity at 1 hour PP

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    End point title
    		 Difference in sore throat pain intensity at 1 hour PP
    End point description
    The endpoint is a difference in sore throat pain intensity ( STPI) between baseline just before the IMP administration and 1 hour after the IMP administration. It was calculated by the statistician. The STPI scores were assessed by the visual analogue scale (VAS), a 100 mm horizontal line with the left end named " not sore" ( 0 mm) and right end named " very sore" . The subject is instructed to put a perpendicular mark on the VAS according to the current level of sore throat. Thereafter, the investigator measures the distance from the left end to the perpendicular mark. The measurement at baseline is later subtracted from the 1-hour measurement by the study statistician and the result for primary endpoint obtained.
    End point type
    Primary
    End point timeframe
    The endpoint is based on a two STPI measurements when administered a single initial dose of the IMP: 1. baseline measurement at time 0 h 2. measurement at 1 h post IMP administation
    End point values
    		 Group A Group B Group C Per protocol set
    Number of subjects analysed
    57
    115
    116
    288
    Units: mm
        arithmetic mean (standard deviation)
    22.4 ± 21.36
    40 ± 26.15
    42.6 ± 26.77
    37.6 ± 26.57
    Attachments
    		 Box plot for primary endpoint
    Box plot for primary efficacy endpoint ( FAS)
    Table: primary endpoint (FAS)
    Table: Primary endpoint ( PP)
    Statistical analysis title
    		 Primary efficacy endpoint equivalence analysis PP
    Statistical analysis description
    Assessment of null and alternative hypothesys is based on a two-sided 95% confidence interval for the treatment difference. It was concluded that TIMP is equivalent to RIMP if the lower and upper bounds of the 95% confidence interval for the treatment difference lie entirely within (–δ, δ) interval. The equivalence margin for the STPID1h is 13 mm of VAS score.
    Comparison groups
    Group B v Group C
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.244 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.087
         upper limit
    		 8.161
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.603
    Notes
    [1] - Statistically, this study is based on equivalence design. The null hypothesis for the primary efficacy endpoint is inequivalence between TIMP and RIMP, and the alternative hypothesis is equivalence defined by pre-specified equivalence margin (δ). In order to achieve essay sensitivity, both active treatment should have been superior to placebo. The latter has been subject in the separate analysis.
    [2] - The P level was higher than standard threshold for alpha error of 0.05. This demonstrated lack of non-equivalence between the treatments. The equivalence was established by means of 95% CI.
    Statistical analysis title
    		 Primary endpoint superiority analysis RIMP PP
    Statistical analysis description
    The analysis of the superiority of two active treatments over placebo is carried out to establish assay sensitivity of the equivalence analysis. Assessment of null and alternative hypotheses is based on a two-sided 95% confidence interval for the treatment difference between placebo and both reference (RIMP) and test (TIMP) investigational medicinal product.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.766
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.458
         upper limit
    		 26.074
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.204
    Notes
    [3] - This is a superiority analysis to establish significant superiority of the RIMP against the placebo treatment. The null hypothesis for the primary efficacy endpoint is the lack of difference between placebo and active treatments. In case of its rejection, the alternative hypothesis is accepted of the RIMP superiority over placebo.
    [4] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between RIMP and placebo.
    Statistical analysis title
    		 Primary endpoint superiority analysis TIMP PP
    Statistical analysis description
    The analysis of the superiority of two active treatments over placebo is carried out to establish assay sensitivity of the equivalence analysis. Assessment of null and alternative hypotheses is based on a two-sided 95% confidence interval for the treatment difference between placebo and both reference (RIMP) and test (TIMP) investigational medicinal product.
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    22.803
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.496
         upper limit
    		 29.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.204
    Notes
    [5] - This is a superiority analysis to establish significant superiority of the TIMP against the placebo treatment. The null hypothesis for the primary efficacy endpoint is the lack of difference between placebo and active treatments. In case of its rejection, the alternative hypothesis is accepted of the TIMP superiority over placebo.
    [6] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between TIMP and placebo.

