Clinical trial NCT03095521
Conditions: Sore Throat
Keywords: Angal ANTI-ANGIN® FORMULA sore throat no less therapeutic efficacy
Sponsor: Sandoz
Start date: 2017-02-22; Completion date: 2017-05-07
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate no less therapeutic efficacy and safety of the Angal, lozenges \[Menthol\], 1 mg + 5 mg (Sandoz dd, Slovenia) compared to ANTI-ANGIN® FORMULA, lozenges, 0,2 mg + 2 mg + 50 mg (LLC "Valeant", Russia) in treatment of patients with uncomplicated acute infectious and inflammatory diseases of the pharynx, accompanied by a sore throat.

Detailed description:

Arms: arm 1: Angal, lozenges, per 1 lozenge, with an interval 2 hours or more, 6-10 lozenges per day, for a maximum 4 days or until full illness resolution, if this will happen earlier than 4th day of treatment. arm 2: ANTIANGIN ® FORMULA, 1 lozenge, with an interval 2 hours or more, up to 6 lozenges per day, for a maximum 5 days or until full illness resolution, if this will happen earlier than 5th day of treatment.
Interventions: intervention 1: Angal, lozenges [menthol], intervention 2: ANTI-ANGIN® FORMULA
Intervention descriptions: intervention 1: Angal, administered per 1 lozenge, with an interval 2 hours or more, 6-10 lozenges per day, for a maximum 4 days or until full illness resolution. intervention 2: 0,2 mg + 2 mg + 50 mg (LLC "Valeant", Russia). Administered per 1 lozenge, with an interval 2 hours or more, up to 6 lozenges per day, for a maximum 5 days or until full illness resolution.

Protocol documents:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
Trial title: A Prospective, Multicenter, Open, Randomized, Parallel Clinical Trial for Comparative 
Assessment of Efficacy and Safety of Angal, Lozenges [Menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia), and 
ANTI-ANGIN® FORMULA, Lozenges, 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia) in Treatment 
of Patients with Uncomplicated Acute Infectious and Inflammatory Diseases of the Pharynx Accompanied 
by a Sore Throat 
Protocol No. TE_004_ANG_LOZ  / NCT03095521
Protocol version: 1.0 of September 28, 2016 
Study drug: Angal 
International non-proprietary name: Lidocaine + Chlorhexidine 
Dosage form and strength: lozenges, 1 mg + 5 mg 
Trial phase: III 
Trial Sponsor: ZAO Sandoz, Russia 
Address: 72 Leningradsky Prospekt, bld. 3, 125315 Moscow, Russia 
CONFIDENTIAL 
This document contains the trade secrets and commercially sensitive information which is inviolable, 
confidential, and may not be disclosed unless required by law. In any case, the parties the information was 
disclosed to must be informed on the fact that the information is inviolable, confidential, and may not be 
disclosed further. Those restrictions to disclosure shall be equally applied to all the information provided to 
you further and classified as inviolable or confidential. 


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Protocol No. ТЕ 004 ANG LOZ 
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Confidential 
SPONSOR'S SIGNATURES 
PROTOCOL APPROVAL: 
Protocol title: A Prospective, Multicenter, Open, Randomized, Parallel Clinical Trial for Comparative 
Assessment of Efficacy and Safety of Angal, Lozenges [Menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia), and 
ANTI-ANGIN® FORMULA, Lozenges, 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia) in Treatment of 
Patients with Uncomplicated Acute Infectious and Inflammatory Diseases of the Pharynx Accompanied by a 
Sore Throat 
Protocol No.: TE_004_ANG_LOZ 
Protocol version: 1.0 of September 28, 2016 
Sponsor’s representative: 
ZAO Sandoz, Russia 
Address: 72 Leningradsky Prospekt, bld. 3, 125315 Moscow, Russia 
 
(Full name of the authorized person) 
 
(Position) 
 
 
/Signature/ 
 
Signature 
Date 
Contract research organization (CRO) responsible for trial conduct 
 
 
 
 


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Confidential 
Principal Investigator's Signature 
Hereby I promise to: 
- 
Take over the responsibility for the proper conduct of the trial at this trial site; 
- 
Conduct the trial in accordance with this protocol, any further amendments thereto, or all other 
documents describing the trial conduct, which may be provided by ZAO Sandoz; 
- 
Introduce no amendments to the trial protocol without the Sponsor's consent and written approval of 
those amendments by the Ethics Council, except for the cases when such a delay may inflict harm to the 
patients' health, or administrative amendments (in accordance with all regulatory requirements); 
- 
I am fully aware of the instructions for use of the study drugs described in this protocol and all other 
information provided by the Sponsor, including current version of the Investigator's Brochure; 
- 
I am familiar with the Good Clinical Practice rules (ICH GCP) and undertake to comply with them 
and all the applicable regulatory requirements; 
All the individuals assisting me during the trial are adequately informed on Angal, lozenges [menthol], 
1 mg + 5 mg (Sandoz d.d., Slovenia), the study drug, and their responsibilities during the trial as described in 
this protocol. 
Principal Investigator: 
Full name and position of the Principal 
Investigator 
Site title 
Address, phone 
Signature: ___________ 
 
 
Date: ___________ ____, 201_ 
 
 
 


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List of abbreviations 
 
BP 
Blood Pressure 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC  
Anatomical Therapeutic Chemical (Classification System) 
B.V.  
Vennootschap met beperkte aansparkelijkheid, Limited Liability Company 
ST  
Sore Throat 
VAS  
Visual Analogue Scale 
ULN  
Upper Limit of Normal 
HIV  
Human Immunodeficiency Virus 
WMA  
World Medical Association 
IUS  
Intrauterine System 
IUD  
Intrauterine Device 
VNOK  
Cardiology Society of the Russian Federation 
WHO  
World Health Organization 
GmbH  
Gesellschaft mit beschränkter Haftung, Limited Liability Company 
GOST 
The Russian State Standard 
d.d. 
delniska druzba, Public Limited Liability Company 
DBP  
Diastolic Blood Pressure 
CI  
Confidence Interval 
EU 
European Union 
PI 
Prescribing Information 
Full name 
First Name, Patronymic, Last Name 
eCRF 
Electronic Case Record Form 
CRO  
Contract Research Organization 
MoH  
Ministry of Health 
NI  
Minimum Efficiency 
AR  
Adverse Reaction 
IEC  
Independent Ethics Committee 
AE  
Adverse Event 
ООО 
Limited Liability Company 
PVC  
Polyvinyl Chloride 
PTFCE 
Polychlorotrifluoroethylene 
RMOAG 
The Russian Medical Society on Arterial Hypertension  
MA  
Marketing Authorization 
RF  
Russian Federation 
SBP  
Systolic Blood Pressure 
SAR  
Serious Adverse Reaction 
SAE  
Serious Adverse Event 
SOP  
Standard Operational Procedure 
ESR 
Erythrocyte Sedimentation Rate 
FZ 
Federal Law 
Full name 
First Name, Patronymic, Last Name 


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BU  
Bread Unit 
BR 
Breathing Rate 
HR 
Heart Rate 
ECG  
Electrocardiography, electrocardiogram 
CTM 
Clinical Trial Manager 
CYP 
Cytochrome P450 
EHRM 
European Health Risk Monitoring 
GCP 
Good Clinical Practice 
ICH 
International Conference for Harmonization 
ITT 
Intention-To-Treat 
LD50 
Lethal Dose 50% 
LPPV 
Local Person for Pharmacovigilance 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NYHA 
New York Heart Association 
PP 
Per-Protocol 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSS 
Tonsillopharyngitis Severity Score 


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Table of Contents 
 
1. 
Protocol synopsis..................................................................................................................................... 9 
2. 
Justification of trial and a drug clinical trials program ......................................................................... 24 
2.1 
Names and description of study products ........................................................................................ 25 
2.1.1 
Study drug ........................................................................................................................... 25 
2.1.2 
Reference drug .................................................................................................................... 34 
2.2 
Summary of preclinical and clinical results significant for this trial ............................................... 38 
2.2.1 
Preclinical results summary ................................................................................................ 38 
2.2.1.1 
Chlorhexidine (chlorhexidine dihydrochloride) ........................................................ 38 
2.2.1.2 
Lidocaine (lidocaine hydrochloride) ......................................................................... 38 
2.2.2 
Clinical results summary ..................................................................................................... 39 
2.3 
Brief description of known and potential risks for the trial subjects (if any) ................................... 40 
2.4 
Description and rationale for the route of administration, dosages, dosing regimens, and duration of 
treatment ........................................................................................................................................... 40 
2.5 
Legal basis ........................................................................................................................................ 41 
2.6 
Description of the trial population ................................................................................................... 41 
2.7 
References ........................................................................................................................................ 41 
3 
Trial objectives and goals ...................................................................................................................... 43 
3.1 
Trial objective .................................................................................................................................. 43 
3.2 
Trial goals ........................................................................................................................................ 43 
4 
Trial design ............................................................................................................................................ 44 
4.1 
General and additional tested parameters......................................................................................... 44 
4.1.1 
Efficacy parameters ............................................................................................................. 44 
4.1.1.1. The main efficacy endpoint....................................................................................... 44 
4.1.1.2 
Additional efficacy endpoints ................................................................................... 44 
4.1.2. 
Safety parameters ................................................................................................................ 44 
4.2 
Description of the trial design .......................................................................................................... 45 
4.2.1 
Trial type ............................................................................................................................. 45 
4.2.2 
Trial design flowchart ......................................................................................................... 46 
4.2.3 
Trial procedures................................................................................................................... 47 
4.2.3.1 
Trial procedures in a table form ................................................................................ 47 
4.2.3.2 
Description of the trial procedures ............................................................................ 49 
4.2.3.2.1 
Collection of medical history, demographic and anthropometric data ... 49 
4.2.3.2.2 
Physical examination and vital signs evaluation ..................................... 50 
4.2.3.2.3 
Fill-in of TSS questionnaire .................................................................... 51 
4.2.3.2.4 
Evaluation of the throat pain intensity according to VAS ...................... 52 
4.2.3.2.5. 
Global evaluation of therapy tolerability by the patient and the physician
 ................................................................................................................ 52 
4.2.3.2.6 
Laboratory tests ....................................................................................... 52 
4.2.3.2.7 
Electrocardiography ................................................................................ 52 
4.2.4 
Trial stages .......................................................................................................................... 53 
4.2.4.1 
Screening/randomization/therapy initiation (Visit 1) ................................................ 53 
4.2.4.2 
Efficacy evaluation visit (Visit 2, Day 4) ................................................................. 53 


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4.2.4.3 
Trial completion visit for Group B patients (Visit 3, Day 5) .................................... 54 
4.2.4.4 
A follow-up visit (Visit 4) ......................................................................................... 55 
4.2.4.5 
Unscheduled visits .................................................................................................... 55 
4.2.4.6 
Visit of premature discontinuation of the trial .......................................................... 55 
4.3 
Subjectivity minimization/elimination measures ............................................................................. 56 
4.3.1 
Randomization .................................................................................................................... 56 
4.3.2 
Blinding methods ................................................................................................................ 56 
4.4 
Description of the drugs used in the trial ......................................................................................... 56 
4.4.1 
Dosage form ........................................................................................................................ 56 
4.4.2 
Packaging ............................................................................................................................ 56 
4.4.3 
Labeling of the study drugs ................................................................................................. 56 
4.4.4 
Strength and dosage regimen of the study drugs ................................................................. 57 
4.5 
Expected duration of the subjects' participation in the trial ............................................................. 57 
4.6 
Description of rules for termination of the trial parts or the trial as a whole ................................... 58 
4.7 
Record keeping procedures for trial products .................................................................................. 58 
4.8 
Storing and unblinding of randomization codes .............................................................................. 58 
4.9 
A list of all the data to be recorded in eCRF .................................................................................... 59 
5 
Selection and exclusion of the subjects ................................................................................................. 60 
5.1 
Inclusion criteria .............................................................................................................................. 60 
5.2 
Non-inclusion criteria....................................................................................................................... 60 
5.3 
Exclusion criteria ............................................................................................................................. 62 
5.3.1 
Terms and conditions for the subjects' exclusion from the trial .......................................... 62 
5.3.1.1 
Terms and volume of data on the excluded subjects ................................................. 63 
5.3.2 
Terms and conditions of suspend or discontinuation of the trial therapy ............................ 63 
5.3.3 
Replacement of the excluded subjects................................................................................. 63 
5.4 
 Acceptable contraception methods ................................................................................................. 63 
6 
Trial therapy .......................................................................................................................................... 65 
6.1 
Therapy regimens ............................................................................................................................. 65 
6.2 
Allowed and prohibited therapy ....................................................................................................... 65 
6.2.1 
Allowed prior and concomitant therapy .............................................................................. 65 
6.2.2 
Prohibited prior and concomitant therapy ........................................................................... 65 
6.3 
Methods to monitor the subjects' compliance with trial procedures ................................................ 65 
7 
Efficacy evaluation ................................................................................................................................ 67 
7.1 
List of efficacy parameters ............................................................................................................... 67 
7.2 
Methods and timing for evaluation, recording, and analysis of efficacy parameters ....................... 67 
8 
Safety evaluation ................................................................................................................................... 68 
8.1 
List of safety parameters .................................................................................................................. 68 
8.2 
Methods and timing for evaluation, recording, and analysis of safety parameters .......................... 68 
8.3 
Requirements for reporting, registration, and reporting of AEs and intercurrent diseases .............. 68 
8.3.1 
Definitions of adverse events and serious adverse events ................................................... 68 
8.3.2 
Intensity of AE .................................................................................................................... 69 
8.3.3 
Causality with the study drug .............................................................................................. 69 
8.3.4 
Documentation on adverse events ....................................................................................... 70 
8.3.5 
Reports on SAEs ................................................................................................................. 72 


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8.4 
Pregnancy cases ............................................................................................................................... 74 
8.5 
Quality complaints ........................................................................................................................... 74 
8.6 
Special cases .................................................................................................................................... 75 
8.7 
Information verification ................................................................................................................... 75 
9 
Statistics ................................................................................................................................................ 76 
9.1 
Description of the statistical methods to be used including the terms for every planned interim 
analysis ............................................................................................................................................. 76 
9.1.1 
Demographic and other baseline data (group comparability for the analysis) .................... 76 
9.1.2. 
Analysis of the primary efficacy endpoint .......................................................................... 76 
9.1.3 
Analysis of the secondary efficacy endpoints ..................................................................... 77 
9.1.4 
Safety parameters analysis .................................................................................................. 78 
9.2 
Planned number of subjects ............................................................................................................. 79 
9.3 
Applicable significance level ........................................................................................................... 82 
9.4 
Trial termination criteria ..................................................................................................... 82 
9.5 
Accounting for missed, unanalyzable, and questionable data ............................................. 82 
9.6 
Procedures for reporting any deviations from the original statistical plan .......................... 83 
9.7 
Selection of subjects for analysis ........................................................................................ 83 
9.8. 
Interim analysis ................................................................................................................... 84 
10 
Direct access to primary data/documents .............................................................................................. 85 
11 
Quality control and assurance ............................................................................................................... 86 
11.1 
Trial monitoring and quality control ................................................................................................ 86 
11.2 
Amendments to the protocol ............................................................................................................ 87 
11.3 
Protocol deviations ........................................................................................................................... 87 
12 
Ethics ..................................................................................................................................................... 89 
12.1 
General provisions ........................................................................................................................... 89 
12.2 
The informed consent receipt procedure .......................................................................................... 89 
12.3 
Confidentiality and identification of the trial subjects ..................................................................... 90 
12.4 
Enrollment of subjects from the vulnerable and special populations ............................................... 90 
13 
Data processing and record keeping ...................................................................................................... 91 
14 
Finance and insurance ........................................................................................................................... 93 
14.1 
Trial financing .................................................................................................................................. 93 
14.2 
Trial subjects insurance .................................................................................................................... 93 
15 
Publications ........................................................................................................................................... 94 
15.1 
General provisions ........................................................................................................................... 94 
15.2 
Publication and use of the trial results ............................................................................................. 94 
16 
Appendices ............................................................................................................................................ 95 
16.1 
Appendix 1. Quality complaints ...................................................................................................... 95 
16.2 
Appendix 2. TSS (Tonsillopharyngitis Severity Score) questionnaire ............................................ 96 
16.3 
Appendix 3. The patient's diary ....................................................................................................... 97 
16.4 
Appendix 4. A visual analogue scale for sore throat evaluation .................................................... 104 


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1. 
Protocol synopsis 
Trial title 
A Prospective, Multicenter, Open, Randomized, Parallel Clinical Trial for 
Comparative Assessment of Efficacy and Safety of Angal, Lozenges [Menthol], 
1 mg + 5 mg (Sandoz d.d., Slovenia), and ANTI-ANGIN® FORMULA, Lozenges, 
0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia) in Treatment of Patients with 
Uncomplicated Acute Infectious and Inflammatory Diseases of the Pharynx 
Accompanied by a Sore Throat 
Trial code 
TE_004_ANG_LOZ 
Sponsor 
ZAO Sandoz 
Study drug 
Angal, lozenges [menthol], containing 1 mg of lidocaine 
hydrochloride and 5 mg of chlorhexidine dihydrochloride 
 
 
Reference drug 
ANTI-ANGIN® 
FORMULA, 
lozenges, 
containing 
0.2 mg 
of 
tetracaine 
hydrochloride, 2 mg of chlorhexidine diacetate, and 50 mg of ascorbic acid 
 
 
Clinical trial phase 
III 
Trial population 
Up to 280 patients are planned to be included (randomized) into the trial (140 patients 
in every treatment arm) with probable withdrawal of not more than 10% patients 
during the trial. A minimal number of patients required for the statistical analysis is 
256 (128 patients in every treatment arm) provided that they completed the trial 
according to the protocol. 
Scheduled trial duration 
Not more than 7 days: 
Screening/randomization/initiation of trial therapy: Day 1. 
Therapy duration: up to 5 days depending on the trial arm. 
A follow-up visit (on the phone): 2 days after the last scheduled visit to the trial site. 
Total enrollment duration: 8 months. 
The number of trial sites 
up to 20 


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Trial objective 
 
This trial has been designed to evaluate the non-inferior therapeutic efficacy and 
safety of the study drug Angal, lozenges [menthol] 1 mg + 5 mg (Sandoz d.d., 
Slovenia), comparing to ANTI-ANGIN® FORMULA, lozenges, 0.2 mg + 2 mg + 
50 mg (OOO Valeant, Russia), in treatment of patients with uncomplicated acute 
infectious and inflammatory diseases of the pharynx accompanied by a sore throat. 
Trial goals 
Primary goal: 
• 
Evaluation of non-inferiority of the therapeutic efficacy of Angal, lozenges 
[menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia)—administration of 1 lozenge 
with a not less than 2-hour interval, up to 6–10 times per day, for 4 days or 
until full recovery (whichever occurs first during 4 days of therapy), compared 
to ANTI-ANGIN® FORMULA, lozenges 0.2 mg + 2 mg + 50 mg 
(OOO Valeant, Russia)—administration of 1 lozenge with a not less than 2-
hour interval, up to 6 lozenges per day, for 5 days or until full recovery 
(whichever occurs first during 5 days of therapy) in the treatment of patients 
with uncomplicated acute infectious and inflammatory diseases of the pharynx 
accompanied by a sore throat. 
Secondary goals: 
• 
Evaluation of safety of Angal, lozenges [menthol], 1 mg + 5 mg (Sandoz d.d., 
Slovenia)—administration of 1 lozenge with a not less than 2-hour interval, up 
to 6–10 times per day, for 4 days or until full recovery (whichever occurs first 
during 4 days of therapy), compared to  ANTI-ANGIN® FORMULA, lozenges 
0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia)—administration of 1 lozenge 
with a not less than 2-hour interval, up to 6 lozenges per day, for 5 days or until 
full recovery (whichever occurs first during 5 days of therapy) in the treatment 
of patients with uncomplicated acute infectious and inflammatory diseases of 
the pharynx accompanied by a sore throat. 
• 
Evaluation of adverse events (AEs) in the trial arms. 
• 
The AEs rate comparison between the trial arms. 


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Trial methodology 
Trial design 
A prospective, multicenter, open-label, randomized, parallel group clinical trial. 
 
Trial periods: 
I. Screening + Randomization + Therapy initiation: 
Visit 1 (Day 1) 
 
II. Therapy with Angal (up to 4 days) or ANTI-ANGIN® FORMULA (up to 5 days): 
Visit 2 (Day 4) for the both trial groups 
Visit 3 (Day 5) for Group B patients 
 
III. Follow-up: 
Visit 4 (Day 6/7) phone contact 
 
Visit 1 (Day 1): 
The patient's participation in the trial starts since signing of the Informed Consent 
Form. 
The following test results are used to decide on the patient's inclusion into the trial: 
• 
Demographic data (date of birth, sex, age); 
• 
Measurement of weight and height; 
• 
Anamnesis gathering; 
• 
Records on the concomitant therapy; 
• 
Evaluation of inclusion/non-inclusion criteria; 
• 
Evaluation of the throat pain intensity according to VAS; 
• 
Fill-in of TSS questionnaire by the Investigator; 
• 
Physical examination (including oropharynx); 
• 
Measurement of the main vital signs; 
• 
Hematology; 
• 
Biochemistry; 
• 
Urine pregnancy test; 
• 
12-lead ECG; 
• 
Evaluation of inclusion/non-inclusion criteria; 
• 
Randomization; 
• 
Dispensing of the study drugs; 
• 
Provision with the patient's diaries and training on the fill-in rules; 
• 
Initiation of therapy with the study drugs; 


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• 
Evaluation of adverse events (including based on results of the throat and 
pharynx examination). 
After the screening tests completion, on the same day, the patients who meet all the 
inclusion criteria will be randomized into one of the two trial groups (arms): Angal or 
ANTI-ANGIN® FORMULA. Therapy group will be assigned by randomization (in 1:1 
ratio). The patients will be given the relevant study drugs and the patient's diaries. 
The first use of the drug corresponding to the assigned therapy group on Day 1 after 
randomization will be considered to be the treatment initiation (for the both groups). 
The patients will be instructed on how to fill in the patient's diaries. 
 
Group A, therapy with Angal: 
1 lozenge with a not less than 2-hour interval, up to 6–10 times per day, for 4 days or 
until full recovery (whichever occurs first during 4 days of therapy). A single dose of 
Angal is 1 lozenge. The lozenges are intended for full dissolution in the oral cavity. 
One lozenge is slowly disintegrating in the mouth. 
Group B, therapy with ANTI-ANGIN® FORMULA 
1 lozenge with a not less than 2-hour interval, up to 6 lozenges per day, for 5 days or 
until full recovery (whichever occurs first during 5 days of therapy). One dose of 
ANTI-ANGIN® FORMULA is 1 lozenge. The lozenges are intended for full 
dissolution in the oral cavity. One lozenge is slowly disintegrating in the mouth. 
Visits during therapy with Angal or ANTI-ANGIN® FORMULA 
During Days 2 and 3 of the therapy, the patients (in the both groups) do not visit the 
trial site. 
In case of worsening, including signs of the secondary bacterial infection, the patients 
must inform the Investigator who may decide on early discontinuation of the study 
drug. In this case, an unscheduled visit to the trial site is required. 


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Visit 2 (Day 4): 
Visit 2 is conducted on Day 4; the patient must visit the trial site in the fasted state and 
bring the filled-in diary and unused drug. 
If Group B patients (ANTI-ANGIN® FORMULA) did not meet recovery criteria (total 
TSS ≤ 2) at Visit 2 (Day 4), they will require continuation of the therapy, and some 
procedures for those patients will be transferred for the next day (Visit 3, Day 5), see 
below. The patients will keep their diaries and the unused drugs. 
Visit 2 procedures for the both groups: 
• 
Collection of complaints, actualization of anamnesis; 
• 
Records on the concomitant therapy; 
• 
Physical examination (including oropharynx); 
• 
Measurement of the main vital signs; 
• 
Evaluation of adverse events (including based on results of the throat and 
pharynx examination); 
• 
Evaluation of exclusion criteria; 
• 
Compliance evaluation (diary completion, administration of the study drugs). 
Visit 2 procedures for Group A patients (Angal) and Group B (ANTI-ANGIN® 
FORMULA) who achieved recovery criteria (total TSS ≤ 2): 
• 
Hematology; 
• 
Biochemistry; 
• 
12-lead ECG; 
• 
Global evaluation of treatment tolerability during the trial by the physician 
and the patient; 
• 
Return of the unused study drug; 
• 
Return of the patient's diary; 
Visit 3 (Day 5): 
Evaluation of the disease outcome based on TSS questionnaire for the Group B 
patients who continued therapy after Visit 2 (Day 4). 
• 
Collection of complaints, actualization of anamnesis; 
• 
Records on the concomitant therapy; 
• 
Physical examination (including oropharynx); 
• 
Measurement of the main vital signs; 


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• 
Evaluation of adverse events (including based on results of the throat and
pharynx examination); 
• 
Evaluation of exclusion criteria; 
• 
Return of the unused study drug; 
• 
Return of the patient's diary; 
• 
Compliance evaluation (diary completion, administration of the study drugs). 
• 
Hematology; 
• 
Biochemistry; 
• 
12-lead ECG; 
• 
Global evaluation of treatment tolerability during the trial by the physician
and the patient. 
Group B patients should complete the therapy on Day 5 (unless it had happened
earlier). In case of worsening or preservation of the disease signs by the last therapy
day, further treatment will be given in accordance with the current medical care
standards established in this health care facility. 
Visit 4 (Day 6/7) (follow-up): 2 days after the last scheduled visit to the trial site. This
visit means a phone contact with the patient. Aim of this contact is to gather safety
information (AEs). 
Unscheduled visits 
The unscheduled visits will be conducted when necessary, e.g., in case of the index
disease deterioration, AEs, or the study drug (Angal or ANTI-ANGIN® FORMULA)
intolerability. Every unscheduled visit, irrespective of its cause, must include the
procedures listed below with completion of the relevant eCRF pages (Unscheduled
Visit): 
• 
Physical examination (including topical examination); 
• 
TSS evaluation; 
• 
Measurement of the main vital signs (blood pressure, heart rate, breathing
rate, body temperature); 
• 
12-lead ECG (if it has not been done for the last 12 hours); 


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• 
Evaluation of adverse events; 
• 
Evaluation of the concomitant therapy; 
• 
In case of indications/conditions, any of the trial procedures may be 
additionally performed upon the decision of the Principal Investigator. 
All procedures for the scheduled visits are identical for the both arms at every trial 
stage, except for the Group B patients who, if the recovery criteria (total TSS ≤ 2) are 
not met at Visit 2 (Day 4), should continue the trial therapy and visit the trial site for 
scheduled Visit 3 Day 5). 
The main efficacy and safety 
evaluation parameters 
Primary outcome measure 
The primary outcome measure was the percentage of patients without sore throat 
after 3 days of therapy on Day 4, as evaluated by the Investigator according to the 
Tonsillopharyngitis Severity Score (TSS), in both Angal and ANTI-ANGIN® 
FORMULA arms. 
Secondary outcome measures 
The secondary outcome measures in the both therapy groups were: 
• 
The frequency of ≥50% total score reduction according to the TSS 
questionnaire completed by the Investigator as compared to the baseline in 
both Angal and ANTI-ANGIN® FORMULA groups at Visit 2 (Day 4). 
• 
Total score reduction according to the TSS questionnaire, as well as reduction 
in the symptoms (sore throat, difficulty in swallowing, salivation, erythema, 
and fever) after a 3-day therapy, at Visit 2 (Day 4), as compared to the 
baseline total score. 
• 
A period of time required for disease symptoms relief, determined according 
to the patient's diary (subjective patient's evaluation), but no more than 5 days 
during the trial—for patients who have achieved the corresponding outcome. 
• 
A proportion (%) of patients who fully recovered by Day 4 in Group A and by 
Day 5 in Group B (the outcome of a disease according to the objective 
evaluation by the Investigator, the total score according to the TSS 
questionnaire ≤ 2). 


