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
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EudraCT number |
2013-002970-32 |
Trial protocol |
SI |
Global end of trial date |
27 Feb 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Aug 2016
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First version publication date |
11 Aug 2016
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Other versions |
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Summary report(s) |
KKL072012_ClinicalTrialResults_synopsis |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
KKL072012
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Krka d. d.
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Sponsor organisation address |
Šmarješka cesta 6, Novo mesto, Slovenia, 8501
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Public contact |
Info točka raziskave, KRKA, tovarna zdravil, d. d., Novo mesto, 00386 14751489, marko.boh@krka.biz
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Scientific contact |
Info točka raziskave, KRKA, tovarna zdravil, d. d., Novo mesto, 00386 14751489, marko.boh@krka.biz
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 May 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
27 Feb 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
27 Feb 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Slovenia: 1
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Country: Number of subjects enrolled |
Russian Federation: 290
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Worldwide total number of subjects |
291
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EEA total number of subjects |
1
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
290
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From 65 to 84 years |
1
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85 years and over |
0
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Recruitment
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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
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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
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Period 1 title |
SIngle dose assessment period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Lozenge
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Routes of administration |
Oropharyngeal use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Gola action
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Pharmaceutical forms |
Orodispersible tablet
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Routes of administration |
Oropharyngeal use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Septolete Total, Septabene
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Pharmaceutical forms |
Lozenge
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Routes of administration |
Oropharyngeal use
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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.
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Period 2
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Period 2 title |
Therapy follow-up
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Lozenge
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Routes of administration |
Oropharyngeal use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Gola action
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Pharmaceutical forms |
Orodispersible tablet
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Routes of administration |
Oropharyngeal use
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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.
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Arm title
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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
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Investigational medicinal product code |
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Other name |
Septolete Total, Septabene
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Pharmaceutical forms |
Lozenge
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Routes of administration |
Oropharyngeal use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Group A
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Reporting group description |
Subjects in this arm have been taking placebo during the entire trial duration. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group B
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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
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Reporting group description |
All the subjects in this arm were administered tested investigational medicinal product. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Full analysis set
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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.
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Subject analysis set title |
Per protocol set
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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.
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End points reporting groups
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Reporting group title |
Group A
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Reporting group description |
Subjects in this arm have been taking placebo during the entire trial duration. | ||
Reporting group title |
Group B
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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
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Reporting group description |
All the subjects in this arm were administered tested investigational medicinal product. | ||
Reporting group title |
Group A
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Reporting group description |
All the subjects in this arm have been taking placebo as in the period I. | ||
Reporting group title |
Group B
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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
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Reporting group description |
All the subjects in this arm were administered tested investigational medicinal product. | ||
Subject analysis set title |
Full analysis set
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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.
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Subject analysis set title |
Per protocol set
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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.
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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.
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End point type |
Primary
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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
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Attachments |
Box plot for primary endpoint Box plot for primary efficacy endpoint ( FAS) Table: primary endpoint (FAS) Table: Primary endpoint ( PP) |
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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.
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Comparison groups |
Group B v Group C
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Number of subjects included in analysis |
231
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [1] | ||||||||||||||||||||
P-value |
= 0.244 [2] | ||||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||||
Point estimate |
3.037
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Confidence interval |
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level |
95% | ||||||||||||||||||||
sides |
2-sided
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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. |
|
|||||||||||||||||||||
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
|
||||||||||||||||||||
|
|||||||||||||||||||||
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. |
|
|||||||||||||||||||||
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
|
||||||||||||||||||||
|
|||||||||||||||||||||
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. |
|
|||||||||||||||||||||
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
|
||||||||||||||||||||
|
|||||||||||||||||||||
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. |
|
|||||||||||||||||||||
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.
|
||||||||||||||||||||
|
|||||||||||||||||||||
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. |
|
||||||||||||||||
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.
|
|||||||||||||||
|
||||||||||||||||
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. |
|
|||||||||||||||||||||
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.
|
||||||||||||||||||||
|
|||||||||||||||||||||
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. |
|
||||||||||||||||
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.
|
|||||||||||||||
|
||||||||||||||||
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. |
|
||||||||||||||||
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.
|
|||||||||||||||
|
||||||||||||||||
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 |
|
|||||||||||||||||||||
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.
|
||||||||||||||||||||
|
|||||||||||||||||||||
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 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
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Reporting group title |
Group A_placebo
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Reporting group description |
This group has been taking placebo along the entire follow-up period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group C- TIMP
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |