Conditions: Cough
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 184
Healthy volunteers: no

Brief summary:
Primary objective:

To assess the efficacy of Levopront® in comparison with Libexin® based on daytime cough resolution rate by Day 8.

The daytime cough symptoms resolution corresponds to 0 or 1 points on the "Six-point daytime and nighttime cough assessment scale".

Secondary objectives:

Treatment effect assessment in terms of the following efficacy and safety parameters:

* To assess the efficacy of Levopront® in comparison with Libexin® based on nighttime cough resolution rate by Day 8.
* Daytime and nighttime cough symptoms resolution according to "Six-point daytime and nighttime cough assessment scale" by Day 4.
* Change in severity and frequency of daytime and nighttime cough according to "Six-point daytime and nighttime cough assessment scale" on Day 4 and Day 8 from baseline on Day 1.
* Cough intensity change according to the visual-analogue scale on Day 4 and Day 8 from baseline on Day 1.
* Change of FEV1 on Day 8 from baseline values on Day 1.
* Rate of Adverse events (AE) and Serious Adverse Events (SAE) of the various severity according to subjective complaints, laboratory test results, physical examination, vital signs and spirometry

Detailed description:
This is a multicenter, open-label, randomized, clinical trial to assess the efficacy and safety of Levopront® syrup 30 mg/5 ml in comparison with Libexin® 100 mg tablets in patients suffering from dry non-productive cough caused by acute upper respiratory infection

Arms:
arm 1: Levopront® (levodropropizine) syrup 30 mg/5 ml 10 ml (60 mg) t.i.d. for 7 days. The study drugs was taken 3 times a day, at intervals of at least 6 hours, between meals for 7 days. arm 2: Libexin® (prenoxdiazine) 100 mg tablets. Libexin® was administered orally, 1 tablet (100 mg) 3 times a day for 7 days.

Interventions: intervention 1: Levopront® syrup 30 mg/5 ml intervention 2: Libexin®
Intervention descriptions: intervention 1: The first study drug administration was performed at the clinical site on the day of randomization; the last study drug administration was performed in the evening before Day 8 (±1). intervention 2: The first study drug administration was performed at the clinical site on the day of randomization; the last study drug administration was performed in the evening before Day 8 (±1). No chewing.

Protocol document:
Prot_000.pdf: 
Study drug: Levopront ® 
Dompé farmaceutici S.p.A. 
Study protocol LDP0114 - Final Ver.2.0 (Amendment 1) 
September 14, 2017 
 
Confidential 
 
Page 1 of 66 
CLINICAL TRIAL PROTOCOL 
LDP0114 
 
Study title: 
Multicenter open-label randomized clinical trial of the efficacy 
and safety of Levopront® syrup 30 mg/5 ml in comparison with 
Libexin® 100 mg tablets in patients suffering from dry non-
productive cough caused by acute upper respiratory infection 
Study number: 
LDP0114 
Phase: 
3 
Study drug: 
Levopront® (levodropropizine) 
Indication: 
Cough 
 
 
Sponsor: 
Dompé farmaceutici S.p.A. 
Contact person: 
Mauro P. Ferrari 
Via San Martino 12-12а 
20122 Milano, Italy 
Tel +39 02 58383271 
Protocol Version: 
2.0 
Amendment 1 date:  
September 14, 2017 
Prevail Version: 
In the event of any inconsistencies between Russian and 
English version, the English  version shall prevail 
Protocol 
Version  
Modification  
Date  
1.0 
Final Version 
09-MAR-2016 
 (as amended on 
06-MAY2017) 
2.0 
Amendment 1: to provide justification of the increasing of the 
patients number based on the results of the analysis, that showed 
lack of power due to lower efficacy rate in both treatment groups 
than had been projected initially.  For this reason this analysis 
are considered interim analysis and an interim report will be 
issued to show these results. The full final report will be issued 
at the end of the study with the inclusion of the results of all 
patients. 
14-SEP-2017 
Confidentiality Statement 
It is agreed that this document is the Confidential Information of the Dompe farmaceutici S.p.A. company. 
You shall not publish, broadcast this document directly or impliedly, or disclose its information in some way 
and provide any part of it to the third parties. Also, you shall use this document only for the purpose for 
which it was provided to you. You can disclose the information only after receiving a written permission 
from the company Dompe farmaceutici S.p.A. or on demand from the state regulatory or the court. Any fact 
of disclose of the information from this document, authorized or not, should be immediately brought to the 
attention of the Dompe farmaceutici S.p.A. company. 




Study drug: Levopront ® 
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Study protocol LDP0114 - Final Ver.2.0 (Amendment 1) 
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Page 3 of 66 
STATEMENT OF THE PRINCIPAL INVESTIGATOR 
Site n°  
Full name:  
 
I, the undersigned, hereby certify that I have read and understood the protocol. I agree to 
follow protocol LDP0114: "Multicenter open-label randomized  clinical trial to assess the 
efficacy and safety of Levopront® syrup 30 mg/5 ml in comparison with Libexin® 100 mg 
tablets in patients suffering from dry non-productive cough caused by acute upper 
respiratory infection". 
I undertake to conduct the study in accordance with the requirements of Good Clinical 
Practice Guidelines of International Conference on Harmonization (ICH GCP) and 
Eurasian Economic Union (EAEU), principles outlined in the Declaration of Helsinki, and 
applicable regulations of Russian Federation. 
Date: 
 
 
Signature: 
 
 


Study drug: Levopront ® 
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Study protocol LDP0114 - Final Ver.2.0 (Amendment 1) 
September 14, 2017 
 
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Page 4 of 66 
CONTACT INFORMATION ON THE CLINICAL TRIAL 
Sponsor 
Dompé farmaceutici S.p.A. 
Via San Martino 12-12а 
20122 Milano, Italy  
Mauro P. Ferrari 
 
Early Clinical Development Manager 
Tel. +39 02 58383271 
e-mail: mauro.ferrari@dompe.com 
Federico Saibene  
Medical Expert - MedicalAffairs Primary Care Director 
Tel. +39 02 58383473 
e-mail: federico.saibene@dompe.com 
Laura Boga 
Senior Safety Manager - Drug Safety 
Tel. +39 02 58383568 
e-mail: laura.boga@dompe.com /  farmacovigilanza@dompe.com 
Contract Research 
Organization 
IPHARMA LLC 
7 Nobel street 
Skolkovo Innovation Center 
143026 Moscow, Russia 
Natalia Vostokova 
Chief Operating Officer 
Tel. +7 (495) 276-1143 
Fax +7 (495) 276-1147 
e-mail: nv@ipharma.ru 
Julia Trakhtenberg 
Medical Director 
Tel. +7 (495) 276-1143 
Fax +7 (495) 276-1147 
E-mail: jat@ipharma.ru  
Dmitry Davydov 
Medical Advisor  
Tel. +7 (495) 276-1143 
Fax +7 (495) 276-1147 
E-mail: dgd@ipharma.ru 
Valeriy Poddubnyy 
Project Manager 
Tel. +7 (495) 276-1143 
Fax +7 (495) 276-1147 
E-mail: vap@ipharma.ru  
SAE/pregnancy reporting 
(available 24 hours a 
day) 
Please, send SAE/pregnancy reports to Medical department of 
IPHARMA LLC 
Medical Monitor: Dmitry Davydov 
Tel. +7 (915) 397-3447 
Fax: +7 (495) 276-1147 
E-mail: SАE@ipharma.ru  
Data Management 
DATA MATRIX  
14 Nekrasova st., 191014, Saint-Petersburg, Russia 
Tel.: +7 (812) 449-86-33 
Fax:  +7 (812) 449 86 35  
E-mail: info@dm-matrix.com 


Study drug: Levopront ® 
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Study protocol LDP0114 - Final Ver.2.0 (Amendment 1) 
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Page 5 of 66 
 