    Primary: Difference in sore throat pain intensity at 1 hour ITT

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    End point title
    		 Difference in sore throat pain intensity at 1 hour ITT
    End point description
    The endpoint is a difference in sore throat pain intensity ( STPI) between baseline just before the IMP administration and 1 hour after the IMP administration. It was calculated by the statistician. The STPI scores were assessed by the visual analogue scale (VAS), a 100 mm horizontal line with the left end named " not sore" ( 0 mm) and right end named " very sore" . The subject is instructed to put a perpendicular mark on the VAS according to the current level of sore throat. Thereafter, the investigator measures the distance from the left end to the perpendicular mark. The measurement at baseline is later subtracted from the 1-hour measurement by the study statistician and the result for primary endpoint obtained.
    End point type
    Primary
    End point timeframe
    The endpoint is based on a two STPI measurements when administered a single initial dose of the IMP: 1. baseline measurement at time 0 h 2. measurement at 1 h post IMP administration
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: mm
        arithmetic mean (standard deviation)
    22.4 ± 21.36
    39.7 ± 26.21
    42.6 ± 26.79
    37.5 ± 26.6
    Statistical analysis title
    		 Primary efficacy endpoint equivalence analysis ITT
    Statistical analysis description
    Assessment of null and alternative hypothesys is based on a two-sided 95% confidence interval for the treatment difference. It was concluded that TIMP is equivalent to RIMP if the lower and upper bounds of the 95% confidence interval for the treatment difference lie lie entirely within (–δ, δ) interval. The equivalence margin for the STPID1h is 13 mm of VAS score.
    Comparison groups
    Group C v Group B
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    P-value
    		 = 0.194 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.378
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.731
         upper limit
    		 8.487
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.595
    Notes
    [7] - Statistically, this study is based on equivalence design. The null hypothesis for the primary efficacy endpoint is inequivalence between TIMP and RIMP, and the alternative hypothesis is equivalence defined by pre-specified equivalence margin (δ). In order to achieve essay sensitivity, both active treatment should have been superior to placebo. The latter has been subject in the separate analysis.
    [8] - The P level was higher than standard threshold for alpha error of 0.05. This demonstrated lack of non-equivalence between the treatments. The equivalence was established by means of 95% CI.
    Statistical analysis title
    		 Primary endpoint superiority analysis TIMP ITT
    Statistical analysis description
    The analysis of the superiority of two active treatments over placebo is carried out to establish assay sensitivity of the equivalence analysis. Assessment of null and alternative hypotheses is based on a two-sided 95% confidence interval for the treatment difference between placebo and both reference (RIMP) and test (TIMP) investigational medicinal product.
    Comparison groups
    Group C v Group A
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    23.114
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.788
         upper limit
    		 29.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.213
    Notes
    [9] - This is a superiority analysis to establish significant superiority of the TIMP against the placebo treatment. The null hypothesis for the primary efficacy endpoint is the lack of difference between placebo and active treatments. In case of its rejection, the alternative hypothesis is accepted of the TIMP superiority over placebo.
    [10] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between RIMP and placebo.
    Statistical analysis title
    		 Primary endpoint superiority analysis RIMP ITT
    Statistical analysis description
    The analysis of the superiority of two active treatments over placebo is carried out to establish assay sensitivity of the equivalence analysis. Assessment of null and alternative hypotheses is based on a two-sided 95% confidence interval for the treatment difference between placebo and both reference (RIMP) and test (TIMP) investigational medicinal product.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.001 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.736
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.401
         upper limit
    		 26.071
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.218
    Notes
    [11] - This is a superiority analysis to establish significant superiority of the RIMP against the placebo treatment. The null hypothesis for the primary efficacy endpoint is the lack of difference between placebo and active treatments. In case of its rejection, the alternative hypothesis is accepted of the RIMP superiority over placebo.
    [12] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between RIMP and placebo.