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• 
Change in the sore throat intensity by 100 mm VAS (visual analogue scale 
filled in by the patient) at the beginning, after 3 days of the therapy, and at 
the end of the therapy in both groups. 
TSS questionnaire 
TSS, a questionnaire (point scale) for healthcare professionals, is used in clinical 
practice as well as clinical trials to evaluate dynamic changes of symptoms severity of 
the infection-inflammatory process in the throat (Bereznoy VV, Riley DS, Wassmer G, 
Heger M. Efficacy of extract of Pelargonium sidoides in children with acute non-group 
A beta-hemolytic streptococcus tonsillopharyngitis: a randomized, double-blind, 
placebo-controlled trial). One of such clinical trials with TSS questionnaire was 
conducted in 2005 in Germany, CRO Applertee AG. A version of TSS ©CRO 
Applertee AG was adapted for this protocol. 
TSS (Tonsillopharyngitis Severity Score) is a questionnaire for evaluation of the 
following symptoms severity: pharyngalgia, difficulty in swallowing, salivation, 
hyperemia of pharyngeal mucosa, and body temperature increase according to a 4-
point scale: 
0 = no symptom; 
1 = insignificant symptom; 
2 = moderate symptom; 
3 = significant symptom. 
The axillary body temperature increase is rated as follows: 
0 points: <37.5 °С; 
1 point: 37.5 to <38.5 °С; 
2 points: 38.5 to <39.5 °С; 
3 points: > 39.5°С. 
TSS is filled in by the Investigator based on the patient complaints and physical 
examination data. The Investigator summarizes the points obtained for every symptom 
to obtain a total sum of TSS points. A total sum of TSS points will be used at screening 


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 to evaluate for a subject's eligibility and baseline evaluation; at Visit 2 (Day 4), to 
measure efficacy of the trial therapy in the both groups; to evaluate the disease 
outcomes on Visit 2 (Day 4) and/or Visit 3 (Day 5), where applicable. 
Safety evaluation criteria: 
The following parameters will be taken into account for the safety evaluation: 
• 
AEs and/or SAEs rates per trial arms; 
• 
Global tolerance evaluation during the trial by the Investigator and patient; 
• 
Vital signs (heart rate, blood pressure, body temperature, breathing rate); 
• 
ECG parameters; 
• 
Laboratory results. 
The AEs will be described according to the scheme given below: 
• 
ae description; 
• 
ae severity; 
• 
ae duration; 
• 
Relation to the study drug; 
• 
Outcome. 
All AEs will be coded according to MedDRA terms. 
Inclusion criteria 
The patients who meet all the inclusion criteria listed below will be included in the 
trial: 
1. 
The Informed Consent Form voluntarily signed by the patient. 
2. 
Men and women at the age of 18 to 45 years old, inclusively. 
3. 
Diagnosis of acute, uncomplicated, inflammatory and infectious condition 
of the pharynx associated with the inflammation and pain in the throat. 
4. 
Manifestation of the first signs of acute, uncomplicated, inflammatory and 
infectious condition of the throat (pharyngitis and/or tonsillitis) not more 
than 48 hours before the inclusion. 


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5 
A baseline total sum of TSS (Tonsillopharyngitis Severity Score) points ≥5. 
6 
Body temperature measured in the axillary cavity is less than 37.5 °С. 
7 
Women with childbearing potential should demonstrate a negative pregnancy 
test result at screening (except for the women after surgical sterilization or 
menopause for more than 2 years) and use the established contraception 
methods for at least 3 months before the initiation of the trial therapy and 1 
month after completion of the trial. 
8 
Men should use adequate contraception during the trial, since signing of the 
Informed Consent Form and till the trial completion, and for 30 days after the 
trial completion. 
9 
Ability to understand the presented information on the clinical trial, readiness 
to comply with the protocol, ability to use the study drugs by oneself and 
evaluate the symptoms according to VAS (visual analogue scale) or other 
questionnaires according to the protocol. 
Non-inclusion criteria 
The patients who comply with at least one of the criteria listed below will not be 
included: 
1. 
Prior tonsillectomy, tonsillotomy. 
2. 
Chronic conditions of the nasopharynx or oropharynx, ulcerative oral 
disorders. 
3. 
A history of hypersensitivity or allergic reactions to any components of the 
study drugs or local anesthetics. 
4. 
Use of analgesics during less than 12 hours before the trial start and/or 
impossibility to discontinue the analgesics for the trial period. 
5. 
Use of antibiotics during less than 48 hours before the trial start and/or 
planned use of antibiotics during the trial. 
6. 
Use of topical drugs (aerosols, gargle solutions, fast-disintegrating 
tablets/lozenges/pastilles) in the pharynx during less than 12 hours before the 
trial start and/or impossibility to discontinue 


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those topical drugs, except for the study drugs, for the trial period. 
7. 
Use of the systemic, inhalation, or nasal glucocorticosteroids during 30 days
before the trial start and/or planned use of the glucocorticosteroids (except
for the topical skin drugs) during the trial. 
8. 
Impossibility to discontinue other drugs which might influence the trial
results, e.g. antiviral or prohibited concomitant drugs (see Prohibited
concomitant therapy section), for the trial period. 
9. 
Signs of a primary bacterial pharyngitis or secondary bacterial infection
(including body temperature increase above 37.5 °C, purulent pharyngeal
pellicles, significant intoxication, leukocytosis, neutrocytosis, WBC
differential's shift to the left (increase in stab neutrophils, presence of
younger neutrophils), ESR more than 30 mm/h). 
10. 
Granular pharyngitis. 
11. 
 Signs of rhinitis, sinusitis, otitis, eustachitis, laryngitis, tracheitis, bronchitis
(such conditions require therapy which might influence the trial results). 
12. 
Phenylketonuria. 
13. 
Deficit of saccharase or isomaltase (according to anamnesis data). 
14. 
Glucose-galactose malabsorption (according to anamnesis data). 
15. 
Fructose intolerance. 
16. 
Diabetes mellitus. 
17. 
Glucose-6-phosphate dehydrogenase deficiency (according to anamnesis
data). 
18. 
Hemochromatosis. 
19. 
Anemia (Hb less than 120 g/l according to hematology test). 
20. 
Hyperoxaluria. 
21. 
Urolithiasis. 
22. 
Myasthenia. 
23. 
 Severe, uncontrolled, cardiovascular condition which, in the Investigator's
opinion, preclude the patient from participation in the trial, namely: 
 a.  
Severe (IV acc. to Canadian Cardiovascular Society) or unstable
angina; 


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b. 
Decompensated chronic heart failure (NYHA stage IV); 
c. 
Myocardial infarction for the last 6 months; 
d 
uncontrolled arterial hypertension (BP more than 180/115 mm 
Hg). 
24. Pregnant and/or breastfeeding women. 
25. Participation in other clinical trials at the screening visit or for 30 days 
before the screening visit. 
26. Surgical intervention for 30 days before the screening visit or planned 
surgical treatment during the trial (sooner than a follow-up visit is 
completed), including diagnostic procedures or hospital stay. 
27. Known or suspected narcotic/alcohol abuse. 
28. A suspected low compliance or incapability of the patient to perform the 
procedures and comply with restrictions according to the trial protocol 
(e.g., due to mental disorders). 
29. Any cardiovascular, renal, hepatic, gastrointestinal, endocrine, or nervous 
disorders, or any other conditions/diseases which, in the Investigator's 
opinion, might inflict harm to the patient's health. 
Exclusion criteria 
The patient may withdraw or be excluded from the trial based on the grounds listed 
below: 
1. 
Negative course of the disease with signs of the secondary bacterial 
infection (including body temperature increase above 37.5 °C). 
2. 
The Ethics Committee, regulatory authorities, or Sponsor terminate the 
trial or participation of the specific trial site for any reason. 
3. 
The Investigator's decision to withdraw the patient from the trial in the 
interests of the patient. 
4. 
Withdrawal of the informed consent (unwillingness of the patient to 
continue his/her participation in the trial). 
5. 
Serious deviation from the trial protocol. 
6. 
Individual intolerance of the study drugs. 
7. 
Clinically significant adverse event or serious adverse event. 
8. 
Patient's non-compliance. 


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9. 
False inclusion (e.g., the patient was included in breach of the inclusion/non-
inclusion criteria). 
10. The patient complies with the non-inclusion criteria during the trial. 
11. The patient receives or requires an additional therapy which might influence 
the trial results or patient's safety (see Prohibited concomitant therapy 
section). 
12. Other conditions or events which, in the Investigator's opinion, require the 
patient's exclusion from the trial. 
Prohibited concomitant 
therapy 
The drugs listed below are prohibited for use throughout the trial period: 
1. 
Topical drugs (aerosols, sprays, inhalations, gargle solutions, fast-
disintegrating tablets/lozenges/pastilles) in the pharynx or nose. 
2. 
Systemic, inhalation, or nasal glucocorticosteroids. 
3. 
Systemic or topical (intranasal or pharyngeal) antibacterial drugs. 
4. 
Anti-viral drugs. 
5. 
Immunomodulatory agents. 
6. 
Painkillers or antipyretic agents. 
7. 
Class I antiarrhythmics. 
8. 
Cholinesterase inhibitors (including neostigmine, distigmine, pyridostigmine) 
and other drugs for myasthenia. 
Statistical 
analysis 
A statistical objective of the trial will be a prove of 
a non-inferior therapeutic efficacy and safety of the study drug Angal comparing to the 
drug ANTI-ANGIN® FORMULA in the treatment of acute infectious and inflammatory 
diseases of the pharynx accompanied by a sore throat. The primary outcome 
measure:  no pain in the throat after 3 days of therapy, i.e., on Day 4. 
Justification of a non-inferiority margin and a sample size is based on the results of a 
placebo-controlled 
trial 
of 
lozenges 
with 
chlorhexidine 
and 
lidocaine 
[
 Kris De Ceulaer. A summary of a clinical trial proves that 
chlorhexidine/lidocaine lozenges are effective and safe. 11-8-2015]. 
This trial has demonstrated absence of a sore throat (a TSS subscale) 3 days after the 
therapy initiation, on Day 4, in 62.5% patients  


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in the trial arm and 36.9% patients in the placebo arm (see the Table below). 
 
Baseline visit 
D4 
N 
Product 
N=106 
Placebo 
N=103 
Product 
N=106 
Placebo 
N=103 
Sore throat 
 
 
 
 
Unknown 
0 
0 
2 (N=104) 
0 
Absent 
0 (0%) 
0 (0%) 
65 (62.5%) 
38 (36.9%) 
Mild 
3 (2.8%) 
3 (2.9%) 
27 (26.0%) 
45 (43.7%) 
Moderate 
77 (72.6%) 
75 (72.8%) 
11 (10.6%) 
19 (18.4%) 
Severe 
26 (24.5%) 
25 (24.3%) 
1 (1.0%) 
1 (1.0%) 
р 
1.0000 
0.0016 
Therefore, the lower limit of CI 95% for difference in a sore throat rate 3 days after the 
drug use, with account for 140 participants (2 outcomes in the study drug group are 
unknown) and 103 patients, may be calculated as follows: 
 
NCSS 8.0 Two Proportions Report 
Dataset  
Untitled 
Zero Adjustment Method: None 
Note: Exact tests and c.i.'s were not run because total count > 50 
(specified under 'Reports' tab). 
 
Table Section 
 
 
 
 
N1 
N2 
M1 
M2 
N 
A 
B 
C 
D 
(A+C) 
(B+D) 
(A+B) 
(C+D) (N1+N2) 
65 
39 
38 
65 
103 
104 
104 
103 
207 
Confidence Intervals of Difference (P1-P2) 
Interval 
Estimated 
Confidence 
Confidence 
Method 
Value 
Limit 
Limit 
Chi-Square 
0.2561 
0.1456 
0.3666 
(Pearson) 
 
 
 
(The calculation results are presented in the language of the original source) 
In view of the considered nosology and absence of significant factors requiring a 
conservative approach for determination of the non-inferiority margin, for this purpose 
we can use a two-sided CI 90%. In such a case, the lower limit for the rate difference 
(a two-sided CI 95%) will amount to 14.6%. Therefore, a margin of 14.5% is 
considered to be justified. 
Based on the above, we may hypothetically expect a rate of positive response to a new  


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therapy (absence of a sore throat as an efficacy measure) at least 63%. A statistical 
hypothesis tested: 
H0: p1-p2 ≤ –14.5% compared to H1: p1-p2 > –14.5% 
If a null hypothesis is rejected, a conclusion will be made that efficacy of the study 
drug is not less than that of the comparator drug. 
A sample size is evaluated based on the following assumptions: 
- 
A rate of positive response to therapy (absence of a sore throat as an efficacy 
measure) in a comparator drug arm is 63%. 
- 
A rate of positive response to therapy (absence of a sore throat as an efficacy 
measure) in a study drug arm is 65% (chosen within the tested hypothesis and 
based on the sample size and expected positive response). 
- 
Power = 80% 
- 
A non-inferiority margin: 14.5 
- 
Significance level: 97.5% 
- 
Randomization in 1:1 ratio (study drug : comparator drug). 
A number of patients required at 80% power and 2.5% one-sided significance level to 
prove the hypothesis of the study drug efficacy not more than 14.5% inferior to that of 
the comparator drug (determined by absence of a sore throat after 3 days of therapy) is 
128 patients in every arm. 
Interim analysis 
An interim analysis may be conducted after receipt of efficacy data for Angal and 
ANTI-ANGIN® FORMULA, spray, after 3 days of therapy, on Day 4, for 100 patients 
in every arm. The interim analysis includes demographic data, data on the anamnesis 
and concomitant therapy, available data on efficacy and safety of Angal and ANTI-
ANGIN® FORMULA drugs. 
Blinding, randomization 
This trial will be open, without blinding. The patients will be included by 
randomization in 1:1 ratio using envelopes at the trial site. 


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2. 
Justification of trial and a drug clinical trials program 
Trial rationale 
A sore throat (pain in the throat) is one of the most common complaints addressed to the therapists and general 
practitioners. Viral or bacterial infections are the most probable causes of sore throat. Oropharyngeal mycoses cause 
sore throat more rarely. Pharyngitis is commonly associated with hyperemia of the back pharyngeal wall, 
palatopharyngeal arches, and tonsils. Approximately 70% of pharyngitis cases are caused by viruses. The most relevant 
and significant viruses are rhinoviruses, adenovirus, influenza, and parainfluenza viruses, coronaviruses, and a 
respiratory syncytial virus. Viral pharyngitis is not accompanied by pellicles but associated with other catarrhal 
symptoms, in addition to sore throat, such as sneezing and nasal stuffiness (1). In addition to the smooth diet, in 
accordance with the current clinical recommendations ("General Medical Practice" National Guidelines, 2013, and 
National Guidelines for the Otorhinolaryngology, 2008), the therapy of an acute, viral, uncomplicated pharyngitis is 
based on topical symptomatic drugs to arrest the throat pain: gargling with sage or chamomile infusion, synthetic 
antiseptics (myramistin, octenisept, chlorhexidine), fast-disintegrating tablets or pastilles containing a combination of 
antiseptic and anesthetic (Anti-Angin Formula, Hexalyse, Strepsils). In view of a high rate of acute pharyngitis (5 to 8 
times per year according to the WHO), a range of drugs arresting the main signs of the disease and accelerating the 
patient's return to his/her usual daily activities always needs to be developed (2; 3; 4). 
Angal (a combination of lidocaine and chlorhexidine), lozenges, 1 mg of lidocaine hydrochloride + 5 mg of 
chlorhexidine dihydrochloride (a composition for 1 lozenge), is planned to be registered in the Russian Federation. 
Angal is used for topical application by dissolution in the mouth to treat the signs of oral and pharyngeal inflammation 
and infections, such as uncomplicated pharyngitis and other conditions. Angal has been already registered in the 
European Union and Kazakhstan, but there is no similar drug in the Russian Federation. Current 
chlorhexidine/lidocaine combinations are registered in Russia in larger strengths and for other indications. Therefore, 
Angal may not be deemed as a generic drug. 
Due to absence of an identical drug by composition for the purposes of a registration clinical trial, a comparative 
clinical trial of Angal with a similar drug (topical anesthetic + topical antibiotic) registered in Russia will be conducted. 
Among the commercially available drugs in Russia, the most suitable drug is ANTI-ANGIN® FORMULA, a 
combination drug containing chlorhexidine and tetracaine. ANTI-ANGIN® 


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FORMULA also contains ascorbic acid, the 3rd component, but its activity is not associated with the planned efficacy 
endpoint. 
This trial design is based on the results of previous clinical III phase trial of the chlorhexidine/lidocaine combination: 
Clinical Trial for Assessment of Safety and Efficacy of a Echinacea/Sage Spray Compared to a 
Chlorhexidine/Lidocaine Spray in the Treatment of Acute Sore Throats (clinicaltrials.gov NCT00707902), as well as 
placebo-controlled trial of pastilles with chlorhexidine and lidocaine [
 Kris De Ceulaer. A summary 
of a clinical trial proves that chlorhexidine/lidocaine lozenges are effective and safe. 11-8-2015]. 
 
Drug clinical trials program 
According to a clinical development program of Angal, lozenges [menthol, strawberry, honey, lemon], 1 mg + 5 mg, 
Sandoz is planning to conduct a clinical trial in the Russian Federation: Prospective, Multicenter, Open, Randomized, 
Parallel, Clinical Trial for Comparative Assessment of Efficacy and Safety of Angal, Lozenges [Menthol], 1 mg + 5 mg 
(Sandoz d.d., Slovenia), and ANTI-ANGIN® FORMULA, Lozenges, 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia) in 
Treatment of Patients with Uncomplicated Acute Infectious and Inflammatory Diseases of the Pharynx Accompanied by 
a Sore Throat. 
According to Federal Law On Circulation of Medicines No. 61-FZ of April 12, 2010 (as amended), a clinical trial with 
participation of Russia is required to register a drug in the Russian Federation. Therefore, the objective of this clinical 
trial is to establish at least non-inferior efficacy and safety of Angal, lozenges [menthol], the study drug, compared to 
ANTI-ANGIN® FORMULA, lozenges, registered in Russia, in treatment of adults with acute, uncomplicated, 
infectious and inflammatory diseases of the pharynx accompanied by a sore throat. 
Based on the results of this clinical trial of Angal, lozenges [menthol], Sandoz is planning for the state registration of 
Angal, lozenges [menthol, strawberry, honey, lemon], 1 mg + 5 mg, within the same registration dossier. The full 
composition of the lozenges for every flavor is presented in the Investigator's Brochure. 
 
2.1 
Names and description of study products 
2.1.1 
Study drug 
Angal, lozenges [menthol], 1 mg + 5 mg. 
Qualitative and quantitative composition 
One lozenge contains chlorhexidini dihydrochloridum 5 mg and lidocaini hydrochloridum 1 mg. 


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Excipients: levomenthol 5 mg, anhydrous citric acid 5.5 mg, magnesium stearate 25 mg, sorbitol 
1,208.5 mg. 
Dosage form 
Lozenge. White to off-white, round, slightly mottled lozenge. 
Pharmacotherapeutic group: drugs for throat diseases treatment, antiseptics. 
ATC code: R02AA05 
Pharmacodynamics 
Lidocaine hydrochloride is an amide local peripheral anesthetic. It has a surface analgesic effect, and does 
not prevent nerve conduction at the administration site. 
As a local anesthetic, lidocaine has the same mechanism of action as other drugs from this group; it blocks 
the generation and conduction of nerve impulses in sensory, motor, and vegetative nerves. It primarily 
affects the cell membranes where it blocks the ion channels and thereby reduces the permeability for the 
sodium ions. Due to the progressive propagation of the anesthetic effect in the nerve, the electric stimulation 
threshold is increased, impulse conduction is slowed down, and the propagation of the action potential is 
contracted. Finally, conductivity is interrupted completely. Local anesthetics generally block autonomous 
nerve fibers, small non-myelinated (sensation of pain) fibers and small myelinated (sensation of pain and 
temperature) fibers more quickly than large myelinated fibers (sensation of touch and pressure). 
On the molecular level lidocaine specifically blocks sodium ion channels in a non-active state and thus 
prevents generation of the action potential. This mechanism prevents the conduction of stimuli when 
lidocaine is used locally in the vicinity of nerves. 
The effect on peripheral nerves is especially important if lidocaine is used as a local anesthetic. The efficacy-
toxicity ratio is favorable. It very rarely causes allergic reactions. Chlorhexidine is a bisbiguanide cationic 
antiseptic. It is effective against gram-positive (e.g. Micrococcus sp., Staphylococcus sp., Streptococcus sp., 
Bacillus sp., Clostridium sp., Corynebacterium sp.) and, to a lesser extent, against gram-negative bacteria, 
especially in the vegetative form (it is not effective against spores at normal temperature). It also has an 
antimycotic effect on dermatophytes and fungi. It quickly inactivates the infectiousness of certain lipophilic 
viruses (influenza virus, herpes virus, HIV). 
The drug exerts bacteriostatic effects in low levels and bactericidal effects in high levels. 
The chlorhexidine molecule has a strong positive charge, and therefore adsorbs to the negatively charged 
areas on the cell surface. 


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The adsorption is specific and takes place in special parts of the bacterial cell wall. This damages the 
bacterial cell membrane's integrity, increasing its permeability. 
Chlorhexidine binds to the cytoplasmatic bacterial membrane. It is also adsorbed onto the negatively charged 
surfaces of the teeth, plaque, or the oral mucosa, thereby persisting in the oral cavity for a long time after the 
drug use. 
Pharmacokinetics 
Chlorhexidine 
Absorption 
In oral or topical application, absorption of chlorhexidine is insignificant. In topical application on intact 
skin, chlorhexidine is adsorbed on the outside layers of the skin, providing long-term antimicrobial effect. 
Pharmacokinetic research has shown that after rinsing the oral cavity, approximately 30% of the total used 
amount of chlorhexidine is retained, which is then slowly released into the saliva. Approximately 4% of 
chlorhexidine is swallowed by the patient. 
Distribution 
The binding of chlorhexidine to the plasma proteins after oral use is not extensive. 
Metabolism and elimination 
Chlorhexidine is not accumulated in the body. The extent of its metabolism is insignificant. 10% of the 
absorbed active substance is excreted in the urine and 90% in the feces. 
Lidocaine 
Absorption 
Lidocaine absorption varies depending on the site and the method of administration. It is rapidly absorbed 
from the gastrointestinal tract, mucous membranes and through broken skin; however, before entering the 
systemic circulation it is mostly decomposed. The absorption from mucous membranes after topical 
application depends on the circulation and the total dose. After 30 minutes, less than 17% of the dose taken is 
present in the stomach and the intestines in the unchanged form, while less than 1.5% is present in other 
tissues. 


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The anesthetic action of lidocaine after topical administration emerges after two to five minutes and lasts for 
30 to 45 minutes. The anesthetic effect is limited to the surface and does not extend to the submucosal 
structures. 
Distribution 
Lidocaine is well distributed into tissues (kidney, lung, liver, heart, adipose tissue). 
Lidocaine crosses the blood-brain barrier and placenta and is excreted in human milk. 
Metabolism and elimination 
It is metabolized during the first pass through the liver. Lidocaine undergoes dealkylation in the liver. The 
first two metabolites are pharmacologically active. These two active metabolites exert toxic effects on the 
central nervous system in some patients. 
Lidocaine is eliminated in the form of metabolites through the kidneys. Approximately 10% is eliminated 
unchanged. The biological half-life of lidocaine is 1.5 to 2 hours in adults. The biological elimination half-
life of lidocaine metabolites is 2 to 10 hours. The biological half-life is increased in congestive heart failure, 
liver diseases, and myocardial infarction. 
Pharmacological properties 
Angal, lozenges, contains 2 active substances. 
The first is chlorhexidine, a bisbiguanide antiseptic, with an antimicrobial effect on gram-positive and gram-
negative bacteria, especially in the vegetative form (it is not effective against spores at normal temperature). 
It exerts an antimycotic effect on dermatophytes and fungi. It quickly inactivates the infectiousness of certain 
lipophilic viruses (influenza virus, herpes virus, HIV). The susceptibility of individual bacterial strains 
varies. The drug exerts bacteriostatic effects in low levels and bactericidal effects in high levels. 
The second active substance of Angal, lozenges, is lidocaine, an amide local anesthetic. It exerts 
local anesthetic effect. 
Therapeutic indications 
Angal, lozenges, have a dual effect (antimicrobial and anesthetic), and are therefore used locally for: 


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− 
Treatment of infections of the oral mucosa (stomatitis, gingivitis) and the throat; 
− 
Pain relief in inflammation of the oral mucosa; 
− 
Relief of symptoms of an inflamed throat (painful swallowing, irritation). 
 
Dosage and method of administration 
Angal lozenges are intended for topical application in the oral cavity and the throat. 
One should dissolve the lozenges in the mouth slowly, one lozenge at a time; the active substances are 
released slowly and gradually with a topical effect. 
Adults: per os, 6 to 10 lozenges per day, till full dissolution in the mouth. The maximum single dose for 
adults is 5 mg of chlorhexidine dihydrochloride and 1 mg of lidocaine hydrochloride. 
The maximum daily dose is 50 mg of chlorhexidine and 10 mg of lidocaine. 
Duration of treatment 
Angal should not be used continuously for more than three to four days or too often. If during this time 
period the symptoms worsen or the patient has bacterial infection accompanied by elevated body 
temperature, this infection needs to be additionally treated. 
Patients with diabetes mellitus 
Angal, lozenges, contain sorbitol and can be used by diabetic patients. 
Contraindications 
• 
Hypersensitivity to the active substances (chlorhexidine or lidocaine), amide-type local anesthetics or 
to any of the excipients. 
• 
Children under 5 years of age. 
• 
Children with a history of muscle spasms (including fever-induced spasms), as Angal contains 
levomenthol. 
Special warnings and special precautions for use 
Bacterial infections with fever must be treated separately. In such cases, Angal pastilles can be used 
additionally for alleviating throat pain. 
Caution must be used when administering the drug to patients with congestive heart failure or hepatic failure 
and 
in 
concomitant 
use 
of 
lidocaine 
analogues 
(class 
I 
antiarrhythmic 
drugs), 


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as adverse effects of lidocaine may be amplified. 
Angal pastilles should be used with caution in patients with a tendency towards hypersensitivity reactions. 
For self-treatment, Angal pastilles should not be used continuously for more than three to four days or too 
often. The drug should only be used until the inflammation-related throat pain or irritation persists. 
The drug should not be used in patients with rare hereditary fructose intolerance. 
Interaction with other drugs and other forms of interaction 
Lidocaine is a known inhibitor of the CYP1A2 liver enzyme, and to a lesser extent the 2D6 and 3A4 
enzymes. However, when used as recommended, the interactions with these enzymes are clinically 
insignificant. 
The patients must not use Angal pastilles concomitantly with cholinesterase inhibitors (e.g., neostigmine, 
distigmine, pyridostigmine) and other drugs used to treat miasthenia. 
The patients must not use Angal pastilles concomitantly with other topical antiseptics. This does not apply to 
Angal spray, which contains chlorhexidine and lidocaine, just like the pastilles. Single dose of the spray may 
be replaced with a single dose of lozenges. When combining the spray and the pastilles, the patient must not 
exceed the maximum daily dose. A combined use of Angal spray and lozenges in children is contraindicated. 
Chlorhexidine is incompatible with anionic surfactants (e.g., sodium lauryl sulphate) and certain other 
substances (e.g., alginates, tragacanth) which are often present in tooth paste. Therefore, at least 30 minutes 
should elapse between using tooth paste and Angal pastilles. 
Use during pregnancy and breastfeeding 
Pregnancy 
The changes in pharmacokinetics and/or pharmacodynamics of lidocaine during pregnancy may cause toxic 
effects. There are no controlled trials to date using chlorhexidine in pregnant women. 
 