Tatiana Medvedeva 
Project Supervisor, Head of Data Management Department 
Tel. +7 (812) 449-86-34  
Tel. +7 (921) 372-47-82 
E-mail: TMedvedeva@dm-matrix.com 
Biostatistics 
«KeyStat» LLC, 
3, Krasnoarmeyskoy svobody str.214000, Smolensk, 2-nd line, 
Russia 
 
Dmitry Khamtsov 
Biostatistics and general 
management 
Tel. +7 (915) 644-47-13 
E-mail: dmitry.khamtsov@keystatsolutions.com 
 
Central Laboratory 
Not applicable 
Local Depot 
COREX LLC 
Letter box 17, 1Э, 1, Komsomolskaya Street, Podolsk, Moscow 
Region, 142100, Russia www.corex-depot.com 
 
Maxim Minkov 
 
Project Manager 
Tel. +7 (905) 726-88-17  
E-mail: mminkov@corex-depot.com 
 
 
Clinical Sites  
Site name 
Address 
Principal investigators 
according to the 
approved list of sites 
Site 02: State Public Healthcare 
Institution of Moscow "City 
Clinical Hospital # 71 of Moscow 
Healthcare Department" 
14 Mozhaiskoye shosse, 
Moscow, 121374, Russia 
Site 03: State Healthcare 
Institution «Regional Clinical 
Hospital» 
1, Smirnovskoye ushelje, 
Saratov, 410053, Russia 
Site 04: State Autonomous 
Healthcare Institution of Yaroslavl 
Region «Clinical Hospital of 
Emergency care n.a. N.V. 
Solovyev» 
11, Zagorodny sad str., 
Yaroslavl, 150003, Russia 
Site 06: The Laboratory of 
Pulmonology, State Budgetary 
Educational Institution of Higher 
Professional Education «Moscow 
State Medical-Stomatological 
University n.a. A.I. Evdokimov» 
under Ministry of Health of the 
Russian Federation (Clinical base 
of state budget health care 
institution "City polyclinic № 62 
Moscow Health Department" 
Branch number 5) 
Legal address: 20/1 
Delegatskaya str.,  Moscow, 
127473, Russia 
Actual Address: 37 Ul. 
Planetarnaya,  Russia 


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Page 6 of 66 
Clinical Sites  
Site name 
Address 
Site 07: Saint-Petersburg State 
Healthcare Institution 
«Nikolaevskaya Hospital» 
1 Petergoff, 
Konstantinovskaya str., Saint-
Petersburg, 198510, Russia 
Site 09: State Budgetary 
Educational Institution of Higher 
Professional Education "Ryazan’ 
State Medical University n.a. 
academician I.P. Pavlov" under 
Ministry of Health of the Russian 
Federation 
9 Vysokovoltnaya str., 
Ryazan, 390026 Russia 
Site 10: «Institute of Medical 
Research» LLC 
 
liter «А» 25, Koli Tomchaka 
str., Saint-Petersburg, 
196084, Russia 
Site 14: LLC Treatment-and-
prophylactic institution on the 
«Smolensk clinic» 
Legal 
address: 
39, 
15th 
district, 
Smolensk 
region, 
Roslavl, Russia 
Actual address:1 Novoseltsi, 
str. Yubileynaya, Smolensk, 
214016, Russia 
 
 
 
 


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Page 7 of 66 
SYNOPSIS 
Sponsor: 
Dompe farmaceutici S.p.A., Italy 
Name of the investigated medicine: 
Levopront® 
Active Substance: 
Levodropropizine 
Trial Title: 
Multicenter open-label randomized clinical trial to assess the efficacy and safety of 
Levopront® syrup 30 mg/5 ml in comparison with Libexin® 100 mg tablets in patients suffering 
from dry non-productive cough caused by acute upper respiratory infection 
Trial ID: 
LDP0114 
Development phase: 3 
Primary objective: 
To assess the efficacy of Levopront® in comparison with Libexin® based on daytime cough 
resolution rate by Day 8. 
The daytime cough symptoms resolution corresponds to 0 or 1 points on the "Six-point 
daytime and nighttime cough assessment scale". 
Secondary objectives: 
Treatment effect assessment in terms of the following efficacy and safety parameters: 
 
To assess the efficacy of Levopront® in comparison with Libexin® based on nighttime 
cough resolution rate by Day 8. 
 