    Secondary: Difference in sore throat pain intensity at 2 h

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    End point title
    		 Difference in sore throat pain intensity at 2 h
    End point description
    The endpoint is a difference in sore throat pain intensity ( STPI) between baseline just before the IMP administration and 2 hours after the IMP administration. It was calculated by the statistician. The STPI scores were assessed by the visual analogue scale (VAS), a 100 mm horizontal line with the left end named " not sore" (0 mm) and right end named " very sore" . The subject is instructed to put a perpendicular mark on the VAS according to the current level of sore throat. Thereafter, the investigator measures the distance from the left end to the perpendicular mark. The measurement at baseline is later subtracted from the result at 2 hours by the study statistician and the result for primary endpoint obtained.
    End point type
    Secondary
    End point timeframe
    The endpoint is based on a two STPI measurements when administered a single initial dose of the IMP: 1. baseline measurement at time 0 h 2. measurement at 2 h post IMP administation
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: mm
        arithmetic mean (standard error)
    14.07 ± 2.856
    28.03 ± 2.044
    34.63 ± 2.043
    29.19 ± 1.42
    Attachments
    		 Table: secondary endpoint (STPID 2h)
    Statistical analysis title
    		 Secondary endpoint STPID2h analysis TIMPvsRIMP
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The equivalence analysis has been applied to comparison between active treatments including also a superiority analysis of both active treatments against placebo. This analysis was not relevant for the equivalence demonstration.
    Comparison groups
    Group B v Group C
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [13]
    P-value
    		 = 0.014 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.596
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.323
         upper limit
    		 11.868
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.678
    Notes
    [13] - Statistically, the STPID2h is based on equivalence design including superiority of both active treatments over placebo and equivalence between the two active treatments. This analysis section reports the comparative analysis between test IMP and reference IMP.
    [14] - The p-value indicates statistically significant difference between TIMP and RIMP since the p value is lower than conventional 0.05. The difference is in favour of the test IMP effect.
    Statistical analysis title
    		 Secondary endpoint STPID2h analysis TIMPvsPlacebo
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis has been applied to provide a comparison between both active treatments against placebo. This analysis was not relevant for the equivalence demonstration.
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.001 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    20.556
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.028
         upper limit
    		 27.084
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.316
    Notes
    [15] - Statistically, this secondary efficacy endpoint analysis is based on superiority of both active treatments over placebo and equivalence between the two active treatments. This analysis section reports the comparative analysis between test IMP and placebo.
    [16] - The p-value indicates statistically significant difference between TIMP and placebo since the p value is lower than conventional 0.05. The difference is in favour of the test IMP effect.
    Statistical analysis title
    		 Secondary endpoint STPID2h analysis RIMPvsPlacebo
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis has been applied to provide a comparison between both active treatments against placebo. This analysis was not relevant for the equivalence demonstration.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.001 [18]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    13.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.422
         upper limit
    		 20.498
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.321
    Notes
    [17] - Statistically, this secondary efficacy endpoint analysis is based on superiority of both active treatments over placebo and equivalence between the two active treatments. This analysis section reports the comparative analysis between reference IMP and placebo.
    [18] - The p-value indicates statistically significant difference between RIMP and placebosince the p value is lower than conventional 0.05. The difference is in favour of the reference IMP effect.