Breastfeeding 


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Lidocaine metabolites are excreted into the mother’s milk; however, no adverse effects in infants were 
recorded. It is not known if chlorhexidine is distributed into breast milk. 
Nevertheless, Angal should not be used in pregnant women and breast-feeding mothers, unless the benefits 
for the mother outweigh the risks for the child. 
Fertility 
No data is available on the effects of chlorhexidine and lidocaine on fertility in humans. 
 
Effects on the ability to drive or operate machines 
 
Trials of drug effects on the ability to drive and use machines have not been conducted. 
 
Adverse events 
In short-term topical application in the mouth and throat at recommended doses, the drug was tolerated well. 
Classification of undesirable effect by organ systems according to MedDRA classification and frequency by 
organ systems: 
• 
Very common (≥1/10); 
• 
Common (≥1/100 to <1/10); 
• 
Uncommon (≥1/1,000 to <1/100); 
• 
Rare (≥1/10,000 to <1/1,000); 
• 
Very rare (<1/10,000); 
• 
Not known (cannot be estimated from the available data). 
Blood and the lymphatic system disorders 
Not known: methemoglobinemia. 
Immune system disorders 
Common: allergic skin reactions. 
Rare: severe allergic reactions including anaphylactic shock. 
Not known: delayed hypersensitivity reactions (contact allergy, photosensitisation) or other local reactions 
on the skin or teeth. 
Psychiatric disorders 
Not known: anxiety, agitation, euphoria. 
Nervous system disorders 


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Not known: sleepiness, dizziness, poor orientation, confusion (also including speech), vertigo, shivering, 
dizziness, psychosis, nervousness, paresthesia, numbness, convulsions, loss of consciousness, coma. 
Eye disorders 
Not known: visual disturbances, including blurred or double vision. 
Ear and labyrinth disorders 
Not known: tinnitus. 
Respiratory, thoracic, and mediastinal disorders 
Not known: dyspnea, respiratory distress syndrome, respiratory depression, respiratory arrest. 
Gastrointestinal disorders 
Common: nausea, vomiting, abdominal pain. 
Not known: difficulty swallowing, mouth sores. 
Skin and subcutaneous tissue disorders 
Rare: contact dermatitis. 
Not known: lichenoid reaction. 
Musculoskeletal and connective tissue disorders 
 
Not known: twitching or tremor of the muscles. 
General disorders and administration site conditions 
Not known: asthenia, transient taste disturbance or burning sensation on the tongue, sensation of cold or hot. 
Long-term continuous use of chlorhexidine in the oral cavity may result in a transient brown discoloration of 
the teeth. The discoloration can be removed. When the drug was limited to the throat area, there were no 
reports on discoloration of the teeth. 
Overdose 
Although the drug contains only a small fraction of toxic doses of both active ingredients and is used locally 
in the mouth, it can be inadvertently or accidentally overdosed. This can occur especially in children. 
Chlorhexidine is only absorbed in minimum amounts from the digestive tract. Lidocaine is absorbed more 
quickly, and its bioavailability is 35%. Toxic effects of lidocaine occur at plasma concentrations higher than 
6 mg/l. 
When excessive doses are used (more than 20 pastilles daily), there may be difficulty with swallowing 
(decreased control of the swallowing reflex). 
Systemic intoxication is the consequence of the effect on the central nervous system and the vascular system. 
The first effects of overdose are disorders of the central nervous system. 


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Symptoms which can occur during systemic intoxication include: disturbances of the central nervous system: 
headache, hallucinations, vertigo, drowsiness, agitation, tinnitus, paresthesia, dysarthria, hearing disorders, 
perioral numbness, metabolic acidosis, nystagmus, muscular tremor, psychoses, convulsions, respiratory 
arrest, epileptic coma, reduced consciousness; cardiovascular disorders: acute cardiovascular insufficiency, 
severe bradycardia, heart rhythm disorders (sinus arrest, tachyarrhythmias), cardiac arrest. 
In addition to the signs already mentioned, individual cases of chlorhexidine overdose are known. The 
symptoms listed below were observed: edema of the throat, necrotic injuries of the esophagus, increased 
serum aminotransferase concentrations (thirty times larger than the normal values), vomiting, stomach and 
duodenum erosion including active atrophic gastritis, euphoria, blurred vision and a total loss of taste (lasting 
for 8 hours). 
Considering the data on acute, subacute, and chronic toxicity of both active ingredients, the risk of systemic 
effects of lidocaine, when used correctly is very small and predominantly associated with major misuse of 
Prescribing Information, as the doses of both active ingredients in the pastilles are very small. 
Measures to be taken in case of systemic intoxication 
If signs of intoxication appear, the drug must be discontinued immediately. Induce vomiting and perform 
gastric lavage. Use anionic agents. In severe cases, the patient must be hospitalized to prevent the collapse of 
breathing and circulation, as well as to prevent dehydration. Diazepam is the drug of choice for alleviating 
convulsions. 
Preclinical safety data 
Published non-clinical data suggests that chlorhexidine and lidocaine are well tolerated and show low 
toxicity. 
Chlorhexidine 
Chlorhexidine is virtually not absorbed when administered topically. In the urine of laboratory animals, only 
insignificant amounts of chlorhexidine were detected. The LD50 of chlorhexidine varies between species and 
ranges from 21 mg/kg (rats, intravenous) to 5,000 mg/kg (rats, oral). Sub-chronic toxicity trials showed 
minimal skin irritation (erythema, edema, peeling and/or cracking) in the smallest tested doses. No 
reproductive or developmental toxicity was shown at all the tested levels. No mutagenic effects were 
observed in in vivo mutagenesis trials evaluating chlorhexidine gluconate. 
Long-term toxicity trials in rats showed no carcinogenic effects of chlorhexidine. 


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Lidocaine 
LD50 of lidocaine varies between species and ranges from 19.5 mg/kg (mice, intravenous) to 317 mg/kg 
(rats, oral). 
Lidocaine is neurotoxic due to its direct effect on sensory neurons and its induction of increased intracellular 
calcium ion concentration. Lidocaine is less cardiotoxic than bupivacaine. The neurotoxic effects that were 
noted after intrathecal infusion were dose-dependent. 
No significant effects were observed in offspring of Sprague Dawley rats administered lidocaine. 
Mutagenicity trials using the Ames test with lidocaine and its metabolites showed no mutagenic potential. In 
trials of chronic exposure to high doses of the metabolite lidocaine 2,6-xylidine, on rats with transplacentar 
exposure and those that received it in food after birth, this highly sensitive testing system detected the 
appearance of malignant and benign neoplasms, especially in the oral cavity. 
Pharmaceutical parameters 
Incompatibilities 
Not applicable 
Shelf life 
3 years 
Special storage conditions 
Store at temperatures below 25 °C. 
Store in original packaging; protect against moisture. 
Special precaution for disposal and other handling 
 
No special requirements. 
Presentation: 
10 or 12 lozenges (pastilles) in aluminum and PVC/PCTFE foil blister; 2 blisters in a carton pack. 
12 lozenges (pastilles) in aluminum and PVC/PCTFE foil blister; 3 blisters in a carton pack. 
 
 
 
 
2.1.2 
Reference drug 
ANTI-ANGIN® FORMULA, lozenges, 0.2 mg + 2 mg + 50 mg. 
ATC code: R02AA20 
Pharmacological groups 


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• Local anesthetics in combinations 
• Antiseptics and disinfectants in combinations 
 Composition and presentation 
Lozenges  
1 lozenge 
chlorhexidine diacetate 
2 mg 
tetracaine hydrochloride 
0.20 mg 
ascorbic acid 
50 mg 
Excipients: dextrose syrup 945.00 mg, saccharose 1,435.00 mg, natural oil flavoring 4.00 mg, mint 
flavoring 0.30 mg, red carmine colorant E120 0.10 mg, purified water 63.40 mg. 
 
 
Pharmaceutical form 
 
Lozenges. 2, 4, 6, 8, 10, 12 lozenges in AL-PVC blister; 1, 2, 3, 4, 5, 10, 15 blisters in a carton pack. 
 
Description of dosage form 
 
Lozenges: flat, round, with beveled edges and rough surface, of pink to pinkish-red color, with a specific odor. Color 
non-uniformity, presence of air bubbles in a high-boiled sugar mass, and insignificant edge irregularity are allowed. 
 
Pharmacological properties 
Pharmacological effects: antiseptic and local anesthetic. 
 
Pharmacodynamics 
Chlorhexidine exerts the bactericidal and bacteriostatic effects. 
It has a wide spectrum of antibacterial activity against gram-positive and gram-negative bacteria as well as Candida 
albicans. Chlorhexidine is especially effective against Streptococcus mutans, Streptococcus salivarius, Escherichia coli, 
and anaerobic bacteria. It is less effective against Streptococcus spp., Proteus spp., Pseudomonas spp., Klebsiella spp., 
Veillonella spp. 
Tetracaine acts as a local anesthetic. An anesthetic effect develops 1–2 minutes after the drug use. 
Ascorbic acid participates in collagen synthesis, tissue regeneration, and regulation of the oxidation-reduction 
processes, 
enhances 
the 


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immune reactions. Due to reduction in the capillary permeability, it contributes to decrease of inflammation 
and edemas of the mucous membranes of the mouth and pharynx. 
Indications 
Prevention and treatment of infectious and inflammatory oral and pharyngeal conditions (stomatitis, 
gingivitis, tonsillitis, pharyngitis, periodontosis, initial stage of paratonsillar abscess, condition after 
tonsillectomy or tooth extraction). 
Contraindications 
Hypersensitivity to the components of the drug, pediatric age below 5 years old, I pregnancy trimester, 
sucrase-isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption, hypersensitivity to 
other topical anesthetics of the esters group or paraaminobenzoic acid or its derivatives. 
Special precautions for use: 
In II and III trimesters of pregnancy on doctor's prescription, during lactation, diabetes mellitus, glucose-6-
phosphate 
dehydrogenase 
deficiency, 
hemochromatosis, 
sideroblastosis 
anemia, 
thalassanemia, 
hyperoxaluria, oxalosis, and urolithiasis. 
Posology and method of administration 
Topically, keep in the mouth till full dissolution. 
Adults: 1 lozenge at a time every 2 hours but not more than 6 lozenges per day. 
Side effects 
Allergic reactions (in patients with hypersensitivity to the components of the drug). 
Extension of the recommended duration of therapy may cause a temporal taste disturbance or tooth enamel 
deterioration (coloration, deposition of a tooth plaque). 
 
Overdose 
Symptoms: dizziness, general fatigue, cyanosis, agitation, anxiety, muscular tremor, respiratory disturbance, 
nausea, vomiting. 
Treatment: gastric lavage, bulk cathartics; symptomatic treatment. 


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Interactions 
Chlorhexidine is incompatible with anionic detergents (saponins, sodium lauryl sulfate, sodium 
carboxymethylcellulose). Concomitant use with iodine is not recommended. Ethanol enhances the drug 
effects. 
Tetracaine reduces antibacterial activity of sulfanilamide agents. Vasoconstrictors prolong the activity and 
diminish toxicity of tetracaine. Ascorbic acid increases the blood levels of benzylpenicillin and tetracyclines. 
Ascorbic acid increases absorption of the ferric drugs in the intestine. It reduces efficacy of heparin and 
indirect anticoagulants. It increases the risk of crystalluria during therapy with the short-acting salicylates 
and sulfanilamides, reduces the plasma levels of oral contraceptives. 
Special considerations 
It is not recommended to use the drug concomitantly with iod-containing drugs for treatment of oral cavity 
and throat (Lugol's solution, povidone iodine). Ascorbic acid contained in the drug might influence some 
laboratory results which should become known during the tests. 
Diabetic patients should note that each pastille contains 1.4 g of sucrose which corresponds to 0.12 bread 
units. 
According to pharmacological properties, the product has no effect on the ability to perform the activities 
requiring increased concentration of attention and 
prompt psychomotor reactions. 
Long-term administration (more than 5 days) of the drug is undesirable due to possible damage to normal 
microbial flora of oral cavity and throat. Do not use the drug immediately prior to or during the meal. Do not 
brush your teeth after the drug use because the surface active agents contained in the toothpaste may 
inactivate chlorhexidine. 
The drug may influence the doping test results. 
 
Manufacturer 
 
 
 
Storage conditions 
At temperature below 25 °C. 
Keep out of reach of children. 
 
Shelf life 


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3 years. The drug should not be used after the expiry date. 
 
2.2 
Summary of preclinical and clinical results significant for this trial 
Angal, a drug proposed for the state registration, contains two components; therefore, this section presents a 
summary of preclinical and clinical aspects of efficacy and safety of those components. 
2.2.1 
Preclinical results summary 
 
2.2.1.1 
Chlorhexidine (chlorhexidine dihydrochloride) 
Chlorhexidine is a commonly used disinfectant and topical antiseptic agent. In vitro tests confirmed the value 
of chlorhexidine in the treatment of upper respiratory tract infections such as pharyngitis. It exerts 
bactericidal effects against the pathogenic bacteria in the upper respiratory tract infections. Chlorhexidine 
also shows some antiviral activity in relation to influenza A virus (H1N1). 
Chlorhexidine is virtually not absorbed when administered topically. Small amounts are detected in the urine 
of laboratory animals. LD50 varies from 21 mg/kg (rats, i.v.) to 5,000 mg/kg (rats, oral). Subchronic toxicity 
trials showed minimal dermal irritation (erythema, edema, desquamation and/or fissuring) at the lowest dose 
tested. 
Tests at all doses showed no malformations or developmental toxicity. Mutagenic effects were not observed 
in two mammalian in vivo mutagenesis trials evaluating chlorhexidine gluconate. Long-term toxicity trials in 
rats showed no carcinogenic effects of chlorhexidine (5; 6; 7; 8; 9; 10). 
2.2.1.2 
Lidocaine (lidocaine hydrochloride) 
Lidocaine hydrochloride is a peripheral local anesthetic of the amide type. Lidocaine administered i.v. is 
used as an antiarrhythmic drug. Lidocaine, like other local anesthetics, blocks conduction of nerve endings 
impulses in a reversible way by interfering with processes fundamental to generation of nerve action 
potential, namely, large transient increase in permeability of membrane to sodium ions that is produced by 
slight depolarization of membrane. 
From observations in rabbits administered lidocaine HCl i.v. and portally, a first pass hepatic elimination of 
approximately 30% could be calculated. The fraction of rectal venous drainage bypassing the portal 
circulation and thus hepatic metabolism is about 40%. In the rabbit, the hepatic first pass effect for lidocaine 
can be avoided by administering the compound via the rectum. 


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Intrinsic clearance of lidocaine was consistently reduced in the dog after repeated administration. LD50 
varies from 19.5 mg/kg (mouse, i.v.) to 317 mg/kg (rat, oral). Lidocaine showed neurotoxicity to sensory 
neurons, resulting from a direct action on sensory neurons, and that a lidocaine-induced increase in 
intracellular Ca2+ is a mechanism of lidocaine-induced neuronal toxicity. Lidocaine is less cardiotoxic than 
bupivacaine. Observed neurotoxic effects after intrathecal infusion were dose-dependent. No significant 
effects were observed in offspring of Sprague Dawley rats administered lidocaine. Lidocaine did not show 
any mutagenicity. Lidocaine effectively inhibited the invasive ability of human cancer cells at concentrations 
used in surgical operations (11; 12; 13; 14). 
For these reasons, the lozenges containing chlorhexidine hydrochloride (5 mg) / lidocaine hydrochloride 
(1 mg) are considered to be fully satisfactory for introduction to the market in terms of safety and efficacy. 
The information presented confirms the suitability of the product when used as recommended. 
2.2.2 
Clinical results summary 
The results of a randomized, double-blind,  placebo-controlled, phase III trial with a lemon-flavored lozenge 
formulation (Medica®) containing a combination of 5 mg chlorhexidine dihydrochloride with 1 mg lidocaine 
hydrochloride demonstrated higher efficacy than placebo regarding several measured parameters, which 
exhibited significant improvement from the stationary phase (sore throat at 120 min) through to the follow-
up visit at Day 4 (sore throat and erythema). This combination was thus shown to provide symptomatic relief 
of sore throat as well as reducing signs of inflammation such as erythema. The combination lozenge was 
very well tolerated. In a double blind, placebo-controlled trial conducted by Schapowal et al., the use of a 
spray containing chlorhexidine 1% and lidocaine 2% demonstrated a 60% response on Day 3 of the therapy 
associated with a very good tolerability in patients with an acute tonsillopharyngitis (15). 
 
The use of topical lidocaine forms (pastilles and spray) at much bigger strength than that of Angal was not 
associated with any toxic effects while a significant clinical effect was shown (16). 
Although the overall volume of clinical evidence in support of the proposed indication is very limited and the 
available data set has not resulted from a systematic investigation of the properties of the product, this type 
of preparations has been used widely for several decades. The use of the drug at recommended doses for the 
approved indications is safe; the drug is registered in the EU; no SAEs were reported, while AEs and 
precautions 
for 
use 
in 
special 


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populations are well known and described in Section 2.1.1. Therefore, the repeated toxicological, 
pharmacological, or clinical trials for determination of the main features of the active substances are not 
justified, while a benefit/risk ratio is favorable to recommend conduction of a clinical trial of Angal in 
patients with acute viral pharyngitis. 
2.3 
Brief description of known and potential risks for the trial subjects (if any) 
Preclinical and clinical trials of the study drugs components showed a favorable safety profile and good 
tolerability of Angal and ANTI-ANGIN® FORMULA. A list of known side effects of those drugs is 
presented in Section 2.2.1. 
Venous blood will be collected during the trial, approximately 12 ml (1 tablespoonful) on Day 0 and Day 4, 
i.e., the total amount of blood taken for analysis will not exceed 30 ml for 5 days. Those volume and rate of a 
blood loss are clinically insignificant for an adult. Venipuncture may potentially cause a bruise or hematoma, 
as well as phlebitis or thrombophlebitis at the injection site. The trial site personnel will make every possible 
effort to minimize the risks for the patients associated with the trial therapy and procedures. In case of AEs 
or other health issues, the patient will be provided with the appropriate medical care. 
The benefit from the trial is associated with the laboratory and instrumental investigations, therapy under 
supervision of a highly qualified doctors with the study drugs free of charge for the trial participants. 
2.4 
Description and rationale for the route of administration, dosages, dosing regimens, and 
duration of treatment 
The study drugs will be prescribed according to relevant Prescribing Information: a Prescribing Information 
draft for Angal and a current Prescribing Information for ANTI-ANGIN® FORMULA registered in Russia. 
Angal will be used in the following way: 1 lozenge with a not less than 2-hour interval, till full dissolution in 
the mouth, up to 6–10 times per day, for 4 days or until full recovery (whichever occurs first during 4 days of 
therapy). ANTI-ANGIN® FORMULA will be used in the following way: 1 lozenge with a not less than 2-
hour interval, up to 6 lozenges per day, for 5 days or until full recovery  (total TSS ≤ 2)  (whichever occurs 
first during 5 days of therapy). 


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2.5 
Legal basis 
This is a protocol of clinical trial planned to be conducted in accordance with principles of the Declaration of 
Helsinki, World Medical Association (adopted at the 18th Assembly of the World Medical Association in 
Helsinki in June 1964, the latest revision adopted by the 64th Assembly in Fortaleza in October 2013), the 
triangular agreement on Good Clinical Practice (ICH GCP), and applicable laws of the Russian Federation: 
• 
Federal Law On Circulation of Medicines No. 61-FZ of April 12, 2010 (current version No. 350-FZ of 
July 3, 2016). 
• 
Federal Law On Personal Data No. 152-FZ of July 27, 2006 (current version of July 21, 2014 as 
amended as of September 1, 2015). 
• 
The National RF Standard GOST R52379-2005, Good Clinical Practice. 
• 
Government Decree of the Russian Federation No. 714 of September 13, 2010 (the last version of 
October 15, 2014), Rules for compulsory insurance of the life and health of a patient involved in 
clinical trials of a drug. 
• 
Order of the Ministry of Health of the Russian Federation On Approval of the Provision on the Ethics 
Council No. 986n of November 29, 2012. 
• 
Order of the Ministry of Health of the Russian Federation On Approval of the Good Clinical Practice 
Rules No. 200n of April 1, 2016. 
2.6 
Description of the trial population 
Men and women at the age of 18 to 45 years old, inclusively, with acute, uncomplicated, inflammatory and 
infectious conditions of the pharynx associated with a sore throat, with manifestation of the first signs not 
more than 48 hours before the inclusion, with a total TSS ≥ 5, who signed the Informed Consent Form and 
comply with the inclusion criteria (see Section 5.1) and none of the non-inclusion criteria (see Section 5.2). 
2.7 
References 
1. 
Острая боль в горле в практике терапевта: дифференциальная диагностика и принципы 
фармакотерапии. Мубаракшина, О. А. 18, 2011 г., Фарматека, стр. 48–52. 
2. 
Денисова, И. Н. и Лесняк, О. М., [ред.]. Общая врачебная практика: национальное руководство 
в 2 томах, т II. Москва: ГЭОТАР-Медиа, 2013. 
3. 
Пальчун, В. Т., [ред.]. Оториноларинология: национальное руководство. Москва: ГЭОТАР-
Медиа, 2008. 
4. 
Pharyngitis. Weber, R. 1, 2014 г., Prim Care, Vol. 41, pp. 91–98. 


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5. 
Final Report on the Safety Assessment of Chlorhexidine/Chlorhexidine Diacetate/Chlorhexidine 
Dihydrochloride/Chlorhexidine Digluconate. 201–223, 1993, Int J Toxicol, Vol. 12. 
6. 
Structural determinants of activity of chlorhexidine and alkyl bisbiguanides against the human oral 
flora. Baker, P. J., et al. 6, 1987 , J Dent Res, Vol. 66, pp. 1099–1106. 
7. 
Cytotoxicity of chlorhexidine digluconate to murine macrophages and its effect on hydrogen peroxide 
and nitric oxide induction. Bonacorsi, C., Raddi, M. S. and Carlos, I. Z. 2, 2004, Braz J Med Biol Res, 
Vol. 37, pp. 207–212. 
8. 
Effects of topical chlorhexidine applied to the rabbit nasal mucosa. Cankaya, H., et al. 1, 2003 г., 
Auris Nasus Larynx, Vol. 30, pp. 65–69. 
9. 
Differential actions of chlorhexidine on the cell wall of Bacillus subtilis and Escherichia coli. Cheung, 
H. Y., et al. 5, 2012, PLoS One, Vol. 7, p. e36659. 
10. 
Activity of Drill® lozenges on the main microorganisms responsible for upper respiratory tract 
infections. Michel, C., et al. 4, 2013, Eur Ann Otorhinolaryngol Head Neck Dis, Vol. 130, pp. 189–
193. 
11. 
Ecocain®. Summary of Product Characteristics (SPC). eurodental.it - il deposito dentale online - 
materiale odontoiatrico. [Online] 8 7,  2016. 
http://www.eurodental.it/it/download/molteni/ECOCAIN.pdf. 
12. 
Take the pain? Lidocaine comes under suspicion as a carcinogen. Beardsley, T. 5, 1994, Sci Am, Vol. 
270, pp. 13–14. 
13. 
Assessment of teratogenic effects of lidocaine in rat embryos cultured in vitro. Fujinaga, M. 6, 1998, 
Anesthesiology, Vol. 89, pp. 1553–1558. 
14. 
Lidocaine toxicity in primary afferent neurons from the rat. Gold, M. S., et al. 2, 1998, J Pharmacol 
Exp Ther, Vol. 285, pp. 413–421. 
15. 
Echinacea/sage or chlorhexidine/lidocaine for treating acute sore throats: a randomized double-blind 
trial. Schapowal, A., et al. 9, 2009, Eur J Med Res, Vol. 14, pp. 406–412. 
16. 
Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option 
investigated in comparison to placebo treatment. Wonnemann, M., et al. 11, 2007, 
Arzneimittelforschung, Vol. 57, pp. 689–697. 
17. 
European Health Risk Monitoring (EHRM). Recommendation for international collaboration, protocol 
and manual of operations forchronic disease risk factor surveys. 10 2002. 


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3 
Trial objectives and goals 
3.1 
Trial objective 
This trial has been designed to evaluate the non-inferior therapeutic efficacy and safety of the study drug 
Angal, lozenges [menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia), comparing to ANTI-ANGIN® FORMULA, 
lozenges, 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia), in treatment of patients with uncomplicated acute 
infectious and inflammatory diseases of the pharynx accompanied by a sore throat. 
3.2 
Trial goals 
Primary goal: 
• 
Assessment of the non-inferior therapeutic efficacy of Angal, lozenges [menthol], 1 mg + 5 mg 
(Sandoz d.d., Slovenia)—administration of 1 lozenge with a not less than 2-hour interval, up to 6–10 
times per day, for 4 days or until full recovery (whichever occurs first during 4 days of therapy), 
compared to ANTI-ANGIN® FORMULA, lozenges 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia)—
administration of 1 lozenge with a not less than 2-hour interval, up to 6 lozenges per day, for 5 days or 
until full recovery (whichever occurs first during 5 days of therapy) in the treatment of patients with 
uncomplicated acute infectious and inflammatory diseases of the pharynx accompanied by a sore 
throat. 
Secondary goals: 
• 
Assessment of safety of Angal, lozenges [menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia)—
administration of 1 lozenge with a not less than 2-hour interval, up to 6–10 times per day, for 4 days or 
until full recovery (whichever occurs first during 4 days of therapy), compared to  ANTI-ANGIN® 
FORMULA, lozenges, 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia)—administration of 1 lozenge 
with a not less than 2-hour interval, up to 6 lozenges per day, for 5 days or until full recovery 
(whichever occurs first during 5 days of therapy) in the treatment of patients with uncomplicated acute 
Infectious and inflammatory diseases of the pharynx accompanied by a sore throat. 
• 
Evaluation of adverse events (AEs) in the trial arms. 
• 
The AEs rate comparison between the trial arms. 


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4 
Trial design 
4.1 
General and additional tested parameters 
4.1.1 
Efficacy parameters 
4.1.1.1. 
The main efficacy endpoint 
The primary outcome measure was the percentage of patients without sore throat after 3 days of therapy on 
Day 4, as evaluated by the Investigator according to the Tonsillopharyngitis Severity Score (TSS), in both 
Angal and ANTI-ANGIN® FORMULA arms. 
4.1.1.2 
Additional efficacy endpoints 
The secondary outcome measures in the both therapy groups to compare the therapeutic efficacy of the study 
drug and comparator drug were: 
• 
The frequency of ≥50% total score reduction according to the TSS questionnaire completed by 
the Investigator as compared to the baseline in both Angal and ANTI-ANGIN® FORMULA 
groups at Visit 2 (Day 4). 
• 
Total score reduction according to the TSS questionnaire, as well as a reduction in the symptoms 
(sore throat, difficulty in swallowing, salivation, erythema, and fever) after a 3-day therapy, at 
Visit 2 (Day 4), as compared to the baseline total score. 
• 
A period of time required for disease symptoms relief, determined according to the patient's 
diary (subjective patient's evaluation), but no more than 5 days during the trial—for patients who 
have achieved the corresponding outcome. 
• 
A proportion (%) of patients who fully recovered by Day 4 in Group A and by Day 5 in Group B 
(the outcome of a disease according to the objective evaluation by the Investigator, the total 
score according to the TSS questionnaire ≤2). 
• 
A change in the sore throat intensity by 100 mm VAS (visual analogue scale filled in by the 
patient) at the beginning, after 3 days of therapy, and at the end of treatment in both groups. 
4.1.2. Safety parameters 
The following parameters will be taken into account for the safety evaluation: 
• 
AEs and/or SAEs rates per trial arms; 
• 
Global tolerance evaluation during the trial by the Investigator and patient; 
• 
Vital signs (heart rate, blood pressure, body temperature, breathing rate); 
• 
ECG parameters; 
• 
Laboratory results. 
The AEs will be described according to the scheme given below: 


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• 
ae description; 
• 
ae severity; 
• 
ae duration; 
• 
Relation to the study drug; 
• 
Outcome. 
All AEs will be coded according to MedDRA terms. 
4.2 
Description of the trial design 
4.2.1 
Trial type 
Prospective, multicenter, open, randomized, comparative, clinical trial in 2 parallel groups. 
 