Daytime and nighttime cough symptoms resolution according to "Six-point daytime 
and nighttime cough assessment scale" by Day 4. 
 
Change in severity and frequency of daytime and nighttime cough according to "Six-
point daytime and nighttime cough assessment scale" on Day 4 and Day 8 from 
baseline on Day 1. 
 
Cough intensity change according to the visual-analogue scale on Day 4 and Day 8 
from baseline on Day 1. 
 
Change of FEV1 on Day 8 from baseline values on Day 1. 
 
Rate of Adverse events (AE) and Serious Adverse Events (SAE) of the various 
severity according to subjective complaints, laboratory test results, physical 
examination, vital signs and spirometry 
Rationale: 
Levopront® is a medicinal product of Dompe farmaceutici S.p.A., Italy, authorized in 
European Union, and established within the past two decades as a reliable and safe cough 
treatment drug. The active ingredient (Levodropropizine) is a levorotary isomer of the 
dropropizine racemic mixture and it is registered as a non-narcotic anti-cough agent of 
predominantly peripheral action. Levodropropizine suppresses coughing by inhibiting the 


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Study protocol LDP0114 - Final Ver.2.0 (Amendment 1) 
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Page 8 of 66 
stimulation of peripheral sensorial nerves and modulations of the neuropeptides involved in the 
coughing reflex. At the same time, it does not modify the spirometry parameters, the rheology 
of the bronchial secretion and the ciliary activity of the bronchial epithelium. Levodropropizine 
does not bind to beta-adrenergic, muscarine and opioid receptors, it does not have the affinity to 
H1-histamine and alpha-adrenergic receptors. The drug has less pronounced effect on the 
central nervous system, it has no effects on cardiovascular system and respiratory functional 
parameters, nor does it promote the development of drug dependence. The sedative effect of the 
drug is mild. 
This Phase 3 clinical trial is designed to assess of the efficacy and safety of Levopront® 
(Levodropropizine) in a form of 30 mg/5 ml syrup in patients with non-productive cough 
caused by acute upper respiratory tract infection. 
Study design: 
The present study is a multicenter open-label randomized comparative Phase 3 clinical trial 
in parallel groups. The study will be conducted at 8 Russian sites.  
A total expected number of enrolled patients is 184 (92 per each group).  
Screening and randomization 
At Visit 1, Day 1 after signing the Informed Consent Form, the patients will be screened 
for assessment of inclusion/exclusion criteria. Demography, medical history, and information 
on concomitant medications will be collected; physical examination, vital signs, weight and 
height measurements will be performed; blood and urine samples for laboratory tests will be 
collected; the cough severity and frequency rate will be assessed using the "Six-point daytime 
and nighttime cough assessment scale"; cough intensity will be assessed using the visual-
analogue scale; ECG and spirometry will be performed (pre- and post-bronchodilator) along 
with the chest x-ray or fluorography. Women of childbearing potential will take the pregnancy 
test before conducting the chest x-ray or fluorography. 
The patients who meet all inclusion/exclusion criteria will be randomized into two groups 
(in 1:1 ratio)  
 Levopront® syrup 30 mg/5 ml — 10 ml t.i.d. for 7 days  
 Libexin® 100 mg tablets — 1 tablet t.i.d. for 7 days 
Study treatment period  
The study drugs will be taken t.i.d. (with the interval of not less than 6 hours, between 
meals) during 7 days. The first study drug administration will be performed at the clinical site 
on the day of randomization; the last study drug administration will be performed in the evening 
before Day 8 (±1). 
During the study treatment period, the patients will maintain a diary on a daily basis and fill 
in the daytime and nighttime cough severity frequency data, and intensity data, study drug 
dosing, concomitant medications and adverse events. The patients will be recommended to 
measure the body temperature twice per day: in the morning after waking up and in the evening 
before retiring to bed. 
Patients will visit the clinical site on Days 4 and 8 for assessment of efficacy and safety 
parameters. Patients should bring the completed Diary and the unused study drug at each visit. 
During the visits, physical examination will be performed, vital signs will be assessed, cough 
severity and frequency assessment will be performed using the "Six-point daytime and 
nighttime cough assessment scale", and also cough intensity assessment will be performed 
using the visual-analogue scale. On Day 8, blood and urine samples for laboratory tests will be 