    Secondary: Difference in sore throat pain intensity at 3 h

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    End point title
    		 Difference in sore throat pain intensity at 3 h
    End point description
    The endpoint is a difference in sore throat pain intensity ( STPI) between baseline just before the IMP administration and 1 hour after the IMP administration. It was calculated by the statistician. The STPI scores were assessed by the visual analogue scale (VAS), a 100 mm horizontal line with the left end named "not sore" (0 mm) and right end named " very sore" . The subject is instructed to put a perpendicular mark on the VAS according to the current level of sore throat. Thereafter, the investigator measures the distance from the left end to the perpendicular mark. The measurement at baseline is later subtracted from the 1-hour measurement by the study statistician and the result for primary endpoint obtained
    End point type
    Secondary
    End point timeframe
    The endpoint is based on a two STPI measurements when administered a single initial dose of the IMP: 1. baseline measurement at time 0 h 2. measurement at 3 h post IMP administration
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: mm
        arithmetic mean (standard error)
    13.03 ± 2.677
    20.96 ± 1.916
    28.8 ± 1.915
    21.64 ± 1.37
    Attachments
    		 Table: secondary endpoint ( STPID 3h)
    Statistical analysis title
    		 Secondary endpoint STPID3h analysis TIMPvsRIMP
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The equivalence analysis has been applied to comparison between active treatments including also a superiority analysis of both active treatments against placebo. This analysis was not relevant for the equivalence demonstration.
    Comparison groups
    Group C v Group B
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [19]
    P-value
    		 = 0.002 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.848
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.906
         upper limit
    		 12.791
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.511
    Notes
    [19] - Statistically, the STPID3h is based on equivalence design including superiority of both active treatments over placebo and equivalence assessment between the two active treatments. This analysis section reports the comparative analysis between test IMP and reference IMP.
    [20] - The p-value indicates statistically significant difference between TIMP and RIMP since the p value is lower than conventional 0.05. The difference is in favour of the test IMP effect.
    Statistical analysis title
    		 Secondary endpoint STPID3h analysis TIMPvsPlacebo
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis has been applied to provide a comparison between both active treatments against placebo. This analysis was not relevant for the equivalence demonstration.
    Comparison groups
    Group C v Group A
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.001 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.774
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.654
         upper limit
    		 21.893
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.109
    Notes
    [21] - Statistically, this secondary efficacy endpoint analysis is based on superiority of both active treatments over placebo and equivalence between the two active treatments. This analysis section reports the comparative analysis between test IMP and placebo.
    [22] - The p-value indicates statistically significant difference between TIMP and RIMP since the p value is lower than conventional 0.05. The difference is in favour of the test IMP effect.
    Statistical analysis title
    		 Secondary endpoint STPID3h analysis RIMPvs Placebo
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis has been applied to provide a comparison between both active treatments against placebo. This analysis was not relevant for the equivalence demonstration.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.011 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.925
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.797
         upper limit
    		 14.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.113
    Notes
    [23] - Statistically, this secondary efficacy endpoint analysis is based on superiority of both active treatments over placebo and equivalence between the two active treatments. This analysis section reports the comparative analysis between reference IMP and placebo.
    [24] - The p-value indicates statistically significant difference between TIMP and RIMP since the p value is lower than conventional 0.05. The difference is in favour of the test IMP effect.

    Secondary: Total pain relief over the time interval 15 -180 min after the IMP administration