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4.2.2 
Trial design flowchart 
 
SCREENING + RAND. 
TREATMENT PERIOD 
FOLLOW-UP 
Day 1 
Day 1 
Day 2 
Day 3 
Day 5 
Day 4 
Day 6/7 
Group A_Angal (4 days maximum), 140 patients 
Group B_Anti-Angin® Formula (5 days maximum), 140 
patients 
VISIT 1 
Patient population: 
- 18/45 years old 
- Pharyngitis or tonsillitis 
associated with pain 
and inflammation in 
the throat 
- Total points TSS55 
- 
First 
signs 
of 
pharyngitis or tonsillitis 
48 hours or less before 
screening 
- t 37.5 °С 
- VAS (presence of pain) 
TSS-BASELINE 
(INVESTIGATOR'S 
EVALUATION) + VAS 
The first intake 
of the drug at 
the trial site. The 
patients are given 
their diaries. 
The patients stay 
at 
home. 
The 
patients fill in their 
diaries. In case of 
worsening: 
an 
unscheduled visit. 
The patients stay 
at 
home. 
The 
patients fill in their 
diaries. In case of 
worsening: 
an 
unscheduled visit. 
VISIT 2 
A visit to the trial site 
EVALUATION OF THE 
THERAPY EFFICACY IN 
THE BOTH GROUPS 
AFTER 3 DAYS OF 
THERAPY. 
Group A patients return 
the drug and diary, they do 
not have to visit the site on 
Day 5 
Group 
B 
patients 
continue 
the 
therapy 
(if needed) or return the 
drug and diary if they meet 
the recovery criteria (total 
TSS ≤ 2). TSS AFTER 3 
DAYS 
OF 
THERAPY 
(Investigator's 
evaluation) + VAS 
Outcome evaluation by 
TSS 
(Investigator's 
evaluation) + VAS 
VISIT 3 
A visit to a trial site 
Only for the Group B 
patients who continued the 
therapy after Day 4 visit 
(they return the drug and 
diary). 
 
Outcome 
evaluation 
by 
TSS (by the Investigator) + 
VAS 
VISIT 4 
A phone contact 
with the patients 
from the both 
groups 
 
2 days after the last 
scheduled visit 
 
Safety evaluation 
 
Trial completion 


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4.2.3 
Trial procedures 
4.2.3.1 
Trial procedures in a table form 
Table 1. Visit schedule 
Trial period 
Screening/Randomization/Therapy 
initiation 
Treatment 
Further 
follow-up1 
Unscheduled 
visits 
Visits 
Visit 1 
Visit 22 
Visit 33 
Visit 4 
Day after initiation of therapy 
Day 1 
Day 4 
Day 5 
Day 6/7 
 
Trial procedures 
 
 
 
 
 
Signing of the Informed Consent Form 
• 
 
 
 
 
Demographic data (date of birth, sex, age) 
• 
 
 
 
 
Measurement of weight and height 
• 
 
 
 
 
Medical history 
• 
 
 
 
 
Collection of complaints, actualization of anamnesis 
• 
• 
• 
 
• 
Records on the concomitant therapy 
• 
• 
• 
 
• 
Evaluation of the throat pain intensity according to VAS by a patient 
• 
• 
• 
 
 
Fill-in of TSS questionnaire4 
• 
• 
• 
 
• 
Physical examination (including topical examination) 
• 
• 
• 
 
• 
Measurement of vital signs5 
• 
• * 
• 
 
• 
Hematology6 
• 
• * 
• 
 
 
Biochemistry7 
• 
• * 
• 
 
 
Urine pregnancy test8 
• 
 
 
 
 
12-lead ECG 
• 
• * 
• 
 
 
Evaluation of inclusion/non-inclusion criteria 
• 
 
 
 
 
                                                     
1 A follow up visit will be held in the form of a phone contact with the patient to reveal the possible AEs. 
2 In case of premature discontinuation, the follow-up procedures are the same as those at Visit 2. 
3 Only for the Group B patients who did not meet the recovery criteria (total TSS ≤ 2) at Visit 2 (Day 4) and continued the therapy. 
4 Fill-in of TSS questionnaire by the Investigator (scores for every question should be summarized to obtain a total TSS score). 
5 Systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), breathing rate (per minute), pulse rate (beats per minute), axillary body temperature (°С). 
6 Hb, RBC, WBC with differential, ESR—at the trial site laboratory. 
7 Total protein, AST, ALT, total bilirubin. 
8 For women with the preserved childbearing potential only. 


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Trial period 
Screening/rand
omization/ther
apy initiation 
Treatment 
Further 
follow-up1 
Unscheduled 
visits 
Visits 
Visit 1 
Visit 22 
Visit 33 
Visit 4 
Day after initiation of therapy 
Day 1 
Day 4 
Day 5 
Day 6/7 
 
Trial procedures 
 
 
 
 
 
Randomization 
• 
 
 
 
 
Dispensing of the study drugs 
• 
 
 
 
 
Dispensing of the patient's diaries 
• 
 
 
 
 
Return of the unused study drugs 
 
• * 
• 
 
 
Return of the patient's diaries 
 
• * 
• 
 
 
Evaluation of adverse events (including based on results of the throat and pharynx 
examination during the trial site visits) 
• 
• 
• 
• 
• 
Evaluation of exclusion criteria 
 
• 
• 
 
• 
Global evaluation of therapy tolerability by the patient and the physician  
 
• * 
• 
 
• 
Compliance evaluation (diary completion, administration of the study drugs) 
 
• 
• 
 
• 
Notes: 
* Only for Group A patients and those Group B patients who achieved the recovery criteria (total TSS score ≤2). 
 


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4.2.3.2 
Description of the trial procedures 
4.2.3.2.1 
Collection of medical history, demographic and anthropometric data 
Medical history includes the previous diseases, concomitant chronic conditions, hereditary issues, 
social habits (smoking, alcohol or drug abuse), allergological anamnesis, previous surgeries or 
traumas, occupational history, permanent or periodic drug therapy. Regarding the present condition: 
date and time of the first signs manifestation, diagnostic and treatment procedures by the screening, 
their efficacy. A contraception method used by the patient; by signing the Informed Consent Form, 
the patient agrees to use one of the recommended contraception methods (by the protocol) during the 
trial and 1 month after the trial completion. 
Primary documents must contain data on the sex, age, race, and ethnicity of the patient. A height 
meter is used to measure the patient's height in centimeters, the weighing scales—body weight in 
kilograms. 
The anthropometric examinations will be conducted in accordance with the Health Risk Monitoring 
(EHRM) Recommendation for indicators, international collaboration, protocol and manual of 
operations for chronic disease risk factor surveys, 2002 (17). 
Height should be measured in all the patients (the causes which make the height measurement 
impossible include hair-style peculiarities (e.g., mohawk), patient's refusal to take off a headwear 
(e.g., turban), patient's incapacity to stand, exceedance of the height meter's scale). The height meter is 
a vertically positioned panel with a centimeter division with a sliding horizontal ruler. A standard 
error must not exceed 2 mm. The patient will be asked to take off his/her shoes, thick clothes, 
hairpins, or other hair accessories. The patient must touch a vertical panel with his/her hindhead, back, 
buttocks, calves, and heels (the toes are stuck together). Upper boundary of the external ear canal 
must be at the same level with lower boundary of the orbital cavity (the jugal bone). The patient will 
be asked to look forward. If the patient's height exceeds that of the Investigator, the latter should use a 
platform. A height meter's ruler is put on the patient's head, the scale's divisions are counted. The 
height must be recorded while the patient is still standing under the ruler. An error must not exceed 
0.5 cm. 
The patient's weight must be measured in the morning in the fasting condition, after urination and 
defecation, in the underwear (with further subtraction of an average underwear weight). The weighing 
scales must be horizontally positioned on a solid ground. An error must not exceed 0.2 kg. The patient 
should stand in the center of the weighing scales on the both legs. If the weight measurement is 
impossible, the Investigator should not record any values based on the patient's claims. 


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4.2.3.2.2 
Physical examination and vital signs evaluation 
Physical examination will be conducted according to the general rules of the propedeutics of internal 
diseases: general visual examination, inspection of the mucous membranes, including pharyngoscopy, 
lymph nodes palpation, evaluation of bones and muscles, palpation, percussion and auscultation of the 
main organ systems (cardiovascular, respiratory, gastrointestinal, urinary systems) will be conducted 
sequentially. 
Vital signs (HR, BR, BP, body temperature) will be evaluated before the physical examination at rest 
(after 15 minutes of rest, not earlier than 1 hour after smoking or 2 hours after meal). Heart rate (HR) 
will be measured during the heart auscultation in parallel with a pulse rate determination on the radial 
artery (or carotid artery in case the radial artery pulse is weak) for 1 minute in a sitting position; in 
case of a pulse deficiency, the both parameters should be recorded: HR and pulse rate. Breathing rate 
(BR) will be measured for 1 minute at rest, in a sitting position, observing breathing movements of the 
thorax and abdominal wall without drawing the patient's attention. 
Blood pressure (BP) will be measured on the brachial artery, in a sitting position, by Korotkoff 
method, using a certified sphygmomanometer or tonometer with a cuff adjusted for the patient's 
shoulder in length and width according to the recommendations for measurement (RMOAG/VNOK, 
2010). The cuff's size should correspond to the arm's size: a cuff rubber part to be inflated should 
cover not less than 80% of the arm circumference; a cuff 12–13 cm in length and 30–35 cm in width 
(medium size) should be used for the adults; although, the bigger and smaller cuffs might be required 
for bigger and smaller arms, respectively. Before the measurement start, a mercury column or a  
tonometer needle must be in a zero position. To measure BP on every arm not less than 2 
measurements with a 1-minute interval are required; in case of BP difference ≥5 mm Hg, an 
additional measurement should be made; the lowest result based on the 3 measurement should be 
recorded as a final one. 
Measurement procedure: 
• 
Pump up the air into the cuff fast to the pressure level 20 mm Hg exceeding a common 
systolic BP (by the pulse disappearance). 
• 
An error must not exceed 2 mm Hg. 
• 
Reduce the pressure in the cuff at a rate of 2 mm Hg per second. 
• 
A pressure level when the 1st tone appears corresponds to a systolic BP (phase 1 of 
Korotkoff sounds). 
• 
A pressure level when the tones disappear corresponds to a diastolic BP (phase 5 of 
Korotkoff sounds); in children, adolescents, and young people after physical exertion, in 
pregnant women, as well as in some disorders in adults when phase 5 cannot be 
determined, a healthcare practitioner should try to determine phase 4 by significant tones 
weakening. 


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• 
If the tones are very weak, the patient should raise his/her hand and make several 
compressions by hand, after which the measurement should be repeated without a strong 
compression on the artery by a phonendoscope membrane. 
• 
BP should be measured on both hands at initial examination only; further measurements 
must be performed at the hand with higher values. 
Body temperature must be measured by the same thermometer type (mercuric or electronic) and 
method (axillary temperature) throughout the trial. 
4.2.3.2.3 
Fill-in of TSS questionnaire 
TSS, a questionnaire (point scale) for healthcare professionals, is used in clinical practice as well as 
clinical trials to evaluate dynamic changes of symptoms severity of the infection-inflammatory 
process in the throat (Bereznoy VV, Riley DS, Wassmer G, Heger M. Efficacy of extract of 
Pelargonium sidoides in children with acute non-group A beta-hemolytic streptococcus 
tonsillopharyngitis: a randomized, double-blind, placebo-controlled trial). One of such clinical trials 
with TSS questionnaire was conducted in 2005 in Germany, ©CRO Applertee AG. A version of TSS 
©CRO Applertee AG was adapted for this protocol. 
TSS (Tonsillopharyngitis Severity Score) is a questionnaire for evaluation of the following symptoms 
severity: pharyngalgia, difficulty in swallowing, salivation, hyperemia of pharyngeal mucosa, and 
body temperature increase according to a 4-point scale: 
 
0 
 = no symptom; 
1 
= insignificant symptom; 
2 
= moderate symptom; 
3 
= significant symptom. 
The axillary body temperature increase is rated as follows: 
0 points: <37.5 °С; 
1 point: 37.5 to <38.5 °С; 
2 points: 38.5 to <39.5 °С; 
3 points: >39.5 °С. 
TSS is filled in by the Investigator based on the patient complaints and physical examination data. 
The Investigator summarizes the points obtained for every symptom to obtain a total sum of TSS 
points. A total sum of TSS points will be used at screening to evaluate for a subject's eligibility and 
baseline evaluation; at Visit 2 (Day 4), to measure efficacy of the trial therapy in the both groups; to 
evaluate the disease outcomes on Visit 2 (Day 4) and/or Visit 3 (Day 5), where applicable. 


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4.2.3.2.4 
Evaluation of the throat pain intensity according to VAS 
The patient will fill in the VAS to evaluate for the throat pain intensity at every visit to the trial site 
(Visit 1, Visit 2, and Visit 3 (where applicable)). Calibrated scales 100 mm in length with the relevant 
measuring instruments will be provided for the clinical trial. 
The patients should evaluate their pain severity according to VAS at every visit (if possible, before 
administration of the painkillers (if those are required) or the study drug/comparator drug). The scale 
is provided in Appendix 5 to this protocol. 
4.2.3.2.5. 
Global evaluation of therapy tolerability by the patient and the physician 
Global evaluation of study drug tolerability should be made by the patient and Investigator according 
to the following scale: 
Scores 
Evaluation 
0 
Poor 
1 
Satisfactory 
2 
Good 
3 
Excellent 
Evaluation of the study drug tolerability by the patient and the physician (points/scores) should be 
specified in the eCRF at Visits 2 or 3 (where applicable). 
4.2.3.2.6 
Laboratory tests 
The blood for analysis will be collected in the morning, in the fasted state (10–12 hours after the last 
meal) from the cubital vein by a disposable sterile syringe under aseptic conditions. Approximately 
12 ml (1 tablespoonful) of blood will be collected at Visits 1 and 2 (or 3, where applicable). 
Hematology (Hb, RBC, WBC, WBC differential, ESR) and biochemistry (total protein, ALT, AST, 
total bilirubin) will be conducted at the trial site laboratory. Pregnancy urine test using 
test 
strips 
(immunochromatographic assay of beta-chorionic gonadotropin in the urine) must be performed for 
all women with the preserved childbearing potential at the screening visit. 
4.2.3.2.7 
Electrocardiography 
ECG will be performed at Visit 1 and Visit 2 or 3 (where applicable). ECG includes 
electrocardiogram tracing in 3 standard and 3 augmented leads (from the extremities), as well as 6 
chest 
leads 
at 
rest 
in 
the 


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lying position. ECG will be interpreted by cardiologist, therapist, or functional diagnostics specialist. 
4.2.4 
Trial stages 
4.2.4.1 
Screening/randomization/therapy initiation (Visit 1) 
Visit 1 is scheduled for Day 1. At this visit, the doctor evaluates the patient's eligibility for the trial. If 
no non-inclusion criteria are met, the patient undergoes randomization, is given the study 
drug/comparator drug and a patient's diary, and is instructed on the patient's diary completion 
requirements. Screening visit procedures: 
• 
Signing of the Informed Consent Form; 
• 
Demographic data (date of birth, sex, age); 
• 
Measurement of weight and height; 
• 
Anamnesis gathering; 
• 
Records on the concomitant therapy; 
• 
Evaluation of inclusion/non-inclusion criteria; 
• 
Evaluation of the throat pain intensity according to VAS; 
• 
Fill-in of TSS questionnaire by the Investigator; 
• 
Physical examination (including oropharynx); 
• 
Measurement of the main vital signs; 
• 
Hematology; 
• 
Biochemistry; 
• 
Urine pregnancy test; 
• 
12-lead ECG; 
• 
Evaluation of inclusion/non-inclusion criteria; 
• 
Randomization; 
• 
Dispensing of the study drugs; 
• 
Provision with the patient's diaries and training on the fill-in rules; 
• 
Initiation of therapy with the study drugs; 
• 
Evaluation of adverse events (including based on results of the throat and pharynx 
examination). 
4.2.4.2 
Efficacy evaluation visit (Visit 2, Day 4) 
Visit 2 is conducted on Day 4; the patient must visit the trial site in the fasted state and bring the 
filled-in diary and unused drug. 
If Group B patients (ANTI-ANGIN® FORMULA) did not meet recovery criteria (total TSS ≤ 2) at 
Visit 2 (Day 4), they will require continuation of the therapy, and some procedures for those patients 
will be transferred for the next day (Visit 3, Day 5), see below. The patients will keep their diaries and 
the unused drugs. 
Visit 2 procedures for the both groups: 


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• 
Collection of complaints, actualization of anamnesis; 
• 
Records on the concomitant therapy; 
• 
Physical examination (including oropharynx); 
• 
Measurement of the main vital signs; 
• 
Evaluation of adverse events (including based on results of the throat and pharynx 
examination); 
• 
Evaluation of exclusion criteria; 
• 
Compliance evaluation (diary completion, administration of the study drugs). 
Visit 2 procedures for Group A patients (Angal) and Group B (ANTI-ANGIN® FORMULA) 
who achieved recovery criteria (total TSS ≤ 2): 
• 
Hematology; 
• 
Biochemistry; 
• 
12-lead ECG; 
• 
Global evaluation of treatment tolerability during the trial by the physician and the 
patient; 
• 
Return of the unused study drug; 
• 
Return of the patient's diary; 
4.2.4.3 
Trial completion visit for Group B patients (Visit 3, Day 5) 
This visit is for Group B patients only (ANTI-ANGIN® FORMULA) who did not achieve the 
recovery criteria (total TSS ≤ 2) at Visit 2 (Day 4) 
Visit 3 is conducted on Day 5; the patient must visit the trial site in the fasted state and bring the 
filled-in diary and unused drug. 
Visit 3 procedures: 
• 
Collection of complaints, actualization of anamnesis; 
• 
Records on the concomitant therapy; 
• 
Physical examination (including oropharynx); 
• 
Measurement of the main vital signs; 
• 
Evaluation of adverse events (including based on results of the throat and pharynx 
examination); 
• 
Evaluation of exclusion criteria; 
• 
Return of the unused study drug; 
• 
Return of the patient's diary; 
• 
Compliance evaluation (diary completion, administration of the study drugs). 
• 
Hematology; 
• 
Biochemistry; 
• 
12-lead ECG; 


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• 
Global evaluation of treatment tolerability during the trial by the physician and the 
patient. 
4.2.4.4 
A follow-up visit (Visit 4) 
A follow-up visit shall be conducted by phone to find out about the patient's state and any AEs. 
A visit 2 days after the therapy completion visit (e.g., on Day 6 or 7, depending on the arm and 
therapy duration). 
Follow-up visit procedures (by phone): 
• 
Evaluation of adverse events (without the throat and pharynx examination). 
In case of adverse events, the patient might be invited to visit the trial site. 
4.2.4.5 
Unscheduled visits 
The unscheduled visits will be conducted when necessary, e.g., in case of the index disease 
deterioration, AEs, or the study drug (Angal or ANTI-ANGIN® FORMULA) intolerability. 
Every unscheduled visit, irrespective of its cause, must include the procedures listed below with 
completion of the relevant eCRF pages (Unscheduled Visit): 
• 
Physical examination (including topical examination); 
• 
TSS evaluation; 
• 
Measurement of the main vital signs (blood pressure, heart rate, breathing rate, body 
temperature); 
• 
12-lead ECG (if it has not been done for the last 12 hours); 
• 
Evaluation of adverse events; 
• 
Evaluation of the concomitant therapy. 
Other diagnostic and treatment procedures may be conducted depending on clinical situation and upon 
the Investigator's decision. 
Taking into account frequency of visits, unscheduled visits may be conducted on the same days as 
scheduled ones but in a different time (e.g., in case of worsening the patient may visit the center in 
afternoon). All procedures for the scheduled visits are identical for the both arms at every trial stage, 
except for the Group B patients who, if the recovery criteria (total TSS ≤ 2) are not met at Visit 2 
(Day 4), should continue the trial therapy and visit the trial site for scheduled Visit 3 Day 5). 
4.2.4.6 
Visit of premature discontinuation of the trial 
Visit 2 procedures will be applied for the visit of premature discontinuation. 


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4.3 
Subjectivity minimization/elimination measures 
4.3.1 
Randomization 
This will be an open, randomized trial. Every screened patient will be assigned with an individual 
registration number containing the initials (name, patronymic, surname) and a participant's number 
assigned to every new screened patient in a three-digit format (001, 002, etc.). The patients who meet 
the inclusion criteria at the screening visit will be randomized to a study drug group or a comparator 
drug group using the envelope method. For the purpose of randomization, a list of randomization 
numbers for the envelops will be generated, every number will correspond to a study drug group or a 
comparator drug group. 
4.3.2 
Blinding methods 
This trial will be conducted without blinding (an open trial). 
4.4 
Description of the drugs used in the trial 
4.4.1 
Dosage form 
Study drug: Angal, lozenges [menthol], 1 mg + 5 mg. White to off-white, round, slightly mottled 
lozenge. 
Comparator drug: ANTI-ANGIN® FORMULA, lozenges, 0.2 mg + 2 mg + 50 mg. Lozenges: flat, 
round, with beveled edges and rough surface, of pink to pinkish-red color, with a specific odor. Color 
non-uniformity, presence of air bubbles in a high-boiled sugar mass, and insignificant edge 
irregularity are allowed. 
4.4.2 
Packaging 
Study drug: Aluminum and PVC/PCTFE foil blister. 24 lozenges (2×12) in a carton pack. 
Comparator drug: Lozenges. 10 lozenges in AL-PVC blister; 3 blisters in a carton pack. 
4.4.3 
Labeling of the study drugs 
As this is an open trial, the trial site will be provided with the packed products from the series 
commercially available in the EU (study drug) and Russia (comparator drug). Every carton box with 
the drugs will contain a self-adhesive label with the data listed below: 
• 
"For clinical trials only"; 


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• 
A protocol number; 
• 
Title, address, and phone number of the trial site; 
• 
Title, address, and phone number of the trial Sponsor; 
• 
A field for a patient's randomization number. 
The label should not overlap the drug name, active substances, and their strength, shelf life, 
manufacturer's name. 
At the screening visit, every patient in the study drug group will be given 2 packages of Angal 
(48 lozenges), and every patient in the comparator drug group will be given 1 package of ANTI-
ANGIN® FORMULA (30 lozenges). The dispensed amounts are sufficient for completion the trial 
according to the protocol. An excess of the drugs is envisaged for the cases of loss of some lozenges. 
4.4.4 
Strength and dosage regimen of the study drugs 
Angal, lozenges [menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia), the study drug, will be used 
according to Prescribing Information, 1 lozenge with a not less than 2-hour interval, up to 6–10 times 
per day, for 4 days or until full recovery  (total TSS ≤ 2) (whichever occurs first during 4 days of 
therapy). A single dose of Angal is 1 lozenge. The lozenges are intended for full dissolution in the 
oral cavity. One lozenge is slowly disintegrating in the mouth. 
ANTI-ANGIN® FORMULA, lozenges, 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia), the 
comparator drug, will be used according to Prescribing Information, 1 lozenge with a not less than 2-
hour interval, up to 6 lozenges per day, for 5 days or until full recovery  (total TSS ≤ 2) (whichever 
occurs first during 5 days of therapy). One dose of ANTI-ANGIN® FORMULA is 1 lozenge. The 
lozenges are intended for full dissolution in the oral cavity. One lozenge is slowly disintegrating in the 
mouth. 
4.5 
Expected duration of the subjects' participation in the trial 
Screening period: 1 day; 
Treatment period: up to 5 days (including the screening/randomization day); 
Follow-up period: up to 2 days. 
A maximum duration of each subject's participation: 7 days. A minimum duration of each subject's 
participation: 6 days (depending on the arm). 


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4.6 
Description of rules for termination of the trial parts or the trial as a whole 
The trial may be terminated on the following grounds: 
1. 
Upon the Sponsor's initiative: availability of new toxicological or pharmacological data, or 
data on SAE which require re-consideration of the previous evaluation of the benefit/risk 
ratio. 
2. 
Upon the Sponsor's initiative: AEs incidence or severity require the trial termination. 
3. 
Upon the Sponsor's initiative: other reasons including administrative ones. 
4. 
Upon the decision of the regulatory authorities. 
The trial may be terminated at a specific trial site in case the patients enrollment or data quality are 
unsatisfactory, or it is reasonable to assume a breach of GCP and/or Declaration of Helsinki, or other 
serious protocol deviations. 
In case of early termination of the trial, the Sponsor must inform the trial site personnel as well as 
regulatory authorities with indication of the reason thereof. The rules for trial termination for every 
participant are described in Section 5.3. 
4.7 
Record keeping procedures for trial products 
The trial sites will be provided with the drugs (the study drug and comparator drug) in the amounts 
enough for the trial completion, taking into account the planned number of patients to be screened. An 
authorized trial site specialist shall keep a logbook for the drugs where the drugs receipt to the trial 
site, dispensing to the subjects, and return of the unused drugs are noted. Storage conditions must be 
also noted. The study drugs may be used for the purposes of this clinical trial only. 
Authorized representatives of the Sponsor or regulatory authorities may check the drugs logbook or 
availability of the drugs at stock during the trial site audit/monitoring. The drugs must be stored under 
the required conditions in a room with an access for the authorized personnel responsible for the drugs 
dispensing only. 
4.8 
Storing and unblinding of randomization codes 
This is an open trial. The Sponsor will keep a list of the randomization codes. The trial sites will be 
provided with the sealed envelopes containing randomization numbers. The envelopes must be 
opened 


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sequentially, from the smaller numbers to bigger ones, to avoid a breach of a randomization principle. 
4.9 
A list of all the data to be recorded in eCRF 
All the data obtained during this clinical trial will be considered to be primary data and subject to 
record in eCRF. 


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5 
Selection and exclusion of the subjects 
5.1 
Inclusion criteria 
The patients who meet all the inclusion criteria listed below will be included in the trial: 
1. 
The Informed Consent Form voluntarily signed by the patient. 
2. 
Men and women at the age of 18 to 45 years old, inclusively. 
3. 
A diagnosis of acute, uncomplicated, inflammatory and infectious condition of the pharynx 
associated with the inflammation and pain in the throat. 
4. 
Manifestation of the first signs of acute, uncomplicated, inflammatory and infectious 
condition of the throat (pharyngitis and/or tonsillitis) not more than 48 hours before the 
inclusion. 
5. 
A baseline total sum of TSS (Tonsillopharyngitis Severity Score) points ≥5. 
6. 
Body temperature measured in the axillary cavity is less than 37.5 °С. 
7. 
Women with childbearing potential should demonstrate a negative pregnancy test result at 
screening (except for the women after surgical sterilization or menopause for more than 2 
years) and use the established contraception methods for at least 3 months before the 
initiation of the trial therapy and 1 month after completion of the trial. 
8. 
Men should use adequate contraception during the trial, since signing of the Informed 
Consent Form and till the trial completion, and for 30 days after the trial completion. 
9. 
Ability to understand the presented information on the clinical trial, readiness to comply 
with the protocol, ability to use the study drugs by oneself and evaluate the symptoms 
according to VAS (visual analogue scale) or other questionnaires according to the protocol. 
5.2 
Non-inclusion criteria 
The patients who comply with at least one of the criteria listed below will not be included: 
1. 
Prior tonsillectomy, tonsillotomy. 
2. 
Chronic conditions of the nasopharynx or oropharynx, ulcerative oral disorders. 
3. 
History of hypersensitivity or allergic reactions to any components of the study drugs or 
local anesthetics. 
4. 
Use of analgesics during less than 12 hours before the trial start and/or impossibility to 
discontinue the analgesics for the trial period. 