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Page 9 of 66 
collected, spirometry (without bronchodilator) will be conducted, and then the study treatment 
period will be completed. If necessary, the patients will continue treatment according to the 
local standards of medical care. 
Follow-up period  
On Day 10, patients will be contacted by the Investigator via the telephone to follow-up for 
possible adverse events. After that, the patient’s participation in the study will be over.  
Study population: 
Patients from 18 to 65 years old with dry non-productive cough caused by acute upper 
respiratory infection. 
The main inclusion/exclusion criteria: 
Inclusion criteria: 
1. Signed Informed Consent Form 
2. Male or female aged from 18 to 65 (inclusive) 
3. Dry non-productive cough as a symptom of acute upper respiratory infection (IDC 
codes J00-J06) 
4. Daytime cough symptom score ≥ 3 points according to the "Six-point daytime and 
nighttime cough assessment scale"  
5. Pre-bronchodilator FEV1 ≥ 70% of the predicted values, post-bronchodilator FEV1 
increase of ≤ 12% or ≤ 200 ml compared to the baseline, FEV1/FVC (Tiffeneau index) 
≥ 0.7 
6. Patient's consent to follow the protocol procedures, including the completion of the 
patient’s diary 
7. Patient’s consent to use the adequate contraception methods throughout the study 
period. The adequate contraception methods are the following: 
o Oral or transdermal contraceptives 
o Condoms or diaphragms (barrier method) with spermicide 
o Intrauterine contraceptive devices 
Exclusion criteria: 
1. Hypersensitivity or individual contraindications to Levodropropizine, Prenoxdiazine or 
additives of the study drug 
2. Hereditary fructose intolerance, glucose-lactose malabsorption, lactase deficiency, 
sucrose-isomaltose deficiency 
3. Tuberculosis, bronchial asthma, malignant tumors of lungs or bronchi, COPD, severe 
respiratory failure (cyanosis, need for respiratory support) or other lung pathology at 
screening or in history 
4. Inhalation anesthesia within 3 months before screening 
5. Smoking history of more than 10 pack-years 
6. Previous use of cough medicines, ACE inhibitors or amiodarone within 30 days before 
screening. Concomitant use of sedative drugs in particularly sensitive individuals. 
7. Contraindications or inability to perform spirometry 