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    End point title
    		 Total pain relief over the time interval 15 -180 min after the IMP administration
    End point description
    Total pain relief over the time interval 15 -180 min after the IMP administration (TOTPAR 15-180min) is the endpoint that assesses pain relief over the over the 15-min to 3-hour interval after the administration of IMP. TOTPAR 15-180min was computed for each subject as the area under the curve of the pain relief scores (measured by a 7-point pain relief scale), according to the trapezoidal rule.
    End point type
    Secondary
    End point timeframe
    Altogether 12 measurements were made in the intervals of 15 minutes from 15 min up to 180 min after the single dose of the tested drugs.
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: point
        arithmetic mean (standard error)
    263.465 ± 27.317
    437.338 ± 19.554
    473.984 ± 19.541
    434.897 ± 12.959
    Attachments
    		 Table: secondary endpoint ( TOTPAR)
    Statistical analysis title
    		 TOTPAR 15-180 min statistical analysis TIMPvsRIMP
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis has been applied to provide a comparison between both active IMP against placebo as well as to investigate the differences between the two active IMPs. It was analyzed based on ANCOVA model including clinical site and treatment as main effects, and baseline pain intensity score as a covariate.
    Comparison groups
    Group C v Group B
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.154 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    36.646
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.791
         upper limit
    		 87.084
    Variability estimate
    Standard error of the mean
    Dispersion value
    25.622
    Notes
    [25] - Statistically, this secondary efficacy endpoint analysis is based on superiority of both active treatments over placebo and absence of any significant difference between the two active IMPs. This analysis section reports the comparative analysis between both active IMPs.
    [26] - The P value is higher than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated lack of significant difference between RIMP and TIMP.
    Statistical analysis title
    		 TOTPAR 15-180 min statistical analysis TIMPvsPlac
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis has been applied to provide a comparison between both active IMP against placebo as well as to investigate the differences between the two active IMPs. It was analyzed based on ANCOVA model including clinical site and treatment as main effects, and baseline pain intensity score as a covariate.
    Comparison groups
    Group C v Group A
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.001 [28]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    210.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 148.068
         upper limit
    		 272.971
    Variability estimate
    Standard error of the mean
    Dispersion value
    31.725
    Notes
    [27] - Statistically, this secondary efficacy endpoint analysis is based on superiority of both active treatments over placebo and absence of any significant difference between the two active IMPs. This analysis section reports the comparative analysis between TIMP and placebo.
    [28] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between TIMP and placebo.
    Statistical analysis title
    		 TOTPAR 15-180 min statistical analysis RIMPvsPlac
    Statistical analysis description
    Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis has been applied to provide a comparison between both active IMP against placebo as well as to investigate the differences between the two active IMPs. It was analyzed based on ANCOVA model including clinical site and treatment as main effects, and baseline pain intensity score as a covariate.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.001 [30]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    173.873
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 111.329
         upper limit
    		 236.417
    Variability estimate
    Standard error of the mean
    Dispersion value
    31.772
    Notes
    [29] - Statistically, this secondary efficacy endpoint analysis is based on superiority of both active treatments over placebo and absence of any significant difference between the two active IMPs. This analysis section reports the comparative analysis between RIMP and placebo.
    [30] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between TIMP and placebo.

    Secondary: Percent of responders after the initial single IMP dose

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    End point title
    		 Percent of responders after the initial single IMP dose
    End point description
    % RESP is defined as the share of subjects who respond to the therapy with respect to the total number of subjects taking the same IMP. The responder criterion is related to minimal clinically significant change in sore throat pain intensity (STPI) at one, two and three hours after the IMP administration. This change is defined as the reduction of 13 mm or more of the STPI value at the Visual analogue scale.
    End point type
    Secondary
    End point timeframe
    The endpoint was assessed at the end of the three hour time interval after a single dose of the IMPs.
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: subjects
    16
    55
    70
    141
    Attachments
    		 Crosstabulation: secondary endpoint (% RESP)
    Statistical analysis title
    		 Secondary efficacy endpoint percent responders 1
    Statistical analysis description
    The endpoint was analyzed by means of the Chi-square and the pairwise Chi-square test with corresponding 95% confidence intervals.
    Comparison groups
    Group B v Group C
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.068 [32]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -11.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.6
         upper limit
    		 0.79
    Notes
    [31] - Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. This section includes the comparison between two active treatments. In the analysis results the TIMP value has been subtracted from the RIMP value.
    [32] - The P value for the difference between the two active treatment groups demonstrates lack of significant difference between the two groups.
    Statistical analysis title
    		 Secondary efficacy endpoint percent responders 2
    Statistical analysis description
    The endpoint was analyzed by means of the Chi-square and the pairwise Chi-square test with corresponding 95% confidence intervals.
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.001 [34]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -31.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.9
         upper limit
    		 -16.6
    Notes
    [33] - Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis of both active treatments against placebo was to be demonstrated and the comparison between the two active group investigated. The type of analysis corresponds to the statistical nature of the endpoint. This section includes comparison between Test IMP and placebo.
    [34] - The P value for the difference between Test IMP and placebo demonstrates superiority of the Test IMP over placebo.
    Statistical analysis title
    		 Secondary efficacy endpoint percent responders 3
    Statistical analysis description
    The endpoint was analyzed by means of the Chi-square and the pairwise Chi-square test with corresponding 95% confidence intervals.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.015 [36]
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -19.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.1
         upper limit
    		 -4.56
    Notes
    [35] - Assessment of null and alternative hypothesis is based on a two-sided 95% confidence interval for the treatment difference. The superiority analysis of both active treatments against placebo was to be demonstrated and the comparison between the two active group investigated. The type of analysis corresponds to the statistical nature of the endpoint. This section includes comparison between Reference IMP and placebo.
    [36] - The P value for the difference between Reference IMP and placebo demonstrates superiority of the Reference IMP over placebo.