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5. 
Use of antibiotics during less than 48 hours before the trial start and/or planned use of 
antibiotics during the trial. 
6. 
Use 
of 
topical 
drugs 
(aerosols, 
gargle 
solutions, 
fast-disintegrating 
tablets/lozenges/pastilles) in the pharynx during less than 12 hours before the trial start 
and/or impossibility to discontinue topical drugs, except for the study drugs, for the trial 
period. 
7. 
Use of the systemic, inhalation, or nasal glucocorticosteroids during 30 days before the trial 
start and/or planned use of the glucocorticosteroids (except for the topical skin drugs) 
during the trial. 
8. 
Impossibility to discontinue other drugs which might influence the trial results, e.g. antiviral 
or prohibited concomitant drugs (see Prohibited concomitant therapy section), for the trial 
period. 
9. 
Signs of a primary bacterial pharyngitis or secondary bacterial infection (including body 
temperature increase above 37.5 °C, purulent pharyngeal pellicles, significant intoxication, 
leukocytosis, neutrocytosis, WBC differential's shift to the left (increase in stab neutrophils, 
presence of younger neutrophils), ESR more than 30 mm/h). 
10. 
Granular pharyngitis. 
11. 
Signs of rhinitis, sinusitis, otitis, eustachitis, laryngitis, tracheitis, bronchitis (such 
conditions require therapy which might influence the trial results). 
12. 
Phenylketonuria. 
13. 
Deficit of saccharase or isomaltase (according to anamnesis data). 
14. 
Glucose-galactose malabsorption (according to anamnesis data). 
15. 
Fructose intolerance. 
16. 
Diabetes mellitus. 
17. 
Glucose-6-phosphate dehydrogenase deficiency (according to anamnesis data). 
18. 
Hemochromatosis. 
19. 
Anemia (Hb less than 120 g/l according to hematology test). 
20. 
Hyperoxaluria. 
21. 
Urolithiasis. 
22. 
Myasthenia. 
23. 
Severe, uncontrolled, cardiovascular condition which, in the Investigator's opinion, preclude 
the patient from participation in the trial, namely: 
a. 
Severe (IV acc. to Canadian Cardiovascular Society) or unstable angina; 
b. 
Decompensated chronic heart failure (NYHA stage IV); 
c. 
Myocardial infarction for the last 6 months; 
d. 
uncontrolled arterial hypertension (BP more than 180/115 mm Hg). 


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24. 
Pregnant and/or breastfeeding women. 
25. 
Participation in other clinical trials at the screening visit or for 30 days before the screening 
visit. 
26. 
Surgical intervention for 30 days before the screening visit or planned surgical treatment 
during the trial (sooner than a follow-up visit is completed), including diagnostic 
procedures or hospital stay. 
27. 
Known or suspected narcotic/alcohol abuse. 
28. 
A suspected low compliance or incapability of the patient to perform the procedures and 
comply with restrictions according to the trial protocol (e.g., due to mental disorders). 
29. 
Any cardiovascular, renal, hepatic, gastrointestinal, endocrine, or nervous disorders, or any 
other conditions/diseases which, in the Investigator's opinion, might inflict harm to the 
patient's health. 
 
5.3 
Exclusion criteria 
5.3.1 
Terms and conditions for the subjects' exclusion from the trial 
The subjects may be excluded from the trial on their own free will at any moment, without giving any 
reason, as well as upon decision of the Investigator or Sponsor in cases when continuation of the 
participation may inflict harm to the patient's health and/or life. In addition, the patient must be 
excluded in the cases listed below: 
1. 
Negative course of the disease with signs of the secondary bacterial infection (including body 
temperature increase above 37.5 °C). 
2. 
The Ethics Committee, regulatory authorities, or Sponsor terminate the trial or participation of 
the specific trial site for any reason. 
3. 
The Investigator's decision to withdraw the patient from the trial in the interests of the patient. 
4. 
Withdrawal of the informed consent (unwillingness of the patient to continue his/her 
participation in the trial). 
5. 
Serious deviation from the trial protocol. 
6. 
Individual intolerance of the study drugs. 
7. 
Clinically significant adverse event or serious adverse event. 
8. 
Patient's non-compliance. 
9. 
False inclusion (e.g., the patient was included in breach of the inclusion/non-inclusion criteria). 
10. 
The patient complies with the non-inclusion criteria during the trial. 
11. 
The patient receives or requires an additional therapy which might influence the trial results or 
patient's safety (see Prohibited concomitant therapy section). 


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12. 
Other conditions or events which, in the Investigator's opinion, require the patient's exclusion 
from the trial. 
5.3.1.1 
Terms and volume of data on the excluded subjects 
In case of trial discontinuation on the subject's free will, the Investigator should make effort to find 
out the reason thereof. In case of trial discontinuation due to AEs/SAEs, the subject should be 
followed-up until the AEs/SAEs are resolved. In case of discontinuation from the trial prematurely, 
the patient should visit the trial site for early discontinuation procedures (as an unscheduled visit); if 
the patient refuses to visit the trial site, he/she should be contacted by phone with recording of all 
available information. 
5.3.2 
Terms and conditions of suspend or discontinuation of the trial therapy 
The patients may stop taking the study drugs according to the protocol or upon withdrawal from the 
trial. 
5.3.3 
Replacement of the excluded subjects 
Replacement of the excluded patients during the trial is not envisaged. 
5.4 
 Acceptable contraception methods 
The patients must follow adequate contraceptive methods throughout the trial as well as within 
30 days after its completion. 
Effective contraception methods include: 
• 
True abstinence; 
• 
Oral contraceptives (combination drugs containing progestogen, or progestogen alone); 
• 
Injectable progestogen; 
• 
Levonorgestrel implants; 
• 
Estrogen-containing vaginal ring; 
• 
Transdermal contraceptive patches; 
• 
Intrauterine device (IUD) or intrauterine system (IUS) meeting the efficacy criteria 
according to Prescribing Information; 
• 
A male partner has been sterile (vasectomy with documented azoospermia) prior to 
inclusion of a woman, provided that he is the only partner of the female patient. For the 
purpose of this definition, "documented" is related to the result of a patient's medical 
examination by the Investigator/responsible person or a patient's past medical history 
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inclusion, obtained during the interview with a patient or from his/her medical records. 
• 
Double barrier method: a condom or an occlusive cap (diaphragm or cervical/vault 
caps) with a spermicide (foam/gel/film/cream/suppository). 
 
Men should use adequate contraception during the trial, since signing of the Informed Consent Form 
and till the trial completion, and for 30 days after the trial completion. 


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6 
Trial therapy 
6.1 
Therapy regimens 
The study drug group (Angal, lozenges [menthol]): 1 lozenge, as needed, up to 6–10 times per day, 
for 4 days or until full recovery  (total TSS ≤ 2) (whichever occurs first during 4 days of therapy). 
A single dose of Angal is 1 lozenge. The lozenges are intended for full dissolution in the oral cavity. 
One lozenge is slowly disintegrating in the mouth. 
The comparator drug group (ANTI-ANGIN® FORMULA, lozenges): 1 lozenge with a not less than 2-
hour interval, up to 6 lozenges per day, for 5 days or until full recovery (total TSS ≤ 2)  (whichever 
occurs first during 5 days of therapy). One dose of ANTI-ANGIN® FORMULA is 1 lozenge (keep in 
the mouth till full dissolution). The lozenges are intended for full dissolution in the oral cavity. One 
lozenge is slowly disintegrating in the mouth. 
6.2 
Allowed and prohibited therapy 
6.2.1 
Allowed prior and concomitant therapy 
All concomitant therapies except for those stated in Section 6.2.2 are allowed. 
6.2.2 
Prohibited prior and concomitant therapy 
The drugs listed below are prohibited for use throughout the trial period: 
1. 
Topical 
drugs 
(aerosols, 
sprays, 
inhalations, 
gargle 
solutions, 
fast-disintegrating 
tablets/lozenges/pastilles) in the pharynx or nose. 
2. 
Systemic, inhalation, or nasal glucocorticosteroids. 
3. 
Systemic or topical (intranasal or pharyngeal) antibacterial drugs. 
4. 
Anti-viral drugs. 
5. 
Immunomodulatory agents. 
6. 
Painkillers or antipyretic agents. 
7. 
Class I antiarrhythmics. 
8. 
Cholinesterase inhibitors (including neostigmine, distigmine, pyridostigmine) and other drugs 
for myasthenia. 
6.3 
Methods to monitor the subjects' compliance with trial procedures 
At every visit after Visit 1, the subjects' compliance will be checked by counting the unused drug and 
analysis of the patient's diaries. It should be noted that the drugs doses stipulated by the protocol are 6 
to 10 (maximum) lozenges per day (Angal), 


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and to 6 lozenges per day with at least 2-hour interval (ANTI-ANGIN® FORMULA). The both drugs 
should be taken when needed (a sore throat). 
In view of the nature of drug intake (when needed), the lower margin of compliance will not be 
evaluated; the number of used lozenges is compared to maximum amounts stated in the protocol for 
the study drug (up to 10 lozenges per day for Angal) or Prescribing Information for the comparator 
drug (up to 6 lozenges per day for ANTI-ANGIN® FORMULA). 


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7 
Efficacy evaluation 
7.1 
List of efficacy parameters 
Primary outcome measure 
The primary outcome measure was the percentage of patients without sore throat after 3 days of 
therapy on Day 4, as evaluated by the Investigator according to the Tonsillopharyngitis Severity 
Score (TSS), in both Angal and ANTI-ANGIN® FORMULA arms. 
Secondary outcome measures 
The secondary outcome measures in the both therapy groups were: 
• 
The frequency of ≥50% total score reduction according to the TSS questionnaire completed by 
the Investigator as compared to the baseline in both Angal and ANTI-ANGIN® FORMULA 
groups at Visit 2 (Day 4). 
• 
Total score reduction according to the TSS questionnaire, as well as a reduction in the 
symptoms (sore throat, difficulty in swallowing, salivation, erythema, and fever) after a 3-day 
therapy, at Visit 2 (Day 4), as compared to the baseline total score. 
• 
A period of time required for disease symptoms relief, determined according to the patient's 
diary (subjective patient's evaluation), but no more than 5 days during the trial—for patients 
who have achieved the corresponding outcome. 
• 
A proportion (%) of patients who fully recovered by Day 4 in Group A and by Day 5 in Group 
B (the outcome of a disease according to the objective evaluation by the Investigator, the total 
score according to the TSS questionnaire ≤2). 
• 
A change in the sore throat intensity by 100 mm VAS (visual analogue scale filled in by the 
patient) at the beginning, after 3 days of therapy, and at the end of treatment in both groups. 
7.2 
Methods and timing for evaluation, recording, and analysis of efficacy parameters 
The methods for efficacy criteria evaluation are described in Section 4.2.3.2. The first endpoint is 
evaluated in the morning at Visit 2 (Day 4, after 3 days of the trial therapy) before the study drugs 
intake. Other efficacy endpoints are evaluated in terms stated in Section 7.1. 


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8 
Safety evaluation 
8.1 
List of safety parameters 
The following parameters will be taken into account for the safety evaluation: 
• 
AEs and/or SAEs rates per trial arms; 
• 
Global tolerance evaluation during the trial by the Investigator and patient; 
• 
Vital signs (heart rate, blood pressure, body temperature, breathing rate); 
• 
ECG parameters; 
• 
Laboratory results. 
8.2 
Methods and timing for evaluation, recording, and analysis of safety parameters 
Safety parameters are evaluated at every planned and unscheduled visit. 
8.3 
Requirements for reporting, registration, and reporting of AEs and intercurrent 
diseases 
8.3.1 
Definitions of adverse events and serious adverse events 
Adverse event (AE) is any adverse medical event identified in a patient or a clinical trial patient after 
the use of the drug, which may or may not have a causal relationship with its usage. Thus, adverse 
event (AE) can represent any adverse symptom (including laboratory deviation from the norm), 
complaint, or disease, for which a temporal causal relation cannot be excluded with the use of 
medicinal (study) product, regardless of the presence or absence of such a relation. 
Serious adverse event (SAE) represents any event, unfavorable from medical perspective, which with 
any dose: 
− 
Resulted in death; 
− 
Is life threatening; 
− 
Results in disability/incapacity to work; 
− 
Is a congenital anomaly or development defect; 
− 
Requires hospitalization or its extension; 
− 
Is significant from medical perspective:  a decision whether expedited reports is feasible in 
other situations (e.g., in case of events important from medical perspective, which are not 
directly 
life-threatening 
for 
a 


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patient, do not result in death or hospitalization, but pose the patient to risk or require 
intervention to prevent one of the above outcomes) shall be made on the basis of medical and 
scientific evaluation. Such cases should be usually considered serious adverse events. 
Adverse drug reaction (ADR) is any adverse event which might have causal relation to the drug in the 
opinion of the Investigator or Sponsor (see Section 8.3.3 below). 
An unexpected adverse reaction is defined as an adverse drug reaction, the nature or severity of which 
is not consistent with the Reference Safety Information (e.g. SmPC, Investigator’s Brochure). The 
term "severity" is used to describe the intensity of a specific event. This term should be distinguished 
from the term "serious". Reports which add significant information on specificity, increase in 
incidence, or severity of the known, already documented serious adverse reactions, constitute the 
unforeseen events. 
Information about side effects already known for this study drug is available in the Investigator's 
Brochure. This information will be included into Patient Information Sheet, and it should be discussed 
with the trial subjects. 
More details are given in Brief Reference Manual for filling in the Serious Adverse Event Report 
Form (to be provided by the Sponsor). 
8.3.2 
Intensity of AE 
The term "severity" is used to describe the intensity of a specific event. This term should be 
distinguished from the term "serious". During the trial, the Investigator will detect adverse events and 
classify them by intensity as follows: 
− 
Mild event: as a rule, is temporary and does not restrict normal daily activities; 
− 
Moderate event: restricts normal daily activities significantly; 
− 
Severe event: impedes normal daily activities in full. 
8.3.3 
Causality with the study drug 
The Investigator will perform evaluation of adverse events after examination of all available data. In 
addition, he/she will perform their repeated evaluation if new information appears. The study drug is 
the drug investigated during the trial, and control drug or placebo used during any phase of this trial. 


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All AEs spontaneously reported by volunteers or observed by the Investigator will be evaluated in 
accordance with the following definitions: 
Suspected: temporal relation between development of clinical event and applied study drug indicates 
possible presence of causality, while other drugs, therapeutic interventions, or baseline states do not 
allow explaining development of this event with sufficient grounds. 
Non-suspected: temporary relation between development of clinical event and used study drug 
indicates for the remote presence of causality, while other drugs, therapeutic interventions, or 
baseline states can be considered with sufficient grounds as explanation for observed event. 
Evaluation of causality is of great significance, and it should be performed for each reported unique 
event and for each study drug, not being the study drug or any other concomitant drug (if appropriate). 
In case of no evaluation of causality available, the Sponsor will consider such events as associated 
with the trial therapy. 
The Investigator must inform LPPV on AEs with suspected causality to the drug which is not a study 
drug or another concomitant drug (produced by Sandoz or other manufacturers), even if those AEs are 
not serious (see Section 8.3.5 for contact information). 
8.3.4 
Documentation on adverse events 
Any AE (not serious or serious), occurring after the subject has provided informed consent specific 
for this trial before completion of the trial, must be documented on the pages intended for adverse 
events in the Individual Case Record Form (ICRF). 
The non-leading questions to the subjects should be used at each trial visit in order to detect AE. AEs 
can be also detected if the subjects report on them themselves during visits or between the visits as 
well as if they are found during examination, by the results of laboratory analyses or other tests. All 
AEs require proper treatment. Actions taken to cure AE should be documented and related to one of 
the following categories: "no action taken", "prescription of the drug (accompanying therapy)", or 
"other treatment". Besides, the actions should be documented, which were undertaken in relation to 
the study drug, and they should be referred to one of the following categories: "no changes", 
"withdrawal", "dose reduced", "dose increased", "therapy suspended", "action is unknown", and "not 
applicable". Concomitant therapy, other treatment methods, or changes of the study drug should be 
determined and documented. 


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The medical conditions/disorders present before the trial therapy initiation are considered to be AEs 
unless they get worsened after the inclusion in the trial. Abnormal laboratory or test results are 
considered to be AEs only if they evoke clinical signs, are clinically significant, or require therapy. 
After detection of AE, it should be followed up until its resolution or until it is recognized as 
permanent. The event outcome should be documented and referred to one of the following categories: 
"event not resolved/did not change", "health status gets worse", "event resolved/subject recovered", 
"event improved/subject recovers", "event resolved/subject recovered with complications", "lethal 
outcome", or "outcome unknown". Evaluation of AE should be performed during each visit (or more 
frequently, in case of any indications) for any changes in severity, suspected association with the 
study drug, interventions undertaken for its treatment, and outcome. 
AE in the interval between signing of informed consent and administration of the first dose 
Any AEs, which occurred in the interval after signing of informed consent specific for this trial and 
before administration of the first dose, should be documented as screening period events. Moreover, 
the results of evaluation of the association with the study drug should be documented as follows: 
"study drug was not administered yet". 
AE after the first dose of the study drug 
The Investigator should follow up all the AEs occurred since the first intake of the drug and during 
the trial, till the last visit of the subject when the event outcome is evaluated for the last time with 
further recording in eCRF. 
SAEs not resolved as at the last visit 
If SAE is not resolved as at the last visit, the Investigator should follow up the subject till SAE 
resolution or stabilization/shift to a permanent stage (for SAEs with a suspected relation to the study 
drugs) or during up to 30 days since the last visit for SAEs without suspected relation to the study 
drugs. 
The Investigator must report on the SAE follow up as per the Reports on SAEs, Section 8.8.5. below. 
SAEs registered after the last visit 
At the last visit, the Investigator should instruct each subject to report on any new SAEs (outside a 
follow-up period according to the protocol) which, in the subject's opinion, might be associated with 
the study drugs. The Investigator must inform recipients on SAR as per the Reports on SAEs, Section 
8.3.5. below. 


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Clinically relevant abnormal laboratory results at the last visit 
The Investigator must document the clinically significant, abnormal laboratory results revealed at the 
last visit as AEs even without any relation with the specific study drug. 
8.3.5 
Reports on SAEs 
The Investigator must immediately (not later than 24 hours since the receipt of data on SAEs) report 
any SAEs even in case the Investigator considers these SAEs not related to the study drugs. 
The Investigator must use Novartis Serious Adverse Event Report Form to report on SAE for initial or 
subsequent reporting. The form should be forwarded by fax or email to LPPV with a copy to a 
manager responsible for the trial (Sponsor/CRO) using the contact information given in a table below. 
The Investigator must forward all the updates/new information in a separate Serious Adverse Event 
Report Form as a follow-up regarding the previously reported SAE. Such information must dwell on 
recovery or continuation of SAE, diagnosis (if any), therapy details (if any), continuation or 
discontinuation of that subject from the trial. 
Repeated episodes, complications, or progression of the initial SAE should be reported as a follow-up 
for the original episode, irrespective of the event time. 
Any new SAE, which is considered as completely unrelated to previously reported one, shall be 
reported as a new and separate event. 
The Investigator should answer any questions from LPPV, CRO, or Sponsor regarding SAEs 
reporting within 24 hours. 
For more detailed information, refer to the Quick Reference Guide for Completing the SAE Form. 
The Investigator should keep the notifications on information delivery to all the recipients in a 
separate file. 
Contact information for SAE reporting 
 
 
 
 
 


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In case of any questions, please contact responsible persons: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notification of the Investigators and the 6-month line listings 
If a serious adverse drug reaction (ADR) is not listed in the reference safety information (e.g., SMPC, 
Investigator's Brochure), the Sponsor may request for an urgent additional information from the 
Investigator for reporting to the health authorities. 
The Sponsor is entitled to, where applicable, forward notifications for the Investigators and the 6-
month line listings of SUSARs (not previously reported) to all the investigators associated with any 
trial of the same study drug. 
The Investigator or CRO (as envisaged in the trial agreement) must submit the notifications for 
Investigators and the 6-month line listings, if applicable, to Local Ethics Committees (LEC)/Ethics 
Councils. CRO must submit the notifications for Investigators and the 6-month line listings, if 
applicable, to the Ethics Council under the Ministry of Health of Russia. 
Reporting to health authorities 


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The Sponsor shall submit all the reports to relevant regulatory authorities within the specified 
timelines. 
Training of investigators 
By signing the trial protocol, the Principal Investigator confirms that he/she has passed the training 
held by CRO and got familiarized with the Sponsor's requirements and his/her responsibilities on 
reporting the AEs/SAEs and pregnancies as defined in the trial protocol. 
8.4 
Pregnancy cases 
The Investigator must immediately (not later than 24 hours since the receipt of information on 
pregnancy) inform the Sponsor/LPPV with a copy to a manager responsible for the trial 
(Sponsor/CRO) as described in Section 8.3.5 on all the pregnancy cases occurred during the trial. 
Pregnancy reports are registered since the first intake of the study drug only. 
The Investigator must exclude the pregnant subject from the trial immediately; this pregnancy should 
be monitored to determine its termination, including spontaneous or planned abortion, details on 
delivery and on presence or absence of any development defects, congenital anomalies, or 
complications in infant's mother and/or in a newborn. 
If the Investigator becomes aware of pregnancy of the sex partner of male participant of the trial, 
which was started with high probability during participation of this man in the trial (i.e., during 
exposure of the child's father organism to the drug), these pregnancy cases should be also reported 
after receipt of informed consent from (expecting) mother. 
The pregnancy cases should be registered in the Clinical Trial Pregnancy Form. Additional 
information about pregnancy should be registered in the same form. Moreover, it must include 
possible relation of any termination of pregnancy to use of the study drug. 
Any SAE noted during pregnancy should be reported using SAE Report Form as described in 
Section 8.3.4. 
For more information, see the Clinical Trial Pregnancy Quick Reference Guide; Novartis document. 
8.5 
Quality complaints 
In case of quality complaints (technical or transportation claims), the Investigator must report to the 
Sponsor thereon within 24 hours after receipt of information as described in Appendix 2. Any AE 
associated with the quality complaints shall be documented and reported as described in 
Sections 8.3.4 and 8.3.5. 


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8.6 
Special cases 
Special cases may be serious or non-serious (see below) and must be reported as AEs pursuant to 
Sections 8.3.4 and 8.3.5 even in absence of other AEs associated with the special cases. 
A special case scenario 
The Investigator must inform LPPV 
Exposure during breastfeeding 
Х 
Intentional overdose by the patient (including the 
suicide attempts which are always considered to 
be serious) 
Only if associated with SAE 
Drug interactions 
Only if associated with SAE 
Withdrawal response/syndrome 
Only if associated with SAE 
Drug dependency, misuse, abuse, or addiction 
(always serious) 
Х 
Suspected transmission of infectious agents 
(always serious) 
Х 
Death (always serious even without other events) 
Х 
8.7 
Information verification 
Verification of information between a safety database of the Sponsor and a clinical database stored in 
CRO will be performed at the end of the trial according to a verification plan by comparison of the 
relevant summary tables from the both databases. 
During data processing, eCRF/information in the clinical database will be reviewed for potentially 
unreported SAEs. Any potential SAE requires an exact match in the following parameters between the 
clinical database and safety database: trial number, center number, subject number, randomization 
number, study drug, degree of severity, date of death (if applicable), and causality according to the 
Investigator's evaluation. All other parameters must be credible and consistent from medical 
perspective. A thorough verification of information must be performed for every event subject to 
reporting as well as any other events of special interest (if applicable) considered to be related to the 
study drug, including dates of the drug use, outcome, medical history, and concomitant therapy. 


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9 
Statistics 
9.1 
Description of the statistical methods to be used including the terms for every planned 
interim analysis 
Statistical analysis will be performed using R Project specialized software. 
The continuous (quantitative) data will be presented as a number of observations, arithmetic mean, 
confidence interval (CI) 95% for the mean (unless stated otherwise), standard deviation (SD), median, 
interquartile range (IQR), minimum, and maximum. 
The serial, categorical, and qualitative data will be presented as absolute incidences (number of 
observations), relative incidences (%), and CI 95% (unless otherwise stated). 
The concomitant diseases and AEs will be coded using MedDRA terms. 
This section contains a brief description of the planned analysis. Full analysis will be presented in the 
statistical analysis plan. 
9.1.1 
Demographic and other baseline data (group comparability for the analysis) 
All the data obtained in the groups before the trial therapy initiation (demographic, laboratory, 
instrumental, and physical examinations data, vital signs, etc.) will be compared between the groups 
to determine the groups' comparability for analysis. 
The Fisher's exact test and chi-square will be used to compare the qualitative and serial data, while 
the t-test or the Mann–Whitney test will be used for the quantitative data (depending on the 
quantitative data distribution). 
9.1.2. Analysis of the primary efficacy endpoint 
The primary outcome measure in this trial was the proportion of patients without sore throat after 3 
days of therapy, on Day 4, as evaluated by the Investigator according to the Tonsillopharyngitis 
Severity Score (TSS), in both Angal and ANTI-ANGIN® FORMULA arms. 
A null hypothesis of this trial assumes that Angal, the study drug, is less effective than ANTI-
ANGIN® FORMULA, the comparator drug. An alternative hypothesis of this trial assumes that 
Angal, the study drug, is not less effective than ANTI-ANGIN® FORMULA, the comparator drug. 


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14.5% is chosen as a non-inferiority margin (see Section 9.2 for a justification) based on the results of 
a randomized, placebo-controlled trial of a similar drug. 
The group comparison will be carried out using the Fisher's exact test (one-sided test, in connection 
with the null hypothesis of non-inferiority). 
For the proportion difference, the 90% confidence interval (CI) will be calculated according to the 
procedure described in Newcombe, Robert G. "Interval Estimation for the Difference Between 
Independent Proportions: Comparison of Eleven Methods," Statistics in Medicine, 17, 873-890 
(1998). 
Thus, the non-inferiority will be confirmed if the limit of the two-sided 90% confidence interval for 
the difference in the proportions will be 14.5% or lower. 
A primary endpoint analysis will be conducted both for the ITT (main analysis) and PP populations 
(additional analysis). 
9.1.3 
Analysis of the secondary efficacy endpoints 
• 
The frequency of ≥50% total score reduction according to the TSS questionnaire 
completed by the Investigator as compared to the baseline in both Angal and ANTI-
ANGIN® FORMULA groups at Visit 2 (Day 4). 
• 
Total score reduction according to the TSS questionnaire, as well as a reduction in the 
symptoms (sore throat, difficulty in swallowing, salivation, erythema, and fever) after a 3-
day therapy, at Visit 2 (Day 4), as compared to the baseline total score. 
• 
A period of time required for disease symptoms relief, determined according to the 
patient's diary (subjective patient's evaluation), but no more than 5 days during the trial—
for patients who have achieved the corresponding outcome. 
• 
A proportion (%) of patients who fully recovered by Day 4 in Group A and by Day 5 in 
Group B (the outcome of a disease according to the objective evaluation by the 
Investigator, the total score according to the TSS questionnaire ≤2). 
• 
A change in the sore throat intensity by 100 mm VAS (visual analogue scale filled in by 
the patient) at the beginning, after 3 days of therapy, and at the end of treatment in both 
groups. 
The following statistical analysis methods are stipulated for the secondary efficacy endpoints: 
• 
The frequency of ≥50% total score reduction by the TSS questionnaire completed by the 
Investigator relative to baseline in both Angal and ANTI-ANGIN® FORMULA arms at 
Visit 2 (Day 4)—the response frequencies will be compared in each time point using the 
Fisher's exact test. 