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Page 10 of 66 
8. Necessity (in the Investigator’s opinion) of prescribing mucolytic agents, expectorants, 
antibiotics or other medications prohibited by the protocol during the study 
9. Excessive mucous excretion which (in the Investigator’s opinion) could be a 
contraindication to prescribing anti-cough medicines; decreased mucociliary function 
(Kartagener's syndrome, ciliary dyskinesia) 
10. Malignant tumors in the past 5 years (except for the basal cell carcinoma) 
11. Serious cardiovascular disease at the moment or within 12 months prior to screening, 
including: Chronic heart failure class III or IV (according to the classification of the 
New York Heart Association), severe arrhythmias requiring treatment with 
antiarrhythmic drugs class Ia, Ib, Ic or III, unstable angina, myocardial infarction, heart 
surgery and coronary arteries, serious valvular heart disease, transient ischemic attack 
or stroke, uncontrolled hypertension with systolic blood pressure > 180 mmHg and 
diastolic blood pressure > 110 mmHg, pulmonary embolism or deep vein thrombosis 
12. Gastric or duodenal ulcers, gastroesophageal reflux disease within a period of 
12 months before screening  
13. Systemic autoimmune disorders and connective tissue diseases that require (currently or 
previously) administration of systemic glucocorticosteroids, cytostatic medications or 
penicillamine 
14. Signs of intensive non-controlled concurrent disease, including disorders of the nervous 
system, endocrine system, kidneys, liver or gastrointestinal tract, which (in the 
Investigator’s opinion) could prevent the patient’s participation in the study 
15. History of alcohol or drug abuse at screening or in the past, which results in the inability 
of the patient to participate in the study at the Investigator’s discretion 
16. Taking part in another clinical trial or use of study drug within 30 days before screening  
17. Pregnant or breast-feeding women or women planning pregnancy during the clinical 
trial; women of childbearing potential (including not sterilized operatively and in 
postmenopausal period of less than 2 years), not using appropriate methods of 
contraception 
18. Inability to read or write; unwillingness to understand and follow the procedures of the 
study protocol; violation of the drug administration regimen or procedure execution 
that, at the discretion of the Investigator, can impact he results of the study or safety of 
the patient and interfere his further participation in the study; any other concomitant 
medical or serious mental conditions that make the patient unsuitable for participation 
in the clinical study, limit the validity of receiving an informed consent or may affect 
the patient's ability to participate in the study 
Patient’s withdrawal  
The randomization procedure will be performed before the laboratory test results 
are available. In case of detecting significant abnormalities that in the Investigator’s 
opinion interfere the patient’s participation in the study, the patient should be 
withdrawn from the study. 
 
 
 


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Page 11 of 66 
Study drug, dosing and mode of administration: 
1. Study drug: Levopront® 
Active substance: Levodropropizine 
Pharmacological class: peripheral cough suppressant 
Pharmaceutical form: syrup 30 mg/5 ml 
Dosing: orally 10 ml (60 mg) t.i.d. with intervals of not less than 6 hours (between the 
meals) 
Package 220 ml brown glass bottle containing 200 ml of solution and closed with an HDPE 
child-proof cap, complete with an LDPE seal and a PP measuring cap. 
Manufacturer: Dompe Farmaceutici S.p.A. (Italy) 
2. Comparator product: Libexin® 
Active substance: Prenoxdiazine 
Pharmacological class: peripheral cough suppressant 
Pharmaceutical form: 100 mg tablets 
Dosing: orally 1 tablet (100 mg) t.i.d., no chewing 
Package: 20 tablets in a blister, one blister per 1 carton 
Manufacturer: Chinoin Pharmaceutical and Chemical Works Private CJSC (Hungary) 
Concomitant and prohibited medications: 
Patients may receive symptomatic treatment of the main disease. 
For symptomatic treatment are permitted antipyretics - NSAIDs: Paracetamol (maximum 
single dose of 2 g, the maximum daily dose of 4 g); ibuprofen (200 mg 3-4 times a day), 
acetylsalicylic acid (a single dose of 0.5-1 g, maximum single dose of 1 g, the intervals between 
doses of the drug for at least 4 hours, the maximum daily dose of 3 g). To improve nasal 
breathing may be used vasoconstrictor nasal drops and sprays. In case of appearing of any 
symptoms of laryngotracheitis it is permitted to use local antiseptics. 
The decision on the appointment of concomitant therapy in each case takes the 
Investigator. 
The patients will take the etiotropic and pathogenetic therapy of the main disease. 
 Patients will not take antibiotics, mucolytics and expectorants, antiviral drugs (except 
Arbidol®); combined "anti-commoncold" drugs; antihistamines; drugs that have a sedative 
effect and reinforcing the depressive effect on the central nervous system, as well as other 
cough suppressants, except for the study drugs. 