    Secondary: Time to Sore Throat Pain relief (TSTPAR)

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    End point title
    		 Time to Sore Throat Pain relief (TSTPAR)
    End point description
    Time to Sore Throat Pain relief (TSTPAR) is defined as the time in minutes to a minimal sore throat pain relief (STPAR). The minimal STPAR is defined as a relief of at least 1 point on the STPAR scale. In order for the minimal STPAR to be confirmed it has to be followed by at least 3-point score at the each of the following two measurements.
    End point type
    Secondary
    End point timeframe
    Time to Sore Throat Pain relief (TSTPAR) Was assessed within the 3 hours after the single dose IMP administration.
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: minutes
        arithmetic mean (standard error)
    97.6 ± 10.2
    48.5 ± 5.4
    46 ± 5.2
    57.1 ± 3.8
    Statistical analysis title
    		 TSTPAR comparative analysis TIMPvs Placebo
    Statistical analysis description
    TSTPAR was analyzed using survival analysis method. The Kaplan-Meier method was used to derive the median time to sore throat pain relief (TSTPAR) with 95% confidence intervals for each treatment group. The log-rank test was used to determine the statistical significance of treatment group differences in the distribution of time to event. For subjects who has not experienced onset of pain relief within 3 hours after dosing, time to onset was right censored and set to 3 hours.
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 < 0.001 [38]
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [37] - The survival analysis seemed most appropriate method for the endpoint related to the time to the event. The analysis was used to investigate differences between the treatments in terms of the onset of the effect. This part of analysis presents a comparison between TIMP and placebo.
    [38] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between TIMP and placebo.
    Statistical analysis title
    		 TSTPAR comparative analysis RIMPvs Placebo
    Statistical analysis description
    TSTPAR was analyzed using survival analysis method. The Kaplan-Meier method was used to derive the median time to sore throat pain relief (TSTPAR) with 95% confidence intervals for each treatment group. The log-rank test was used to determine the statistical significance of treatment group differences in the distribution of time to event. For subjects who has not experienced onset of pain relief within 3 hours after dosing, time to onset was right censored and set to 3 hours.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 < 0.001 [40]
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Notes
    [39] - The survival analysis seemed most appropriate method for the endpoint related to the time to the event. The analysis was used to investigate differences between the treatments in terms of the onset of the effect. This part of analysis presents a comparicon between RIMP and placebo.
    [40] - The P value is lower than conventional 0.05 threshold for the statistical relevance of alpha error which demonstrated significant difference between RIMP and placebo.