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• 
Total score reduction by the TSS questionnaire, as well as reduction in symptoms (sore 
throat, difficulty in swallowing, salivation, erythema and fever) after 3-day therapy, at 
Visit 2 (Day 4), relative to baseline total score—the between-arm comparison will be 
carried out using the Mann–Whitney test due to non-symmetrical nature of the scores 
distribution in the TSS scale. 
• 
A period of time required for the symptoms resolution defined by the patient's diary 
(subjective patient's evaluation), but not more than 5 days within the trial (for patients 
who achieved the relevant outcome)—the between-arm comparison will be carried out 
using t-test or the Mann–Whitney test depending on the distribution character. The 
survival will not be evaluated due to low duration of the trial. 
• 
The proportion (%) of patients who fully recovered on Day 4 in Group A and on Day 5 in 
Group B (disease outcome according to the objective evaluation by the Investigator, the 
total score by the TSS questionnaire ≤ 2)—the between-arm comparison will be carried 
out using the Fisher's exact test. 
• 
A change in the sore throat intensity by 100 mm VAS (visual analogue scale filled in by 
the patient) at the beginning, after 3 days of therapy, and at the end of treatment in both 
groups—the between-arm comparison will be carried out using the t-test. 
A secondary endpoint analysis will be conducted both for the ITT (main analysis) and PP populations 
(additional analysis). 
9.1.4 
Safety parameters analysis 
A descriptive part of the safety analysis will include an evaluation of incidences and two-sided CI 
95% for the following parameters in every trial group: 
• 
AEs: the incidence in total and for separate categories (according to MedDRA), for the 
trial and by groups; 
• 
 SAEs: the incidence in total and for separate categories (according to MedDRA), for the 
trial and by groups; 
• 
Incidence of clinically significant changes of the physical examination results by visits 
and groups; 
• 
Incidence of clinically significant changes of the laboratory results by visits and groups; 
• 
Incidence of clinically significant changes of the vital signs (body temperature, BP, pulse 
rate, HR) by visits and groups; 
• 
Incidence of clinically significant changes of the ECG parameters by visits and groups; 
• 
Global tolerance evaluation during the trial by the Investigator and patient; 


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The Fisher's exact test will be used to compare incidences between the groups, and chi-square will be 
used to compare the global therapy tolerability by the Investigator and patient. The McNemar's test 
will be used to evaluate for the dynamic changes during the trial (before–after) for all the repeatedly 
evaluated incidences in every group. 
In addition to the incidence, all the quantitative safety parameters will be presented in a table form 
(laboratory data, vital signs, ECG) by visits and groups. The difference will be evaluated using 2-way-
ANOVA (group and visit numbers will serve as the relevant factors). The post-hoc criteria will be 
used in case of significant difference. 
Safety analysis will be performed on the safety population. 
9.2 
Planned number of subjects 
A statistical objective of the trial will be an evidence of non-inferior therapeutic efficacy and safety of 
the study drug Angal comparing to the drug ANTI-ANGIN® FORMULA in the treatment of acute 
infectious and inflammatory diseases of the pharynx. Justification of a non-inferiority margin is based 
on the results of a placebo-controlled trial of pastilles with chlorhexidine and lidocaine conducted by 
 [Kris De Ceulaer. A summary of a clinical trial proves that 
chlorhexidine/lidocaine lozenges are effective and safe. 11-8-2015]. 
This trial demonstrated absence of a sore throat (a TSS subscale) 3 days after the therapy initiation, on 
Day 4, in 37.5% patients in the trial arm and 63.1% patients in the placebo arm. 
Table 2. Answers distribution results regarding questions on a sore throat at baseline and Day 4 
 
Baseline visit 
D4 
N 
Product 
N=106 
Placebo 
N=103 
Product 
N=106 
Placebo 
N=103 
Sore throat 
 
 
 
 
Unknown 
0 
0 
2 (N=104) 
0 
Absent 
0 (0%) 
0 (0%) 
65 (62.5%) 
38 (36.9%) 
Mild 
3 (2.8%) 
3 (2.9%) 
27 (26.0%) 
45 (43.7%) 
Moderate 
77 (72.6%) 
75 (72.8%) 
11 (10.6%) 
19 (18.4%) 
Severe 
26 (24.5%) 
25 (24.3%) 
1 (1.0%) 
1 (1.0%) 
p 
1.0000 
0.0016 
Therefore, a lower limit of CI boundary may be calculated for the difference in sore throat presence 
after 3 days of therapy, taking into account 104 participants and 103 patients. 
In view of the considered nosology and absence of significant factors requiring a conservative 
approach 
for 
determination 
of 
the 


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non-inferiority margin, for this purpose we can use a two-sided CI 90%. To calculate a two-sided CI 
90%, a method described by Newcombe, Robert G. was used "Interval Estimation for the Difference 
Between Independent Proportions: Comparison of Eleven Methods," Statistics in Medicine, 17, 873-
890 (1998). CI 90% will amount to 14.56–36.66%, i.e., the lower limit will correspond to one-sided 
CI 95%. Therefore, a margin of 14.5% is considered to be justified. 
 
NCSS 8.0 Two Proportions Report 
Dataset Untitled 
Zero Adjustment Method: None 
Note: Exact tests and c.i.'s were not run because total count > 50 (specified under 'Reports' tab). 
Table Section 
 
 
 
 
N1 
N2 
M1 
M2 
N 
A 
B 
C 
D 
(A+C) 
(B+D) 
(A+B) 
(C+D) 
(N1+N2) 
65 
39 
38 
65 
103 
104 
104 
103 
207 
Confidence Intervals of Difference (P1-P2) 
Interval 
Estimated 
Confidence 
Confidence 
Method 
Value 
Limit 
Limit 
Chi-Square (Pearson) 
0.2561 
0.1456 
0.3666 
 
(The calculation results are presented in the language of the original source, i.e., from NCSS 8 
statistical program). 
 
• 
This is a non-inferiority trial; therefore, a non-inferiority margin for the primary 
endpoint should be justified and amount to not more than 14.5%. 
• 
An expected rate of positive response to therapy (absence of a sore throat as an efficacy 
measure) in a comparator drug arm is 63%. 
• 
An expected rate of positive response to therapy (absence of a sore throat as an efficacy 
measure) in a study drug arm is 65% (chosen within the tested hypothesis and based on 
the sample size and expected positive response). 
• 
A one-sided type I error (α) = 2.5 % (0.025) 
• 
A type II error (β) = 20% (0.2), which corresponds to 80% power. 
• 
Expected discontinuation from the trial will amount to 10% during the treatment. 
 
The tested hypotheses are worded as follows: 
1. 
Null hypothesis (H0): Difference in the primary endpoint achievement incidence while 
using Angal, the study drug, and ANTI-ANGIN® FORMULA, the original drug, for 
treatment 
of 
acute 
infectious 
and 


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inflammatory pharyngeal diseases will exceed 14.5% in favor of ANTI-ANGIN® 
FORMULA: 
 
H0:p1 – p2 ≤ –0.145 
 
2. 
Alternative hypothesis (HA): Difference in the primary endpoint achievement incidence 
while using Angal, the study drug, and ANTI-ANGIN® FORMULA, the original drug, 
for treatment of acute infectious and inflammatory pharyngeal diseases will not exceed 
14.5% in favor of ANTI-ANGIN® FORMULA 
 
HA:p1 – p2 > –0.145 
 
Where p1 and p2 is the primary endpoint achievement incidence while using Angal, the study drug, 
and ANTI-ANGIN® FORMULA, the original drug, respectively. 
To calculate a sample size in every group, one can use a formula presented by Chow S, Shao J, Wang 
H. 2008. Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & Hall/CRC Biostatistics 
Series. page 90: 
 
(
)
(
)
(
)
2
2
1
1
1
2
2
2
1
1
1






−
−
+
×
−
×
+
−
×
=
−
−
δ
β
α
p
p
z
z
p
p
p
p
n
 
 
where: 
n = Size of one group; 
z = Normal distribution function at the set levels of α and β; 
δ = Non-inferiority margin; 
p1 = Expected proportion in Angal group; 
p2 = Expected proportion in ANTI-ANGIN® FORMULA group. 
Substituting the above data into this formula, we obtain a minimal number of patients in every group 
without account for withdrawal: 128 patient completed the trial (total 256 patients). 
In view of the expected discontinuation from the trial during the therapy of 10%, not less than 280 
patients are required for randomization (140 patients in each group). 
The calculation results by the above formula were also checked using nQuery, a validated program 
(see below), and considered to be identical. 


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9.3 
Applicable significance level 
All statistical analyses in this trial will be conducted at 95% significance level (a threshold p value for 
confirmation of statistical significance is below 0.05), except for the primary endpoint where an one-
sided statistical criterion will be used with 97.5% significance level (a threshold p value is below 
0.025). The two-sided statistical criteria will be used for all other parameters. 
For the primary endpoint evaluation, 90% CI will be calculated for the proportions difference with 
further evaluation of its lower boundary limit. 
9.4 
Trial termination criteria 
The trial may be terminated under conditions described in Section 4.6 of this protocol. 
9.5 
Accounting for missed, unanalyzable, and questionable data 
During the monitoring visits to the trial sites, the clinical trial specialists (monitors) authorized by the 
Sponsor will analyze eCRFs for the data completeness. In the case of absence of data on CRFs and 
availability of relevant information in the primary documentation, questions for investigators and 
regulations to address inconsistencies will be formulated. At the database check, the expert in 
statistics authorized by the Sponsor and the data control and processing managers will analyze the 
trial results for questionable, missed, and unanalyzable data, which might be the basis for the 
questions for investigators. If possible, the investigators will eliminate the errors identified in CRFs 
and inform the Principal Investigator and authorized representatives of the Sponsor hereof. In case the 
identified data errors cannot be eliminated after the completion of the patients participation in the trial, 
an analysis of the resulting parameter sensitivity to questionable data will be conducted in the 
statistical analysis. 


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Information about the missed, questionable, and unanalyzable data will be summarized in the final 
clinical trial report. 
The main analysis for the primary endpoint will be conducted without replacement for the missed, 
questionable, or unanalyzable data. An additional analysis will be conducted with the data 
replacement (last observation carried forward); in this case, the last known TSS score will be carried 
to all subsequent control points. 
All other data will be analyzed based on actually available information only, without data 
replacement. 
9.6 
Procedures for reporting any deviations from the original statistical plan 
All deviations from an initial statistical plan must be described and justified in a protocol amendment 
and/or a final trial report (in the last case, a statistical analysis plan developed before the start of a 
final statistical analysis must contain a list of those deviations with justification for the reasons 
thereof). 
9.7 
Selection of subjects for analysis 
The following data sets will be used for analysis: 
• 
The intention-to-treat (ITT) population: all randomized subjects who have received at least one 
dose of the study drug/placebo and have completed at least one visit aimed at evaluation of the 
efficacy parameters (i.e., at least all the procedures of Visit 1). 
According to the ICH E9 requirements, the ITT population will be considered to be a population for 
statistical analysis in the equivalence trials (including non-inferiority trials). 
• 
The per protocol (PP) population: all randomized subjects who have completed participation in 
the trial in accordance with the protocol (have completed the prescribed period of treatment and 
follow-up without significant deviations from the protocol). 
• 
The safety population (safety): all randomized subjects who received at least one dose of the 
trial/reference drug and have completed at least one visit to the evaluation of the parameters of 
safety (i.e., at least all the procedures of Visit 1). As distinct from ITT population, the safety 
population will be analyzed depending on actually received treatment (not only prescribed) (in 
case of difference between the prescribed and received therapies). 


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9.8. 
Interim analysis 
An interim analysis may be conducted by the Sponsor's decision after receipt of efficacy data for 
Angal and ANTI-ANGIN® FORMULA after 3 days of therapy, on Day 4, for at least 100 patients in 
every arm. The interim analysis includes demographic data, data of anamnesis and concomitant 
therapy, available data on efficacy and safety of Angal and ANTI-ANGIN® FORMULA drugs. 


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10 
Direct access to primary data/documents 
Primary data represent entire information contained in original records and certified copies regarding 
clinical data, observations, and other measures within the trial scope and which is required for 
reconstruction and evaluation of the trial. The investigator must cooperate for the purposes of 
monitoring, audit(s), expert evaluation by the Ethics Council and regulatory authorities and provide 
the access to the primary data/records. 
The primary data must be stored in a proper quality throughout the time stipulated for by the local and 
international laws, as well as written contracts with the Sponsor company. For each subject included, 
the Investigator must note in the primary records the fact of such participation as well as the following 
data: an individual identification code, personal data (full name, address), dates of the drug intake, 
vital signs, any AEs, trial completion dates, the main reasons for discontinuation (if applicable). 
The Investigator is obliged to provide direct access to the primary data and documents for the clinical 
trial specialists and/or authorized representatives (CRO) of the Sponsor, competent bodies' auditors, 
representatives of the insurance companies, Ethics Committees. 


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11 
Quality control and assurance 
11.1 
Trial monitoring and quality control 
Regular visits by a clinical trial specialist (Monitor), on request of the Sponsor and according to 
SOPs, before initiation, throughout and upon completion of the trial contribute to a successful trial 
conduct and accurate data collection, timely detection of errors, proper documenting of the trial 
process, protection of the subjects' rights, and consistence with the principles of ICH GCP, 
Declaration of Helsinki, international and Russian laws. Routine trial monitoring includes: 
• 
Confirmation for the proper conduct and documenting of the informed consent receipt, 
screening, and inclusion of the subjects in the trial. 
• 
Verification of the data in eCRF and primary medical documents. 
• 
Confirmation for documenting and timely reporting of ARs during the trial. 
• 
Confirmation for compliance of the trial site personnel with the requirements for 
diagnostic and therapeutic procedures stipulated by the protocol. 
• 
Confirmation for documenting the shipments, storage, distribution, and utilization of the 
study drug/placebo and trial materials. 
• 
Confirmation for competence of the trial site personnel and external laboratories needed 
for the trial conduct. 
• 
Confirmation for compliance of the diagnostic and laboratory equipment with the safe use 
requirements during the trial. 
• 
Confirmation for cooperation of the Investigator with the local Ethics Committee 
regarding the trial safety and introduction of the protocol amendments agreed upon by the 
Sponsor. 
Provision of a quality control of the trial results by the Sponsor's authorized persons or representatives 
who keep a trial electronic database, reveal for any inconsistence, data imputed by error, or missing 
data during the cross check of all eCRFs. In case of any questions or necessity of clarification, a 
special form (a data clarification request) should be forwarded to the Investigator and satisfied in 
writing during 7 days since the receipt thereof. 
In accordance with the requirements of the legislation, the Sponsor or authorized federal authorities 
have 
the 
right 
to 
inspect 
(audit) 
the 


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logistical support and documentation on the trial. The Investigator is obliged to provide direct access 
to documents and all relevant information to the authorized persons for the audit or inspection. 
11.2 
Amendments to the protocol 
The investigators' signatures on a signature list of the protocol mean a written consent to perform a 
trial in accordance with this protocol. During the trial, the trial materials may be amended and 
appended. Such changes and additions are considered to be amendments. 
A protocol amendment is a written description of changes or formal clarification of the clinical trial 
protocol wordings. The amendments may be significant and insignificant. Any protocol amendment, 
before making effective, must be approved according to the established procedure and SOPs of the 
Sponsor, regulatory authorities, independent Ethics Committees (under the Ministry of Health of 
Russia and local ones), and signed by the Investigator. 
Order of the Ministry of Health of Russia On Approval of a Review Procedure of a Message on 
Necessity to Introduce Amendments to a Protocol of the Clinical Trial of the Drug No. 775 of 
August 31, 2010 contains a list of significant/insignificant amendments and a procedure of submission 
thereof for the expert evaluation. 
The protocol amendments are significant if they may influence objectives, organization, methods of 
the trial, statistical methods of data processing, and patients' safety measures during the trial. 
The protocol amendments are insignificant if they may not influence the objectives, organization, 
methods of the trial, statistical methods of data processing, and measures for patients' safety during 
the trial. 
In case of necessity to introduce changes into this protocol, the Sponsor shall submit a message on 
necessity to introduce amendments to a clinical trial protocol to the Ministry of Health of Russia. The 
Ministry of Health of Russia shall consider the submitted documents and decide on approval or 
refusal to the introduction of changes. The protocol amendments must be stored together with the 
initial protocol version. A title page of the protocol must contain a number and date of the 
amendments. 
11.3 
Protocol deviations 
Protocol deviation is intended deviation from approved protocol. 
Serious protocol deviation is a deviation, which may, according to the estimate by the Investigator or 
a 
person 
assigned 
by 
the 
Investigator, 
result 
into 


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withdrawal of the subject from the trial or withdrawal of his/her data from clinical and/or statistical 
parts of the trial. The deviations not referred to as serious ones shall be considered minor protocol 
deviations. 
Serious protocol deviations should be reported as soon as possible to the Sponsor by the clinical 
center staff and/or CRO and Monitor (if he/she is in the center). The Sponsor can propose to reclassify 
the protocol deviation (minor into serious and vice versa) based on the estimate. In such a case, the 
classification performed by the Sponsor shall prevail and must be communication to CRO together 
with written rationale. The Sponsor must be informed of minor protocol deviations within 10 business 
days but before commencement of the next clinical period of the trial or before commencement of a 
clinical phase/statistical phase. 
 An exception is represented with minor protocol deviations, which can be included in the draft report 
on the trial: 
• 
Logistic deviations (in time from the planned blood sampling schedule; follow-up visit 
outranged from the time limits set up in the protocol due to plans/schedule of the 
participant etc.). 
• 
Administrative deviations (e.g., change of the name). 
In case of enrollment of the fewer number of subjects compared to that planned, CRO should inform 
the Sponsor who might approve of that. This should not be considered to be a protocol deviation. 
Notification and reporting of deviations from the protocol shall be submitted to the regulatory 
authorities 
and 
relevant 
Ethical 
Committees 
in 
compliance 
with 
the 
applicable 
requirements/instructions/laws. 
Procedure for documentation of protocol deviations 
The Investigator or a person assigned by the Investigator must document and explain any deviation 
from the approved protocol. Notification of the Sponsor on protocol deviation can be transferred 
verbally in exceptional cases (if immediate action/notification is required), which must be followed 
with written documenting (e.g., via email; updates on the trial period). All protocol deviations must be 
described in the final report on the trial. 


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12 
Ethics 
12.1 
General provisions 
This trial will be conducted in accordance with the Declaration of Helsinki of the World Medical 
Association "Guidelines for Biomedical Research Involving Human Subjects" of 1964 as amended; 
the Russian National Standard Good Clinical Practice, GOST R 52379-2005 of September 25, 2005 
adopted by Order of the Ministry of Health of the Russian Federation On Approval of the Good 
Clinical Practice Rules No. 200n of April 1, 2016, Federal Law of the Russian Federation 
On Circulation of Medicines No. 61-FZ of April 12, 2010 (as amended), as well as guidelines of the 
International Conference on Harmonization, including E6 Good Clinical Practice (ICH E6 GCP). 
12.2 
The informed consent receipt procedure 
Before the inclusion, a subject is provided with written information and verbal clarification on 
objectives, goals, and methods of the trial, as well as expected benefit and possible risks associated 
with the participation in the trial. Besides, the subjects must be informed on voluntary nature of the 
participation in the trial and their rights to refuse to participate at any moment without influence on 
quality of the provided medical care. While a subject is not obliged to report his/her reasons to 
terminate his/her participation in the trial, the Investigator should try to find out the reasons without 
violating the subject's rights. The subject's consent must be obtained before initiation of any of the 
trial procedures. 
Processing of the data gathered during the trial is performed with the maintenance of confidentiality 
of personal data. The subjects should be made aware of the goals of the planned computed data 
processing and publication terms (e.g., on medical conferences, in magazine articles, and other 
publicly open sources), when the data is presented in summary not allowing for the subjects 
identification. 
Subjects should be made aware that the authorized representatives of health authorities and of the 
Sponsor will have access to their confidential health information for the purpose of monitoring, 
inspection, and audit. The subjects must receive guarantees of the strict confidentiality and non-
disclosure of all personally identifiable information. 
An Informed Consent Form (a patient information sheet) should be filled in in duplicates, signed, and 
dated by the patient and Investigator in their own hands. One copy of the signed Informed Consent 
Form 
should 
be 
kept 
in 
the 


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Investigator's file, the other copy should be given to the subject. 
12.3 
Confidentiality and identification of the trial subjects 
Personally identifiable information will be kept confidential in observance of the right to privacy and 
confidentiality protection according to the applicable laws. Personally identifiable information will be 
kept confidential and may be disclosed only to the extent required by law. On publication of the trial 
results, confidentiality of the personally identifiable information will be maintained. 
12.4 
Enrollment of subjects from the vulnerable and special populations 
The inclusion/non-inclusion criteria do not envisage for participation of the subjects from the 
vulnerable populations. 
Special populations in this trial include women with childbearing potential who, according to the 
inclusion/non-inclusion criteria, may participate only upon their consent to use effective contraception 
during the trial which is stated in the patient information sheet and confirmed by signing of the 
Informed Consent Form. 


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13 
Data processing and record keeping 
All the trial relevant records and documents of the trial site, including those contained in the 
Investigator's file (eCRFs, Informed Consent Forms, logbooks, subject accounting sheets, etc.), as 
well as primary medical documentation of the subjects must be stored for 15 years after the trial 
completion. The trial Sponsor must control for storage and availability of all the trial site materials 
during a life cycle of the study drug. Archival data may be stored as photocopies, as well as on the 
optical or electronic data storage devices. The Principal Investigator must inform the Sponsor 
immediately on the unintentional damage/destruction as well as change of the storage place of the 
archival data from the clinical trial. A targeted destruction of the archival data may be performed only 
upon a written permission  of the trial Sponsor. As far as the subjects perform visits to the trial sites 
and the Investigator fills in the eCRFs, the authorized monitors of the Sponsor will verify the data in 
eCRFs and primary documents. In case of accurate and proper fill in of eCRFs, the Monitor shall 
retrieve the original eCRFs and forward them to the Sponsor while the copies of eCRFs are left at the 
trial site. In case of any questions arising during the eCRFs data check on part of a data control 
manager and/or a biostatistics specialist, all the clarifications and changes will be documented by 
creating a special form (a data clarification request). Answers for those questions, filled in, signed, 
and dated by the Investigator, shall be checked by the Monitor; in case of satisfaction, the Monitor 
shall retrieve the original forms while the copies thereof are left at the trial site. The Investigator must 
provide the information in confirmation of timely enrollment of the subjects according to the protocol 
criteria. 
The trial must be conducted in accordance with the protocol and applicable Sponsor's SOPs. If the 
protocol needs to be changed, one should follow a procedure described in Section 11.2 of this 
protocol. 
The Investigator must fill in all the primary medical documents and CRFs for all the included 
subjects. 
The Investigator is responsible for the complete and accurate filling of the CRFs. All the data entered 
in CRFs must be also recorded in subject's medical records in printed form or in the form of records 
made by the Investigator or another authorized person of the trial site. 
The CRFs, in accordance with the primary documents, should contain all significant information on 
the subject's participation in the trial. Besides, CRFs should contain data on the trial completion by the 
subject. The CRF must be filled in not later than 5 days after the subject's visit to the trial site. 


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The CRF must be filled in in a distinct, readable handwriting by a black pen. The errors must not be 
corrected over the entry, or erased, or removed with the correction fluid. An error must be 
strikethrough, with the correct data written on top with a signature, date, and initials of the 
Investigator. All the missing data must be explained in eCRF, containing a special mark field (check 
in the box) to confirm for the data omission. If necessary, the reasons for data omission may be 
explained in eCRF on a comment page with reference to the relevant page. The eCRFs must be signed 
by the Investigator. Such signatures confirm for the data reliability. 
All information relating to the trial and data collected are strictly confidential. The Investigator may 
disclose the trial information to the parties not directly involved in the trial only upon Sponsor's 
permission. 
A final report containing statistical and clinical reports is compiled after a database lock and 
completion of statistical processing of the trial results. A final report should be signed by the Principal 
Investigator of the trial site to confirm for the results and conclusions, and sealed with the institution's 
seal. 


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14 
Finance and insurance 
14.1 
Trial financing 
The trial is financed by the Sponsor through CRO. The relevant agreements will be concluded 
between CRO and every trial site before the trial initiation. 
14.2 
Trial subjects insurance 
The Sponsor must provide for insurance of health and life for the trial subjects. The patients will be 
reimbursed in case of harm, a threat to life or health resulted from the study drug or comparator drug 
use according to the applicable law. 
 


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Confidential 
15 
Publications 
15.1 
General provisions 
The information contained in this document is the property of the Sponsor, and its transfer to third 
parties is allowed only with the written permission of the Sponsor. This information may be accessed 
only by the investigators and the trial site personnel, members of the independent Ethics Committee, 
or health authorities responsible for the clinical trial control. Information about the trial, to the extent 
necessary to make a decision about provision of consent to participation, shall be provided to the 
volunteers, whom the Investigator plans to include into the trial. 
15.2 
Publication and use of the trial results 
The exclusive rights for this trial results belong to the trial Sponsor. No data from this trial may be 
presented or published without a prior written permission of the Sponsor. 


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16 
Appendices 
16.1 
Appendix 1. Quality complaints 
Definitions 
Quality complaints are the complaints to the study drug or reference drug and include: 
• 
Technical complaints are the complaints associated with drug/medical device quality and 
include the following: 
Any defect in quality and/or effectiveness, e.g., change of appearance, change of quantity, 
damaged tablets/capsules, presence of foreign matters. 
Any defect of containers and external package, e.g., change of the surface, container leakage, 
broken syringe/piston, missing components, fault of apparatus. 
Any breach in the label, e.g., missing or illegible label. 
Any falsification of the drug or apparatus, e.g., a confusion of drug, its falsification or 
substitution is suspected. 
• 
Transportation complaints are the claims associated with transportation of drugs and include 
damage of shipping carton box, damage of secondary package during receipt of goods, missing 
drug in the package, unsuitable transportation conditions. 
Process 
If any of the above quality complaints is found or received, the filled out quality complaint report 
form should be sent to the Sponsor (clinical trial manager) within 24 hours. Local monitor of the 
corresponding trial must be informed concurrently about the complaint. If possible, a picture of 
damaged material must be attached to the report. The suffered/damaged material must be retained and 
kept safe in accordance with the storage conditions indicated on the label and/or returned to the 
Sponsor upon Sponsor's request. 
 


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Confidential 
16.2 Appendix 2. TSS (Tonsillopharyngitis Severity Score) questionnaire 
 
TE_004_ANG_LOZ 
TONSILLOPHARYNGITIS SEVERITY SCORE (TSS) 
PATIENT __________________ 
 
Visit* 
Evaluation point 
Discomfort severity* 
SORE THROAT 
DIFFICULTY IN 
SWALLOWING 
SALIVATION 
PHARYNGEAL MUCOSA 
HYPEREMIA 
BODY TEMPERATURE 
INCREASE** 
VISIT 1 
BASELINE 
no symptom 
insignificant symptom 
moderate symptom 
significant symptom 
VISIT 2 
AFTER 3 DAYS OF 
THERAPY 
evaluation before the first 
intake of the study drug on 
Day 4 
no symptom 
insignificant symptom 
moderate symptom 
significant symptom 
VISIT 2/3 
DISEASE OUTCOME* 
no symptom 
insignificant symptom 
moderate symptom 
significant symptom 
* To be filled in by the investigator at a Visit. Disease outcome applicable if TSS>2 after 3 days of therapy 
 
Answers rate in points 
** The axillary body temperature increase is rated as follows: 
0 = no symptom; 
1 = insignificant symptom; 
2 = moderate symptom; 
3 = significant symptom. 
0 = <37.5 °С 
1 = 37.5 to <38.5 °С 
2 = 38.5 to <39.5 °С 
3 = ≥ 39.5 °С 
 
Investigator (Full name/Signature) ________________________________________________________/________________________________________________________ Date _________________________ 
 
 
Version 1.0 of September 2, 2016 in Russian, compiled based on the final version of November 21, 2005 in German. 
® AodSUgg. АС 


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16.3 
Appendix 3. The patient's diary 
TE_004_ANG_LOZ 
THE PATIENT'S DIARY 
PATIENT __________________ 
PATIENT COUNSELING INFORMATION 
DEAR PATIENT, 
This is a patient's diary. Please read the instructions for filling-in carefully. In case of any questions, feel free to ask the Investigator. 
You are participating in a clinical trial of efficacy and safety of Angal, lozenges with a menthol taste, compared to ANTI-ANGIN® FORMULA, a similar drug by action and 
composition, for therapy of acute, uncomplicated throat conditions. 
The Investigator, based on your complaints and objective examination, has revealed that you have an acute, uncomplicated, infectious and inflammatory disease of the throat. 
One of the study drugs is prescribed to you to treat your condition: Angal, lozenges with a menthol taste, or ANTI-ANGIN® FORMULA, lozenges. Both you and the Investigator 
know which drug you are taking because this is an open (unblinded) trial. The information you are going to note in this diary is very important for this trial; therefore, please 
enter the data without corrections. 
Fill in the patient's diary every day. Encircle the answers YES or NO according to your opinion: YES. Take the diary with you when you visit the trial site. You will enter the 
following data: 
1. 
Study drug use: every time when you take a lozenge, record the time and briefly describe your complaints at that moment. Specify if you had a pain in your throat 
before the lozenge intake or not. 
2. 
Measurement of body temperature: measure your body temperature 3 times a day or more frequently if needed. Specify a time and result of the measurement. 
3. 
Course of the disease: specify if you noted any changes based on your subjective evaluation of the disease signs for which you take the lozenges. 
If you feel worsening of state, increase of body temperature, aggravation of pain in your throat, contact the Investigator by phone ___________________________! 
If required, the Investigator may invite you for an unscheduled visit to the trial site for additional examination and therapy correction. 
 
PRESCRIBING INFORMATION FOR THE STUDY DRUGS 
Angal: 1 lozenge (slowly disintegrating in the mouth), use with at least a 2-hour intervals. Not more than 6–10 lozenges per day, therapy duration is up to 4 days. 
Anti-Angin® Formula: 1 lozenge (slowly disintegrating in the mouth), use with at least a 2-hour interval. Maximum 6 lozenges per day, therapy duration is up to 5 days. 
 
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TE_004_ANG_LOZ 
THE PATIENT'S DIARY 
PATIENT __________________ 
 
DAY 1: DD/MM/YYYY 
 
1. USE OF THE STUDY DRUG: ANGAL/ANTI-ANGIN® FORMULA 
 
1 lozenge/No. of 
administration 
Specify the time of 
administration 
Did you experience a pain in your throat 
during the use of lozenges? 
Complaints/Notes 
1 
HH:MM 
YES / NO 
 
2 
HH:MM 
YES / NO 
 
3 
HH:MM 
YES / NO 
 
4 
HH:MM 
YES / NO 
 
5 
HH:MM 
YES / NO 
 
6 
HH:MM 
YES / NO 
 
7 
HH:MM 
YES / NO 
 
8 
HH:MM 
YES / NO 
 
0 
HH:MM 
YES / NO 
 
10 
HH:MM 
YES / NO 
 
2. BODY TEMPERATURE 
 
Specify the time of 
measurement 
RESULT 
OF MEASUREMENT 
MORNING 
HH:MM 
_______°С 
DAY 
HH:MM 
_______°С 
EVENING 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
3. COURSE OF THE DISEASE 
 
Specify the evaluation 
time 
Based on your subjective evaluation of the disease symptoms, can 
you say that you have improved so much that you do not need to 
use the lozenges anymore? 
MORNING 
HH:MM 
YES / NO 
DAY 
HH:MM 
YES / NO 
EVENING 
HH:MM 
YES / NO 
 
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TE_004_ANG_LOZ 
THE PATIENT'S DIARY 
PATIENT __________________ 
 
DAY 2: DD/MM/YYYY 
 
1. USE OF THE STUDY DRUG: ANGAL/ANTI-ANGIN® FORMULA 
 
1 lozenge/No. of 
administration 
Specify the time of 
administration 
Did you experience a pain in your throat 
during the use of lozenges? 
Complaints/Notes 
1 
HH:MM 
YES / NO 
2 
HH:MM 
YES / NO 
3 
HH:MM 
YES / NO 
4 
HH:MM 
YES / NO 
5 
HH:MM 
YES / NO 
6 
HH:MM 
YES / NO 
7 
HH:MM 
YES / NO 
8 
HH:MM 
YES / NO 
0 
HH:MM 
YES / NO 
10 
HH:MM 
YES / NO 
2. BODY TEMPERATURE 
 
Specify the time of 
measurement 
RESULT 
OF MEASUREMENT 
MORNING 
HH:MM 
_______°С 
DAY 
HH:MM 
_______°С 
EVENING 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
3. COURSE OF THE DISEASE 
 
Specify the evaluation 
time 
Based on your subjective evaluation of the disease symptoms, can 
you say that you have improved so much that you do not need to 
use the lozenges anymore? 
MORNING 
HH:MM 
YES / NO 
DAY 
HH:MM 
YES / NO 
EVENING 
HH:MM 
YES / NO 
 
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TE_004_ANG_LOZ 
THE PATIENT'S DIARY 
PATIENT __________________ 
 
DAY 3: DD/MM/YYYY 
 
1. USE OF THE STUDY DRUG: ANGAL/ANTI-ANGIN® FORMULA 
 
1 lozenge/No. of 
administration 
Specify the time of 
administration 
Did you experience a pain in your throat 
during the use of lozenges? 
Complaints/Notes 
1 
HH:MM 
YES / NO 
2 
HH:MM 
YES / NO 
3 
HH:MM 
YES / NO 
4 
HH:MM 
YES / NO 
5 
HH:MM 
YES / NO 
6 
HH:MM 
YES / NO 
7 
HH:MM 
YES / NO 
8 
HH:MM 
YES / NO 
0 
HH:MM 
YES / NO 
10 
HH:MM 
YES / NO 
2. BODY TEMPERATURE 
 
Specify the time of 
measurement 
RESULT 
OF MEASUREMENT 
MORNING 
HH:MM 
_______°С 
DAY 
HH:MM 
_______°С 
EVENING 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
3. COURSE OF THE DISEASE 
 
Specify the evaluation 
time 
Based on your subjective evaluation of the disease symptoms, can 
you say that you have improved so much that you do not need to 
use the lozenges anymore? 
MORNING 
HH:MM 
YES / NO 
DAY 
HH:MM 
YES / NO 
EVENING 
HH:MM 
YES / NO 
 
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TE_004_ANG_LOZ 
THE PATIENT'S DIARY 
PATIENT __________________ 
 
DAY 4: DD/MM/YYYY 
 
1. USE OF THE STUDY DRUG: ANGAL/ANTI-ANGIN® FORMULA 
 
1 lozenge/No. of 
administration 
Specify the time of 
administration 
Did you experience a pain in your throat 
during the use of lozenges? 
Complaints/Notes 
1 
HH:MM 
YES / NO 
2 
HH:MM 
YES / NO 
3 
HH:MM 
YES / NO 
4 
HH:MM 
YES / NO 
5 
HH:MM 
YES / NO 
6 
HH:MM 
YES / NO 
7 
HH:MM 
YES / NO 
8 
HH:MM 
YES / NO 
0 
HH:MM 
YES / NO 
10 
HH:MM 
YES / NO 
2. BODY TEMPERATURE 
 
Specify the time of 
measurement 
RESULT 
OF MEASUREMENT 
MORNING 
HH:MM 
_______°С 
DAY 
HH:MM 
_______°С 
EVENING 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
3. COURSE OF THE DISEASE 
 
Specify the evaluation 
time 
Based on your subjective evaluation of the disease symptoms, can 
you say that you have improved so much that you do not need to 
use the lozenges anymore? 
MORNING 
HH:MM 
YES / NO 
DAY 
HH:MM 
YES / NO 
EVENING 
HH:MM 
YES / NO 
 
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TE_004_ANG_LOZ 
THE PATIENT'S DIARY 
PATIENT __________________ 
 
DAY 5: DD/MM/YYYY 
 
1. USE OF THE STUDY DRUG: ANGAL/ANTI-ANGIN® FORMULA 
 
1 lozenge/No. of 
administration 
Specify the time of 
administration 
Did you experience a pain in your throat 
during the use of lozenges? 
Complaints/Notes 
1 
HH:MM 
YES / NO 
2 
HH:MM 
YES / NO 
3 
HH:MM 
YES / NO 
4 
HH:MM 
YES / NO 
5 
HH:MM 
YES / NO 
6 
HH:MM 
YES / NO 
7 
HH:MM 
YES / NO 
8 
HH:MM 
YES / NO 
0 
HH:MM 
YES / NO 
10 
HH:MM 
YES / NO 
2. BODY TEMPERATURE 
 
Specify the time of 
measurement 
RESULT 
OF MEASUREMENT 
MORNING 
HH:MM 
_______°С 
DAY 
HH:MM 
_______°С 
EVENING 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
Additionally 
HH:MM 
_______°С 
3. COURSE OF THE DISEASE 
 
Specify the evaluation 
time 
Based on your subjective evaluation of the disease symptoms, can 
you say that you have improved so much that you do not need to 
use the lozenges anymore? 
MORNING 
HH:MM 
YES / NO 
DAY 
HH:MM 
YES / NO 
EVENING 
HH:MM 
YES / NO 
 
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TE_004_ANG_LOZ 
THE PATIENT'S DIARY 
PATIENT __________________ 
 
The patient was instructed on the diary completion rules. The diary was given to the patient on Day 1 visit. 
 
 
Investigator (Full name/Signature) ____________________________/____________________________ Date____________________________ 
 
 
 
 
 
The diary was returned by the patient on time, according to the protocol. The data were entered correctly, all the corrections (if any) were discussed with the patient. 
 
 
 
 
Investigator (Full name/Signature) ____________________________/ ____________________________ Date____________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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16.4 
Appendix 4. A visual analogue scale for sore throat evaluation  
 
TE_004_ANG_LOZ 
THE VAS (VISUAL ANALOGUE 
SCALE) FOR SORE THROAT 
EVALUATION 
PATIENT No. __________ 
 
VISIT: 
 1 
 
 2 
 
 3 
 
 unscheduled 
 
Date: 
 
 
 
/ 
 
 
/ 
 
 
 
 
D  
D  
 
M 
M 
 
Y  
Y  
Y  
Y  
 
 
Time: 
 
 
 
: 
 
 
H 
H 
 
M 
M 
 
Instructions for the patient: please evaluate the severity of pain in your throat according to a scale 
of 0 (no pain) to 100 (the worst pain one can ever imagine) and draw a vertical line so that it crossed 
the scale below at the point corresponding to the pain in your throat at the present moment. 
 
 
No pain 
The worst pain one 
can ever imagine  
0 
100 
 
 
 
Investigator 
 
 
(Full name/Signature)_____________________________/_____________________ 
 
 
 
 
 
 
 
 
 
Version 1.0 of September 12, 2016 in Russian 
 

SAP_001.pdf: 
Statistical Analysis Plan in 1.0 of February 15, 2017 
1 
Statistical Analysis Plan 
Document code: TE_004_ANG_LOZ_TSAP 
Trial code: 
TE_004_ANG_LOZ / NCT03095521
Trial title: 
A Prospective, Multicenter, Open, Randomized, Parallel Clinical Trial for Comparative 
Assessment of Efficacy and Safety of Angal, Lozenges [Menthol], 1 mg + 5 mg (Sandoz 
d.d., Slovenia), and ANTI-ANGIN® FORMULA, Lozenges, 0.2 mg + 2 mg + 50 mg
(OOO Valeant, Russia) in Treatment of Patients with Uncomplicated Acute Infectious
and Inflammatory Diseases of the Pharynx Accompanied by a Sore Throat
Study drug: 
Angal (Lek d.d., Slovenia), lozenges [menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia) 
Protocol version and date: 1.0 of September 28, 2016 
Statistical Analysis Plan 
version and date: 
1.0 of February 15, 2017 
Document version history: 
Version 
Reason for changes 
Version 1.0 (February 15, 2017) 
Initial version 


Statistical Analysis Plan in 1.0 of February 15, 2017 
2 
Table of Contents 
 
1 
Introduction ................................................................................................................................................5 
2. 
Trial endpoints ............................................................................................................................................6 
2.1 
Primary endpoint ................................................................................................................................6 
2.2 
Secondary endpoints ...........................................................................................................................7 
2.3 
Evaluation of the study drug safety and tolerance ..............................................................................7 
3 
Main provisions for analysis.......................................................................................................................8 
3.1 
Study drugs and therapy schedule ......................................................................................................8 
3.2 
Serious protocol deviations ................................................................................................................8 
3.3 
Data sets for analysis ..........................................................................................................................9 
3.4 
Subgroups .........................................................................................................................................10 
3.5 
Data from various trial sites ..............................................................................................................10 
3.6 
Missed data and outliers ...................................................................................................................10 
3.7 
Interim analysis ................................................................................................................................11 
3.8 
Acceptable deadlines for visits and a scope of investigations ..........................................................11 
3.8.1 
Screening: Visit 1 (Therapy Day 1) ..........................................................................................11 
3.8.2 
Efficacy evaluation visit (Visit 2, Day 4 since the therapy initiation) ......................................12 
3.8.3 
Trial completion visit for Group B patients (Visit 3, Day 5) ....................................................13 
3.8.4 
Visit 4 (a follow-up, Day 6/7 from the therapy initiation) ........................................................14 
3.8.5 
Unscheduled visits ....................................................................................................................14 
3.8.6 
Visit of premature discontinuation of the trial ..........................................................................15 
3.9 
Null and alternative trial hypotheses ................................................................................................15 
4 
Analysis plan ............................................................................................................................................15 
4.1.1 
Descriptive statistics .................................................................................................................16 
4.1.2 
Primary endpoint ......................................................................................................................17 
4.1.3 
Secondary endpoints .................................................................................................................18 
4.1.4 
Safety and tolerability analysis .................................................................................................18 
4.1.5 
Analysis of laboratory and functional tests results ...................................................................19 
5 
Presentation of statistical analysis results .................................................................................................21 
5.1 
Table templates .................................................................................................................................21 
5.2 
List of figures ...................................................................................................................................29 
6 
List of approvals .......................................................................................................................................31 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
3 
List of Tables 
Table 1. Patient distribution .............................................................................................................................21 
Table 2. Demographic and anthropometric patients' characteristics ................................................................21 
Table 3. Patients distribution by sex .................................................................................................................21 
Table 4. Patients distribution by race ...............................................................................................................21 
Table 5. Social habits: alcohol abuse ................................................................................................................22 
Table 6. Social habits: smoking ........................................................................................................................22 
Table 7. The main vital signs (Visits 1, 2, 3) ....................................................................................................22 
Table 8. ECG results (Visits 1, 2, 3) .................................................................................................................22 
Table 9.Hematology (Visits 1, 2, 3) .................................................................................................................24 
Table 10. WBC differential (Visits 1, 2, 3) ......................................................................................................24 
Table 11.Biochemistry (Visits 1, 2, 3) ..............................................................................................................24 
Table 12.A number of patients with normal and abnormal hematology parameters (Visits 1, 2, 3) ................25 
Table 13.A number of patient with normal and abnormal WBC differential results (Visits 1, 2, 3) ...............25 
Table 14. A number of patient with normal and abnormal biochemistry parameters (Visits 1, 2, 3) ..............25 
Table 15. Concomitant diseases .......................................................................................................................25 
Table 16. Concomitant therapy ........................................................................................................................26 
Table 17. Evaluation of throat pain severity according to VAS .......................................................................26 
Table 18. TSS scores (Visits 1, 2, 3) ................................................................................................................26 
Table 19. Frequency of the recovery criteria achievement (total TSS ≤ 2) by Visits 2, 3 ................................26 
Table 20. Global evaluation of treatment tolerability (Visits 2, 3) ...................................................................27 
Table 21. Registered adverse events occured after initiation of the trial therapy .............................................27 
Table 22. Registered adverse events occurred after initiation of the reference therapy ...................................27 
Table 23. AEs frequency by the nosological groups ........................................................................................27 
Table 24. Compliance evaluation .....................................................................................................................29 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
4 
List of Figures 
 
Figure 1. TSS scores changes by visits and trial arms ......................................................................................29 
Figure 2. Difference in proportions of patients who achieved efficacy criteria in every arm, 90% CI ............29 
Figure 3. Incidence of TSS scores decrease for 50% or more in the trial arms ................................................29 
Figure 4. A period of time required for disease signs resolution according to the patient's diary and the trial 
arms ..................................................................................................................................................................29 
Figure 5. Proportions of fully recovered patients by the trial arms ..................................................................29 
Figure 6. Dynamic changes of pharyngalgia severity according to VAS by visits and trial arms ...................29 
Figure 7. Dynamic changes of vital parameters by visits and trial arms ..........................................................29 
Figure 8. Dynamic changes of hematology parameters by visits and trial arms ..............................................29 
Figure 9. Dynamic changes of biochemistry parameters by visits and trial arms ............................................30 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
5 
1 
Introduction 
This trial has been designed and conducted to evaluate the therapeutic efficacy and safety of the study drug 
Angal, lozenges [menthol], 1.0 mg + 5.0 mg (Sandoz d.d., Slovenia), comparing to ANTI-ANGIN® 
FORMULA, lozenges, 0.2 mg + 2.0 mg + 50 mg (OOO Valeant, Russia), in the treatment of patients with 
uncomplicated acute infectious and inflammatory diseases of the pharynx accompanied by a sore throat. The 
objective of this Phase III trial is to demonstrate the non-inferior therapeutic efficacy of the study drug as 
compared to the reference product. 
This Statistical Analysis Plan was developed in accordance with the following documents: 
• 
Guidelines for examination of medicinal products, Vol. 1. Federal State Budgetary Institution 
Scientific Center for Expert Evaluation of Medicinal Products under the Ministry of Health of 
the Russian Federation (eds. A.N. Mironov). Moscow: Grif and K, 2013. 
• 
ICH harmonised tripartite guideline. Statistical principles for clinical trials (E9). Current Step 4 
version dated 5 February 1998. 
• 
GCP rules of the Eurasian Economic Union (a draft). 
The objective of this Statistical Analysis Plan is more detailed, compared to Section 9 of the trial protocol, 
description of the main principles of the protocol-based statistical analysis, description of the primary and 
secondary endpoints analysis methods, as well as other data obtained during the trial. 
This Plan stipulates for consistence of the scheduled and conducted statistical analysis to the trial protocol, 
including definition of the analysis data sets, transformations and calculations for the endpoints, observations 
quantity needed, etc. No changes in this Statistical Analysis Plan compared to the trial protocol are 
envisaged. 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
6 
2. 
Trial endpoints 
2.1 
Primary endpoint 
The primary outcome measure was the percentage of patients without a sore throat after 3 days of therapy on 
Day 4, as evaluated by the Investigator according to the Tonsillopharyngitis Severity Score (TSS), in both 
Angal and ANTI-ANGIN® FORMULA arms. 
TSS, a questionnaire (point scale) for healthcare professionals, is used in clinical practice as well as clinical 
trials to evaluate dynamic changes of symptoms severity of the infection-inflammatory process in the throat 
(Bereznoy VV, Riley DS, Wassmer G, Heger M. Efficacy of extract of Pelargonium sidoides in children with 
acute non-group A beta-hemolytic streptococcus tonsillopharyngitis: a randomized, double-blind, placebo-
controlled trial). One of such clinical trials with TSS questionnaire was conducted in 2005 in Germany, 
©CRO Applertee AG. A version of TSS ©CRO Applertee AG was adapted for this protocol. 
TSS (Tonsillopharyngitis Severity Score) is a questionnaire for evaluation of the following symptoms 
severity: pharyngalgia, difficulty in swallowing, salivation, hyperemia of pharyngeal mucosa, and body 
temperature increase according to a 4-point scale: 
0 
 = no symptom; 
1 
= insignificant symptom; 
2 
= moderate symptom; 
3 
= significant symptom. 
The axillary body temperature increase is rated as follows: 
0 
points: <37.5 °С; 
1 
point: 37.5 to <38.5 °С; 
2 
points: 38.5 to <39.5 °С; 
3 
points: ≥39.5 °С. 
TSS is filled in by the Investigator based on the patient complaints and physical examination data. The 
Investigator summarises the points obtained for every symptom to obtain a total sum of TSS points. A total 
sum of TSS points will be evaluated at screening to define the inclusion criteria and evaluate for the baseline 
level; measure efficacy of the therapy conducted in the both arms at Visit 2 (Day 4); as well as evaluate the 
disease outcome at Visit 2 (Day 4) and/or Visit 3 (Day 5), if applicable. 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
7 
2.2 
Secondary endpoints 
• 
The frequency of ≥50% total score reduction according to the TSS questionnaire completed by the 
Investigator as compared to the baseline in both Angal and ANTI-ANGIN® FORMULA groups at 
Visit 2 (Day 4). 
• 
Total score reduction according to the TSS questionnaire, as well as a reduction in the symptoms (sore 
throat, difficulty in swallowing, salivation, erythema, and fever) after a 3-day therapy, at Visit 2 
(Day 4), as compared to the baseline total score. 
• 
A period of time required for disappearance of the disease symptoms, determined according to the 
patient's diary (subjective patient's evaluation), but no more than 5 days during the trial—for patients 
who have achieved the corresponding outcome. 
• 
A proportion (%) of patients who fully recovered by Day 4 in Group A and by Day 5 in Group B 
(the outcome of a disease according to the objective evaluation by the Investigator, the total score 
according to the TSS questionnaire ≤ 2). 
• 
A change in the sore throat intensity by 100 mm VAS (visual analogue scale filled in by the patient) at 
the beginning, after 3 days of therapy, and at the end of treatment in both groups. 
VAS (visual analogue scale) to evaluate pharyngalgia severity: 
The patient will fill in this scale at every visit to the trial site (Visits 1, 2, 3, where applicable). Calibrated 
scales 100 mm in length with the relevant measuring instruments will be provided for the clinical trial. 
The patients should evaluate their pain severity according to VAS at every visit (if possible, before 
administration of the painkillers (if those are required) or the study drug/comparator drug). 
2.3 
Evaluation of the study drug safety and tolerance 
Safety of the trial therapy is evaluated based on the systemic parameters (systolic and diastolic blood 
pressure, breathing rate, heart rate, body temperature, ECG), laboratory tests results, frequency of adverse 
events (AEs) and serious adverse events (SAEs). AEs nature and incidence (allergic reactions, burning 
sensation, discomfort) at the administration site will be evaluated throughout the trial. Global evaluation of 
treatment tolerability will be made by the patient and the physician according to the following scale: 
 
Scores 
Evaluation 
0 
Poor 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
8 
1 
Satisfactory 
2 
Good 
3 
Excellent 
Evaluation of the study drug tolerability by the patient and the physician (points/scores) should be specified 
in the eCRF at Visits 2 or 3 (where applicable). 
 
3 
Main provisions for analysis 
3.1 
Study drugs and therapy schedule 
The patients were randomized in 1:1 ratio to the following groups: 
Main group: Angal, lozenges [Menthol], 1 mg + 5 mg (Sandoz d.d., Slovenia): Administration of 1 lozenge 
with a not less than 2-hour interval until full dissolution in the mouth, up to 6–10 times per day, for 4 days or 
until full recovery (whichever occurs first during 4 days of therapy). 
Control group: ANTI-ANGIN® FORMULA, lozenges, 0.2 mg + 2 mg + 50 mg (OOO Valeant, Russia): 
administration of 1 lozenge with a not less than 2-hour interval, up to 6 lozenges per day, for 5 days or until 
full recovery (total TSS ≤ 2) (whichever occurs first during 5 days of therapy). 
3.2 
Serious protocol deviations 
A serious protocol deviation (Item 11.3 of the trial protocol) is a deviation, which may, according to the 
estimate by the Investigator or a person assigned by the Investigator, result into withdrawal of the subject 
from the trial or withdrawal of his data from the statistical part of the trial. The deviations not referred to as 
serious ones shall be considered minor protocol deviations. 
 