    Other pre-specified: Percent subjects complete disease resolution (%RESOL)

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    End point title
    		 Percent subjects complete disease resolution (%RESOL)
    End point description
    Patients were defined as having conpletely resolved condition by fullfilling the following criteria: o The Tonsilopharyngitis Assessment (TPA) score of 1 or less o The score of 6 on the Sore Throat Pain Release (STPAR) scale o The score of 0 millimetres on the pain intensity visual analogue scale (VAS)
    End point type
    Other pre-specified
    End point timeframe
    The end point has been evaluated 4 days and 7 days after the therapy initiation. In this report, only 7-day data are presented.
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: Subjects
    57
    116
    118
    291
    Attachments
    		 Table: tertiary endpoint ( %RESOL)
    Statistical analysis title
    		 % RESOL comparative analysis part 1
    Statistical analysis description
    Pearson chi-square test has been used to carry out parwise comparisons between the treatment groups.
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 < 0.001 [42]
    Method
    		 Chi-squared
    Parameter type
    		 Percent count
    Point estimate
    -22.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.8
         upper limit
    		 -8.84
    Notes
    [41] - The analysis type fits the statistical profile of the endpoint including the normality of the distribution. In a nutshell, a superiority of both active IMPs over placebo was tested and also the absence of superiority of any of the active treatments over another was investigated. This part contains the results of comparison between placebo and Test IMP (TIMP).
    [42] - The p value has confirmed the superiority of TIMP over placebo.
    Statistical analysis title
    		 % RESOL comparative analysis part 2
    Statistical analysis description
    Pearson chi-square test has been used to carry out parwise comparisons between the treatment groups.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.037 [44]
    Method
    		 Chi-squared
    Parameter type
    		 Percent count
    Point estimate
    -14.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.53
         upper limit
    		 -0.2
    Notes
    [43] - The analysis type fits the statistical profile of the endpoint including the normality of the distribution. In a nutshell, a superiority of both active IMPs over placebo was tested and also the absence of superiority of any of the active treatments over another was investigated. This part contains the results of comparison between placebo and reference IMP.
    [44] - The p value has confirmed the superiority of reference IMP over placebo.
    Statistical analysis title
    		 % RESOL comparative analysis part 3
    Statistical analysis description
    Pearson chi-square test has been used to carry out parwise comparisons between the treatment groups.
    Comparison groups
    Group B v Group C
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.088 [46]
    Method
    		 Chi-squared
    Parameter type
    		 Percent count
    Point estimate
    -7.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.05
         upper limit
    		 1.15
    Notes
    [45] - The analysis type fits the statistical profile of the endpoint including the normality of the distribution. In a nutshell, a superiority of both active IMPs over placebo was tested and also the absence of superiority of any of the active treatments over another was investigated. This part contains the results of comparison between both active IMPs.
    [46] - The p value has confirmed the absence of a significant difference between the two active IMPs.

    Other pre-specified: Percent rescue medication users (%SRM)

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    End point title
    		 Percent rescue medication users (%SRM)
    End point description
    % SRM is defined as the share of subjects who had to take the rescue medication (paracetamol 500 mg up to 4 times daily) at least once during the treatment with respect to the total number of subjects having been taking the same IMP. %SRM have been assessed at Visit 2 and Visit 3. The patients were defined as rescue medication users if they have taken at least one dose of rescue medication during the 4-day or 7-day follow-up.
    End point type
    Other pre-specified
    End point timeframe
    The end point has been evaluated 4 days and 7 days after the therapy initiation.
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: subjects
    12
    25
    17
    54
    Attachments
    		 Table:tertiary endpoint (% SRM)
    Statistical analysis title
    		 % SRM comparative analysis
    Statistical analysis description
    Pearson chi-square test has been used to comparisons between the three treatment groups.
    Comparison groups
    Group A v Group B v Group C
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 0.322 [48]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [47] - The analysis type fits the statistical profile of the endpoint including the normality of the distribution. In a nutshell, the differences betrween the three groups were tested in a single statistical procedure.
    [48] - The p value has confirmed the lack of significant difference between the three groups

    Other pre-specified: Tonsilopharyngitis assessment score (TPAS)