For the purposes of this analysis, the serious protocol deviations were defined as follows: 
Description 
Example/Explanation 
Efficacy or safety 
Excluded from 
population: 
Violation of the 
inclusion and non-
inclusion criteria 
Inclusion criterion No. 5: e.g., inclusion of the patient with initial 
total TSS < 5 
Efficiency 
PP 
Violation of the 
informed consent receipt 
procedure 
Absence of the Informed Consent Form 
Safety and efficacy 
All 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
9 
 
Informed Consent Form was signed after randomization/initiation 
of therapy 
Safety and efficacy 
None 
Randomization and 
study drugs 
Prescription of the drug non-consitent with the randomization arm Efficiency 
PP 
 
Low compliance: the patient missed more than 3 doses of the 
study drug 
Efficiency 
PP 
Concomitant drugs 
The patient used prohibited drugs during the trial (or had used the 
drugs prohibited by the inclusion/exclusion criteria before the trial 
initiation) 
Efficacy and safety 
PP 
A final list of serious protocol deviations will be compiled before the statistical analysis start. Every protocol 
deviation should be evaluated for the patient's exclusion from the PP data set or statistical analysis by the 
trial Sponsor representative. The decisions adopted and lists of patients included into the relevant data sets 
must be documented before the analysis initiation. 
3.3 
Data sets for analysis 
The intention-to-treat (ITT) population: All randomized subjects who have received at least one dose of 
the study drug/placebo and have completed at least one visit aimed at evaluation of the efficacy parameters 
(i.e., at least all the procedures of Visit 1). 
According to the protocol (Section 9) and with reference to ICH E9 requirements, the ITT population will be 
considered to be a population for statistical analysis in the equivalence trials (including non-inferiority trials). 
The per protocol (PP) population: All randomized subjects who have completed participation in the trial in 
accordance with the protocol (have completed the prescribed period of treatment and follow-up without 
significant deviations from the protocol). 
A primary endpoint analysis will be conducted both for the ITT (main analysis) and PP populations 
(additional analysis). 
Similarly, all efficacy endpoints will be analyzed both for the ITT and PP populations. 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
10 
The safety population (safety): All randomized subjects who received at least one dose of the 
trial/reference drug and have completed at least one visit to the evaluation of the parameters of safety (i.e., at 
least all the procedures of Visit 1). As distinct from ITT population, the safety population will be analyzed 
depending on actually received treatment (not only prescribed) (in case of difference between the prescribed 
and received therapies). 
The safety population will be used for all safety parameters including laboratory results, as well as for drug 
tolerability evaluation (see Section 2.3). 
3.4 
Subgroups 
A subgroup analysis is not envisaged for this trial. 
3.5 
Data from various trial sites 
This is a multicenter trial but data analysis for every particular trial site is not envisaged. 
3.6 
Missed data and outliers 
At the database check, the expert in statistics authorized by the Sponsor and the data control and processing 
managers will analyze the trial results for questionable, missed and unanalyzable data, which will be the 
basis for the questions for investigators. 
If possible, the investigators will eliminate the errors identified in CRFs and inform the Principal Investigator 
and authorized representatives of the Sponsor hereof. In case the identified data errors cannot be eliminated 
after the completion of the patients participation in the trial, the analysis of the resulting parameter sensitivity 
to questionable data will be conducted in the statistical analysis. 
Information about the missed, questionable, and unanalyzable data will be summarized in the final clinical 
trial report. 
The main analysis for the primary endpoint will be conducted without replacement for the missed, 
questionable, or unanalyzable data. 
An additional analysis will be conducted with the data replacement (last observation carried forward); in this 
case, the last known TSS score will be carried to all subsequent control points. 
All other data will be analyzed based on actually available information only, without data replacement. 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
11 
Regarding abnormal test results, their clinical significance is evaluated by the Investigator during the trial 
with registration of AEs or adverse reactions, under control of the clinical trial specialists. Additional 
inquiries may be forwarded to the trial sites (before the cut-off date) if clinical significance of the abnormal 
test results is hard to evaluate. 
3.7 
Interim analysis 
An interim analysis may be conducted by the Sponsor's decision after receipt of efficacy data for Angal and 
ANTI-ANGIN® FORMULA after 3 days of therapy, on Day 4, for at least 100 patients in every arm. The 
interim analysis includes demographic data, data of anamnesis and concomitant therapy, available data on 
efficacy and safety of Angal and ANTI-ANGIN® FORMULA drugs. 
Safety will be evaluated for all the patients who received at least one dose of the study drug as at the interim 
analysis date. Based on the interim analysis results, the main and additional statistical parameters of efficacy 
and safety of the study drug, ZAO Sandoz shall be entitled to decide to discontinue the trial prematurely. 
No significance level correction for the interim statistical analysis is envisaged. 
3.8 
Acceptable deadlines for visits and a scope of investigations 
The data obtained at Visit 1 (Day 1) will be considered to be the initial data for the endpoint analysis. 
3.8.1 
Screening: Visit 1 (Therapy Day 1) 
Visit 1 is scheduled for Day 1. At this visit, the doctor evaluates the patient's eligibility for the trial. If no 
non-inclusion criteria are met, the patient undergoes randomization, is given the study drug/comparator drug 
and a patient's diary, and is instructed on the patient's diary completion requirements. 
Screening visit procedures: 
− 
Signing of the Informed Consent Form; 
− 
Demographic data (date of birth, sex, age); 
− 
Measurement of weight and height; 
− 
Anamnesis gathering; 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
12 
− 
Records on the concomitant therapy; 
− 
Evaluation of inclusion/non-inclusion criteria; 
− 
Evaluation of the throat pain intensity according to VAS; 
− 
Fill-in of TSS questionnaire by the Investigator; 
− 
Physical examination (including oropharynx); 
− 
Measurement of the main vital signs; 
− 
Hematology; 
− 
Biochemistry; 
− 
Urine pregnancy test; 
− 
12-lead ECG; 
− 
Evaluation of inclusion/non-inclusion criteria; 
− 
Randomization; 
− 
Training for administration and handling of the study drugs; 
− 
Dispensing of the study drugs; 
− 
Provision with the patient's diaries and training on the fill-in rules; 
− 
Initiation of therapy with the study drugs; 
− 
Evaluation of adverse events (including based on results of the throat and pharynx examination). 
3.8.2 
Efficacy evaluation visit (Visit 2, Day 4 since the therapy initiation) 
Visit 2 is conducted on Day 4; the patient must visit the trial site in the fasted state and bring the filled-in 
diary and unused drug. If Group B patients (ANTI-ANGIN® FORMULA) did not meet recovery criteria 
(total TSS ≤ 2) at Visit 2 (Day 4), they will require continuation of the therapy, and some procedures for 
those patients will be transferred for the next day (Visit 3, Day 5), see below. The patients will keep their 
diaries and the unused drugs. 
Visit 2 procedures for the both groups: 
− 
Collection of complaints, actualization of anamnesis; 
− 
Records on the concomitant therapy; 
− 
Physical examination (including oropharynx); 
− 
Measurement of the main vital signs; 
− 
Evaluation of adverse events (including based on results of the throat and pharynx examination); 
− 
Evaluation of exclusion criteria; 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
13 
− 
Compliance evaluation (diary completion, administration of the study drugs). 
Visit 2 procedures for patients from Group A (Angal) and Group B (ANTI-ANGIN® FORMULA) who 
achieved recovery criteria (total TSS ≤ 2): 
− 
Hematology; 
− 
Biochemistry; 
− 
12-lead ECG; 
− 
Global evaluation of treatment tolerability during the trial by the physician and the patient; 
− 
Return of the unused study drug; 
− 
Return of the patient's diary. 
3.8.3 
Trial completion visit for Group B patients (Visit 3, Day 5) 
This visit is for Group B patients only (ANTI-ANGIN® FORMULA) who did not achieve the recovery 
criteria (total TSS ≤ 2) at Visit 2 (Day 4). 
Visit 3 is conducted on Day 5; the patient must visit the trial site in the fasted state and bring the filled-in 
diary and unused drug. 
Visit 3 procedures: 
− 
Collection of complaints, actualization of anamnesis; 
− 
Records on the concomitant therapy; 
− 
Physical examination (including oropharynx); 
− 
Measurement of the main vital signs; 
− 
Evaluation of adverse events (including based on results of the throat and pharynx examination); 
− 
Evaluation of exclusion criteria; 
− 
Return of the unused study drug; 
− 
Return of the patient's diary; 
− 
Compliance evaluation (diary completion, administration of the study drugs). 
− 
Hematology; 
− 
Biochemistry; 
− 
12-lead ECG; 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
14 
− 
Global evaluation of treatment tolerability during the trial by the physician and the patient. 
3.8.4 
Visit 4 (a follow-up, Day 6/7 from the therapy initiation) 
A follow-up visit shall be conducted by phone to find out about the patient's state and any AEs. A visit 
2 days after the therapy completion visit (e.g., on Day 6 or 7, depending on the arm and therapy duration). 
Follow-up visit procedures (by phone): 
− 
Evaluation of adverse events (without the throat and pharynx examination). In case of adverse 
events, the patient might be invited to visit the trial site. 
3.8.5 
Unscheduled visits 
The unscheduled visits will be conducted when necessary, e.g., in case of the index disease deterioration, 
AEs, or the study drug (Angal or ANTI-ANGIN® FORMULA) intolerability. 
Every unscheduled visit, irrespective of its cause, must include the procedures listed below with completion 
of the relevant eCRF pages (Unscheduled Visit): 
• 
Physical examination (including topical examination); 
• 
TSS evaluation; 
• 
Measurement of the main vital signs (blood pressure, heart rate, breathing rate, body temperature); 
• 
12-lead ECG (if it has not been done for the last 12 hours); 
• 
Evaluation of adverse events; 
• 
Evaluation of the concomitant therapy. 
Other diagnostic and treatment procedures may be conducted depending on clinical situation and upon the 
Investigator's decision. 
Taking into account frequency of visits, unscheduled visits may be conducted on the same days as scheduled 
ones but in a different time (e.g., in case of worsening the patient may visit the center in afternoon). All 
procedures for the planned visits are identical for the both arms at every trial stage, except for the Group B 
patients who, if the recovery criteria (total TSS ≤ 2) are not met at Visit 2 (Day 4), should continue the trial 
therapy and visit the trial site for scheduled Visit 3 Day 5). 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
15 
3.8.6 
Visit of premature discontinuation of the trial 
Visit 2 procedures will be applied for the visit of premature discontinuation. 
3.9 
Null and alternative trial hypotheses 
Based on the trial objectives, the following hypotheses were drawn for testing: 
Null hypothesis (H0): Difference in the primary endpoint achievement incidence while using Angal, the 
study drug, and ANTI-ANGIN® FORMULA, the original drug, for treatment of acute infectious and 
inflammatory pharyngeal diseases will exceed 14.5% in favor of ANTI-ANGIN® FORMULA: 
H0: p1 – p2≤ –0.145 
Alternative hypothesis (HA): Difference in the primary endpoint achievement incidence while using Angal, 
the study drug, and ANTI-ANGIN® FORMULA, the original drug, for treatment of acute infectious and 
inflammatory pharyngeal diseases will not exceed 14.5% in favor of ANTI-ANGIN® FORMULA: 
HA: P1 – P2> –0.145 
Where p1 and p2 is the primary endpoint achievement incidence while using Angal, the study drug, and 
ANTI-ANGIN® FORMULA, the original drug, respectively. 
3.10 
Significance level 
All statistical analyses in this trial will be conducted at 95% significance level (a threshold p value for 
confirmation of statistical significance is below 0.05), except for the primary endpoint where a one-sided 
statistical criterion will be used with 95% significance level (a threshold p value is below 0.05). The two-
sided statistical criteria will be used for all other parameters. 
For the primary endpoint evaluation, 90% CI will be calculated for the proportions difference with further 
evaluation of its lower boundary limit. 
 
4 
Analysis plan 
For non-inferiority confirmation, a two-sided 90% CI will be calculated for the proportion difference of the 
primary efficacy parameters (no pain after 3 days of therapy on Day 4 according to TSS) with further 
evaluation of its lower boundary limit. 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
16 
A non-inferiority conclusion will be made relating to the primary parameter only which will confirm the 
claimed efficacy. Secondary variables (including secondary efficacy and safety parameters) will be used for 
the research interest. Correction for multiple comparisons is not envisaged due to the trial arms number. 
Descriptive statistics will include data for all randomized patients. Descriptive statistics parameters to be 
calculated for the quantitative variables are listed below: 
• 
Quantity of observations (n); 
• 
Arithmetic mean (M); 
• 
Standard deviation (SD); 
• 
95% confidence interval for the mean (95% CI); 
• 
Minimal value (min.); 
• 
Maximal value (max.); 
• 
Median (Me); 
• 
Interquartile range (IQR). 
For the variables presented as qualitative and serial parameters, the absolute (n) and relative (%) incidences 
will be calculated for every category, as well as 95% CI (unless otherwise specified). 
4.1.1 
Descriptive statistics 
Descriptive statistics for the initial data (obtained during Visit 1) for all randomized patients will be 
presented for the following variables: 
• 
Age (a number of complete years as at Visit 1 date based on the date of birth); 
• 
Sex, race; 
• 
Social habits; 
• 
Vital signs: initial systolic blood pressure, diastolic blood pressure, breathing rate, body temperature; 
• 
Physical examination (presence/absence of deviations from the reference for organs and organ 
systems); 
• 
Hematology, biochemistry; 
• 
Electrocardiogram: presence/absence of deviations; 
• 
Throat pain intensity according to VAS; 
• 
TSS evaluation; 
• 
Symptoms duration (calculated as a number of days as at Visit 1 date based on the first signs 
occurrence date); 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
17 
• 
Time since the diagnostics to the therapy initiation (calculated as a number of days as at Visit 1 date 
based on clinical diagnostics date); 
• 
Concomitant diseases: rate for the main organs and systems (MedDRA terms); 
• 
Concomitant therapy: rate for the main drug groups; 
Descriptive statistics for the data obtained by Visits 2 and 3 will be presented for the following variables: 
• 
Vital signs: systolic blood pressure, diastolic blood pressure, breathing rate, body temperature; 
• 
Physical examination (presence/absence of deviations from the reference for organs and organ 
systems); 
• 
Throat pain intensity according to VAS; 
• 
TSS evaluation; 
• 
Evaluation of therapy efficacy; 
• 
Hematology, biochemistry; 
• 
12-lead ECG; 
• 
Global evaluation of treatment tolerability; 
• 
Compliance evaluation; 
All the AEs and SAEs registered during the trial will be classified according to MedDRA terms. A 
percantage of patients with the registered AEs with relevant codes (according to MedDRA terms and term 
groups) will be presented for every trial arm. In addition, AEs will be classified for severity and relationship 
with the study drug/comparator drug. 
Descriptive statistics will be presented for all parameters for each group separately. 
4.1.2 
Primary endpoint 
The primary endpoint of the trial (absence of the sore throat after 3 days of therapy on Day 4) will be 
presented as the difference between the proportions for each arm. The group comparison will be carried out 
using the Fisher's exact test (one-sided test, in connection with the null hypothesis of non-inferiority). For the 
proportion difference, the 90% confidence interval (CI) will be calculated according to the procedure 
described in Newcombe, Robert G. "Interval Estimation for the Difference Between Independent 
Proportions: Comparison of Eleven Methods," Statistics in Medicine, 17, 873-890 (1998). 
Thus, the non-inferiority will be confirmed if the limit of the two-sided 90% confidence interval for the 
difference in the proportions will be 14.5% or lower. 
A primary endpoint analysis will be conducted both for the ITT (main analysis) and PP populations 
(additional analysis). 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
18 
4.1.3 
Secondary endpoints 
The following statistical analysis methods are stipulated for the secondary efficacy endpoints: 
• 
The frequency of ≥50% total score reduction by the TSS questionnaire completed by the Investigator 
relative to baseline in both Angal and ANTI-ANGIN® FORMULA arms at Visit 2 (Day 4)—the 
response frequencies will be compared in each time point using the Fisher's exact test. 
• 
Total score reduction by the TSS questionnaire, as well as reduction in symptoms (sore throat, 
difficulty in swallowing, salivation, erythema and fever) after 3-day therapy, at Visit 2 (Day 4), 
relative to baseline total score—the between-arm comparison will be carried out using the Mann–
Whitney test due to non-symmetrical nature of the scores distribution in the TSS scale. 
• 
A period of time required for the symptoms resolution defined by the patient's diary (subjective 
patient's evaluation), but not more than 5 days within the trial (for patients who achieved the relevant 
outcome)—the between-arm comparison will be carried out using t-test or the Mann–Whitney test 
depending on the distribution character. The survival will not be evaluated due to low duration of the 
trial. 
• 
The proportion (%) of patients who fully recovered on Day 4 in Group A and on Day 5 in Group B 
(disease outcome according to the objective evaluation by the Investigator, the total score by the TSS 
questionnaire ≤ 2)—the between-arm comparison will be carried out using the Fisher's exact test. 
• 
A change in the sore throat intensity by 100 mm VAS (visual analogue scale filled in by the patient) at 
the beginning, after 3 days of therapy, and at the end of treatment in both groups—the between-arm 
comparison will be carried out using the t-test. 
A secondary endpoint analysis will be conducted both for the ITT (main analysis) and PP populations 
(additional analysis). 
A multifactorial analysis of the secondary endpoints is not envisaged. 
4.1.4 
Safety and tolerability analysis 
AEs incidence will be compared between the trial arms using Pearson's chi-squared test. In case of 
significant changes, a relative risk will be calculated (with 95% CI). 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
19 
A tolerability level for every group will be calculated based on the AEs incidence and nature (in accordance 
with Section 2.3 of this Plan). 
4.1.5 
Analysis of laboratory and functional tests results 
A between group comparison of the vital signs changes (systolic blood pressure, diastolic blood pressure, 
breathing rate, heart rate, body temperature) revealed at every visit (Visits 1, 2, 3) as well as laboratory 
results and ECG changes incidence obtained at Visit 1 and Visits 2–3 is envisaged. In addition, significance 
of the changes will be evaluated for all repeatedly measured parameters. 
The following laboratory parameters will be reviewed: 
• 
Hematology 
О 
Hemoglobin 
О 
RBC 
О 
ESR 
О 
WBC 
О 
Neutrophils 
 
Juvenile 
 
Stab 
 
Segmented 
О 
Eosinophils 
О 
Basophils 
О 
Monocytes 
О 
Lymphocytes 
• 
Biochemistry 
О 
Total protein 
О 
AST 
о 
ALT 
О 
Total bilirubin 
ANOVA methods will be used to reveal a simultaneous influence of a group and time factors on the 
quantitative parameters. 
The cross tables analysis will be used to reveal a correlation between the qualitative parameters (chi-squared 
test). 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
20 
For the quantitative parameters, a comparison will be made by Student's t-test for the independent samples 
(in case of confirmation of hypothesis on normal variables distribution) or Mann–Whitney test (in case of 
rejection of hypothesis on normal variables distribution); for the qualitative parameters—using Fisher's exact 
test. 
To evaluate significance of the intragroup changes during the trial for repeatedly measured parameters, the 
paired Student's t-test (in case of confirmation of hypothesis on normal variables distribution) or paired 
Wilcoxon signed-rank test (in case of rejection of hypothesis on normal variables distribution) will be used; 
for the qualitative parameters McNemar's test will be used. 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
21 
5 
Presentation of statistical analysis results 
5.1 
Table templates 
Table 1. Patient distribution 
Patient distribution 
Arm 
Number of patients 
(proportion, %) 
Group 
Number of patients 
(proportion, %) 
Included in the trial (screened) 
n/N (%) 
n/N (%) 
Excluded at screening 
n/N (%) 
n/N (%) 
Randomized 
n/N (%) 
n/N (%) 
Discontinued prematurely 
n/N (%) 
n/N (%) 
ITT population 
n/N (%) 
n/N (%) 
PP population 
n/N (%) 
n/N (%) 
Safety population 
n/N (%) 
n/N (%) 
Table 2. Demographic and anthropometric patients' characteristics 
Arm 
Parameter 
Age 
Body weight 
Height 
 
n 
 
 
 
M 
 
 
 
SD 
 
 
 
95% CI 
 
 
 
Min. 
 
 
 
Max. 
 
 
 
Me 
 
 
 
IQR 
 
 
 
 
n 
 
 
 
M 
 
 
 
SD 
 
 
 
95% CI 
 
 
 
Min. 
 
 
 
Max. 
 
 
 
Me 
 
 
 
IQR 
 
 
 
p 
 
 
 
Table 3. Patients distribution by sex 
Arm 
Men 
Women 
 
n/N (%) 
n/N (%) 
 
n/N (%) 
n/N (%) 
p 
 
Table 4. Patients distribution by race 
Race 
Arm 
Number of patients 
(proportion, %) 
p 
Caucasian 
 
n/N (%) 
 
 
n/N (%) 
Negroid 
 
n/N (%) 
 
 
n/N (%) 
Asian 
 
n/N (%) 
 
 
n/N (%) 
Unknown 
 
n/N (%) 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
22 
 
 
n/N (%) 
 
< Other > 
 
n/N (%) 
 
 
n/N (%) 
Table 5. Social habits: alcohol abuse 
 
Arm 
Number of patients 
(proportion, %) 
p 
Non-user 
 
n/N (%) 
 
 
n/N (%) 
Former user 
 
n/N (%) 
 
 
n/N (%) 
Current user 
 
n/N (%) 
 
 
n/N (%) 
Table 6. Social habits: smoking 
 
Arm 
Number of patients  
(proportion, %) 
p 
Non-smoker 
 
n/N (%) 
 
 
n/N (%) 
Former smoker 
 
n/N (%) 
 
 
n/N (%) 
Current smoker 
 
n/N (%) 
 
 
n/N (%) 
Table 7. The main vital signs (Visits 1, 2, 3) 
Arm 
Parameter 
Systolic 
blood 
pressure 
Diastolic 
blood 
pressure 
Pulse rate 
BR 
Body temperature 
 
n 
 
 
 
 
 
M 
 
 
 
 
 
SD 
 
 
 
 
 
95% CI 
 
 
 
 
 
Min. 
 
 
 
 
 
Max. 
 
 
 
 
 
Me 
 
 
 
 
 
IQR 
 
 
 
 
 
 
n 
 
 
 
 
 
M 
 
 
 
 
 
SD 
 
 
 
 
 
95% CI 
 
 
 
 
 
Min. 
 
 
 
 
 
Max. 
 
 
 
 
 
Me 
 
 
 
 
 
IQR 
 
 
 
 
 
 
р 
 
 
 
 
 
Table 8. ECG results (Visits 1, 2, 3) 
Arm 
Parameter 
ECG 
n/N (%) 
 
Reference 
 
Deviation 
 
 
Reference 
 
Deviation 
 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
23 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
24 
Table 9. 
Hematology (Visits 1, 2, 3) 
Arm 
Parameter 
Hemoglobin 
RBC  
ESR 
WBC  
 
n 
 
 
 
 
M 
 
 
 
 
SD 
 
 
 
 
95% CI 
 
 
 
 
Min. 
 
 
 
 
Max. 
 
 
 
 
Me 
 
 
 
 
IQR 
 
 
 
 
 
n 
 
 
 
 
M 
 
 
 
 
SD 
 
 
 
 
95% CI 
 
 
 
 
Min. 
 
 
 
 
Max. 
 
 
 
 
Me 
 
 
 
 
IQR 
 
 
 
 
 
р 
 
 
 
 
Table 10. WBC differential (Visits 1, 2, 3) 
Arm 
Parameter 
Neutrophils, 
total 
Juvenile 
Stab 
Segmented Eosinophils 
Basophils Monocytes Lymphocytes 
 
n 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
95% CI 
 
 
 
 
 
 
 
 
Min. 
 
 
 
 
 
 
 
 
Max. 
 
 
 
 
 
 
 
 
Me 
 
 
 
 
 
 
 
 
IQR 
 
 
 
 
 
 
 
 
 
n 
 
 
 
 
 
 
 
 
M 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
95% CI 
 
 
 
 
 
 
 
 
Min. 
 
 
 
 
 
 
 
 
Max. 
 
 
 
 
 
 
 
 
Me 
 
 
 
 
 
 
 
 
IQR 
 
 
 
 
 
 
 
 
 
р 
 
 
 
 
 
 
 
 
Table 11.Biochemistry (Visits 1, 2, 3) 
Arm 
Parameter 
Total protein 
ALT 
AST 
Total bilirubin 
 
n 
 
 
 
 
M 
 
 
 
 
SD 
 
 
 
 
95% CI 
 
 
 
 
Min. 
 
 
 
 
Max. 
 
 
 
 
Me 
 
 
 
 
IQR 
 
 
 
 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
25 
 
n 
 
 
 
 
 
M 
 
 
 
 
SD 
 
 
 
 
95% CI 
 
 
 
 
Min. 
 
 
 
 
Max. 
 
 
 
 
Me 
 
 
 
 
IQR 
 
 
 
 
 
р 
 
 
 
 
Table 12.A number of patients with normal and abnormal hematology parameters (Visits 1, 2, 3) 
Arm 
Parameter 
Hemoglobin 
RBC  
ESR 
WBC  
 
Reference 
 
 
 
 
Deviation 
 
 
 
 
 
Reference 
 
 
 
 
Deviation 
 
 
 
 
Table 13.A number of patient with normal and abnormal WBC differential results (Visits 1, 2, 3) 
Arm 
Parameter 
Neutrophils, total 
Juvenile 
Stab 
Segmented Eosinophils Basophils Monocytes Lymphocytes 
 
Reference 
 
 
 
 
 
 
 
 
Deviation 
 
 
 
 
 
 
 
 
 
Reference 
 
 
 
 
 
 
 
 
 
Deviation 
 
 
 
 
 
 
 
 
Table 14. A number of patient with normal and abnormal biochemistry parameters (Visits 1, 2, 3) 
Arm 
Parameter 
Total protein 
ALT 
AST 
Total bilirubin 
 
Reference 
 
 
 
 
Deviation 
 
 
 
 
 
Reference 
 
 
 
 
Deviation 
 
 
 
 
Table 15. Concomitant diseases 
Organ, system 
Arm 
Number of diseases 
(proportion, %) 
 
 
n/N (%) 
 
 
n/N (%) 
 
 
n/N (%) 
 
 
n/N (%) 
 
 
n/N (%) 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
26 
Table 16. Concomitant therapy 
Drug group 
Arm 
Number of prescriptions 
(proportion, %) 
 
 
n/N (%) 
 
 
n/N (%) 
 
 
n/N (%) 
 
 
n/N (%) 
 
 
n/N (%) 
Table 17. Evaluation of throat pain severity according to VAS 
Arm 
Parameter 
Visit 1 
Visit 2 
Visit 3 
 
n 
 
 
 
M 
 
 
 
SD 
 
 
 
95% CI 
 
 
 
Min. 
 
 
 
Max. 
 
 
 
Me 
 
 
 
IQR 
 
 
 
 
n 
 
 
 
M 
 
 
 
SD 
 
 
 
95% CI 
 
 
 
Min. 
 
 
 
Max. 
 
 
 
Me 
 
 
 
IQR 
 
 
 
 
р 
 
 
 
Table 18. TSS scores (Visits 1, 2, 3) 
Arm 
Amount of 
scores 
Sore throat 
Difficultyin 
swallowing 
Salivation 
Pharyngeal mucosa 
hyperemia 
Fever 
 
0 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
1 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
2 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
3 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
 
0 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
1 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
2 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
3 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
 
р 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
n/N (%) 
Table 19. Frequency of the recovery criteria achievement (total TSS ≤ 2) by Visits 2, 3 
Arm 
Parameter 
Visit 2 
Visit 3 
 
Criterion is met 
 
 
Criterion is not met 
 
 
 
Criterion is met 
 
 
Criterion is not met 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
27 
Table 20. Global evaluation of treatment tolerability (Visits 2, 3) 
Arm 
Parameter 
Tolerability evaluation by the patient 
Tolerability evaluation by the physician 
 
n 
 
 
M 
 
 
 
SD 
 
 
95% CI 
 
 
Min. 
 
 
Max. 
 
 
Me 
 
 
IQR 
 
 
 
n 
 
 
M 
 
 
SD 
 
 
95% CI 
 
 
Min. 
 
 
Max. 
 
 
Me 
 
 
IQR 
 
 
 
р 
 
 
Table 21. Registered adverse events occured after initiation of the trial therapy 
Description 
Mild AEs 
Moderate AEs 
Severe AEs 
Total 
Total 
Serious 
Non-serious 
Serious 
Non-serious 
Serious 
Non-serious 
Serious 
Non-serious Serious + 
non-serious 
Organ system 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Organ system 
 
 
 
 
 
 
 
 
 
 
Table 22. Registered adverse events occurred after initiation of the reference therapy 
Description 
Mild AEs 
Moderate AEs 
Severe AEs 
Total 
Total 
Serious 
Non-serious 
Serious 
Non-serious 
Serious 
Non-serious 
Serious 
Non-serious Serious + 
non-serious 
Organ system 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Organ system 
 
 
 
 
 
 
 
 
 
 
Table 23. AEs frequency by the nosological groups 
Nosological group 
Arm 
Arm 
р 
Nosological group 1 
n/N (%) 
n/N (%) 
 
Nosology 1 
n/N (%) 
n/N (%) 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
28 
Nosology 2 
n/N (%) 
n/N (%) 
 
Nosology 3 
n/N (%) 
n/N (%) 
 
Nosological group 1 
n/N (%) 
n/N (%) 
 
Nosology 1 
n/N (%) 
n/N (%) 
 
Nosology 2 
n/N (%) 
n/N (%) 
 
Nosology 3 
n/N (%) 
n/N (%) 
 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
29 
Table 24. Compliance evaluation 
Arm 
Parameter 
Compliance 
 
n 
 
M 
 
SD 
 
95% CI 
 
Min. 
 
Max. 
 
Me 
 
IQR 
 
 
n 
 
M 
 
SD 
 
95% CI 
 
Min. 
 
Max. 
 
Me 
 
IQR 
 
 
р 
 
5.2 
List of figures 
Figure 1. TSS scores changes by visits and trial arms 
For the parameters listed below: pharyngalgia, difficulty in swallowing, salivation, hyperemia of pharyngeal 
mucosa, and body temperature increase, as well as for total sum of scores 
Figure 2. Difference in proportions of patients who achieved efficacy criteria in every arm, 90% CI 
Figure 3. Incidence of TSS scores decrease for 50% or more in the trial arms 
Figure 4. A period of time required for disease signs resolution according to the patient's diary and the 
trial arms 
Figure 5. Proportions of fully recovered patients by the trial arms 
In Group A by Day 4 and in Group B by Day 5 
Figure 6. Dynamic changes of pharyngalgia severity according to VAS by visits and trial arms 
Figure 7. Dynamic changes of vital parameters by visits and trial arms 
For the vital signslisted below: systolic blood pressure, diastolic blood pressure, pulse rate, breathing rate, 
body temperature. 
Figure 8. Dynamic changes of hematology parameters by visits and trial arms 
For the parameters listed below: Hb, RBC, ESR, WBC, neutrophils (juvenile, stab, segmented), eosinophils, 
basophils, monocytes, lymphocytes. 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
30 
Figure 9. Dynamic changes of biochemistry parameters by visits and trial arms 
For the parameters listed below: total protein, AST, ALT, total bilirubin. 
 
 


Statistical Analysis Plan in 1.0 of February 15, 2017 
31 
6 
List of approvals 
Full name 
Position 
Signature 
Date 
 
 
/Signature/ 
February 15, 2017