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    End point title
    		 Tonsilopharyngitis assessment score (TPAS)
    End point description
    Tonsilopharyngitis assessment (TPA) is a method of the upper respiratory tract infection signs. It contains five categories, scored with the ratings from 0 to 2. The ratings are summed up to yield the TPAS. The range of TPAS is 0 - 10 points.
    End point type
    Other pre-specified
    End point timeframe
    The endpoint was assessed after 7-day and/or 4-day therapy. Subjects who have already finished the treatment after 4 days, were included into the end-therapy analysis with TPAS values obtained after 4 days. Here, only end therapy analysis is presented.
    End point values
    		 Group A Group B Group C Full analysis set
    Number of subjects analysed
    57
    116
    118
    291
    Units: points
        arithmetic mean (standard deviation)
    0.8 ± 1.33
    0.5 ± 0.96
    0.3 ± 0.63
    0.5 ± 0.95
    Attachments
    		 Figure: Tertiary endpoint , TPAS
    Statistical analysis title
    		 Tonsilopharingitis assessment score (TPAS) Part 1
    Statistical analysis description
    TPAS was analysed by the non-parametric one way ANOVA. In this part, comparison between TIMP and RIMP is reported
    Comparison groups
    Group B v Group C
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.013 [50]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [49] - The analysis has been chosen with regard to the statistical nature of the endpoint including the distribution type.
    [50] - The p - value is smaller as the conventional 0.05 indicating the significant difference between TIMP and RIMP.
    Statistical analysis title
    		 Tonsilopharingitis assessment score (TPAS) part 2
    Statistical analysis description
    TPAS was analysed by the non-parametric one way ANOVA. In this part, comparison between RIMP and placebo is reported.
    Comparison groups
    Group A v Group B
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.294 [52]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [51] - The analysis has been chosen with regard to the statistical nature of the endpoint including the distribution type.
    [52] - The p - value is greater as the conventional 0.05 indicating no significant difference between RIMP and placebo.
    Statistical analysis title
    		 Tonsilopharingitis assessment score (TPAS) part 3
    Statistical analysis description
    TPAS was analysed by the non-parametric one way ANOVA. In this part, comparison between TIMP and placebo is reported.
    Comparison groups
    Group A v Group C
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 0.003 [54]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [53] - The analysis has been chosen with regard to the statistical nature of the endpoint including the distribution type.
    [54] - The p - value is greater as the conventional 0.05 indicating no significant difference between RIMP and placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events ( AE) were recorded along entire trial i.e. after a single dose and later up to 7 days of therapy.
    Adverse event reporting additional description
    All AE were stratified into drug-related (adverse reactions- AR) and not related to IMP. Only AR were analysed thoroughly. Interview and physical inspection were used for safety assessment. AE were reported according to drug relatedness, severity, seriousness, time to onset, frequency, a requirement for the treatment, and expectedness.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Group A_placebo
    Reporting group description
    		 This group has been taking placebo along the entire follow-up period.

    Reporting group title
    Group C- TIMP
    Reporting group description
    		 This Group of patients has been taking reference IMP along the entire trial follow - up up to 7 days. They have taken at least one dose of the IMP.

    Reporting group title
    Group B - RIMP
    Reporting group description
    		 This Group of patients has been taking reference IMP along the entire trial follow - up up to 7 days. They have taken at least one dose of the IMP.

    Serious adverse events
    		 Group A_placebo Group C- TIMP Group B - RIMP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 118 (0.00%)
    0 / 116 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A_placebo Group C- TIMP Group B - RIMP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 118 (2.54%)
    5 / 116 (4.31%)
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 57 (0.00%)
    2 / 118 (1.69%)
    0 / 116 (0.00%)
         occurrences all number
    0
    2
    0
    Heartburn
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 118 (0.85%)
    0 / 116 (0.00%)
         occurrences all number
    0
    1
    0
    Meteorism
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 118 (0.00%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    0
    1
    Numbness of tongue
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    0
    1
    Parageusia
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    0
    1
    Stomach pain
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 118 (0.00%)
    1 / 116 (0.86%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Erythema facial
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 118 (0.00%)
    0 / 116 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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