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Page 12 of 66 
Duration of the study: 
Each patient’s study participation will last for approximately 10 days and include the 
following stages: screening and randomization (Day 1), study treatment period (7 days), follow-
up period (2 days). 
The first part of the study started on 09 November 2016 (First Visit First Patient) and it has 
been completed on 27 April 2017 (Last Visit Last Patient). For the second part of the study, the 
start of patient enrollment is expected in November, 2017 and the completion of the study visits 
in February 2018. 
Efficacy Endpoints 
The primary efficacy endpoint is the rate of patients responded to the treatment — daytime 
cough symptoms resolution — by Day 8. The daytime cough symptoms resolution corresponds 
to 0 or 1 point according to the "Six-point daytime and nighttime cough assessment scale". 
The secondary efficacy endpoints include:  
 
Rate of patients responded to the treatment — nighttime cough symptoms resolution 
— by Day 8. 
 
Rate of responders with daytime and nighttime cough symptoms resolution according 
to the "Six-point daytime and nighttime cough assessment scale" by Day 4. 
 
Mean change in cough severity and frequency according to the "Six-point daytime and 
nighttime cough assessment scale" on Day 4 and 8 from baseline on Day 1. 
 
Mean change in cough intensity according to the visual-analogue scale on Day 4 and 8 
from baseline on Day 1. 
 
Mean change of FEV1 on Day 8 from baseline on Day 1. 
Safety assessment 
The safety will be evaluated based on the rate of AE and SAE of different severity 
according to the data from subjective complaints, laboratory testing results, physical 
examination, vital signs and spirometry. 
Statistic methods: 
Efficacy analysis 
Per-protocol population analysis (PP) includes all randomized patients completing 
treatment with the study drug, having primary efficacy analysis assessment done and considered 
to be compliant. PP population will be the primary population for efficacy analysis22. 
The primary objective is to demonstrate the "non-inferiority" of Levopront® comparing to 
Libexin® with regards to the primary endpoint. For this purpose, the 97,5% one-sided 
Confidence Interval (CI) will be calculated for the two proportions difference — the rate of 
patients who responded to treatment by Day 8 in the study treatment group and in the control 
group with a non-inferiority margin of δ = 20%. The null hypothesis (H0) that in the study 
treatment group the rate of treatment responders is less than in the control group, will be 
declined if the lower bound of the 97,5% one-sided CI for the two proportions difference is 
located to the right of the  -0.20, with the final conclusion of non-inferiority of Levopront® 
versus Libexin® . 
For the secondary efficacy endpoints analysis, the descriptive statistic methods will be used 
along with calculating the 95% CI and independence testing. To compare the dynamic changes 
of the parameters obtained for the study groups, independent samples T-test will be used. 


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Page 13 of 66 
Safety analysis: 
All patients who receive at least one dose of the study drug will be included into the safety 
population. 
The number and percentage of the patients with AE and SAE for every treatment group 
(along with the total numbers) will be summarized in tables by system organ class and preferred 
term, relationship to the study drug and severity; the laboratory results will be summarized in 
tables with change from baseline. The vital signs, laboratory and spirometry results will be 
summarized by means of descriptive statistics. 
Distribution of patients, demographic and baseline characteristics: 
Distribution of patients, demographic and baseline characteristics will be presented using 
descriptive statistics. Number and percent of patients taking concomitant medications will be 
presented in frequency tables by the therapeutic class and name of active substance. Number of 
patients with preceding medical conditions will be presented. Information about dosing, 
including daily dose, exposure period and total dose will be presented descriptively in each 
treatment group. 
Sample size: 
The sample size is calculated for the primary efficacy endpoint - the proportion of patients 
with response to therapy (daily cough symptoms permission to visit Day 8), and the non-
inferiority hypothesis to the efficacy. 
The sample size estimation in the protocol amendment is based on the results of the study 
interim analysis that showed approximately 70% efficacy in both groups vs. 80% efficacy that 
had been projected initially. Thus the interim analysis at α = 0.05 (one-sided) showed lack of 
power for the hypothesis testing (< 80%).  
In order to achieve power 80%, with corrected α = 0.025 (one-sided)20,21, expected efficacy 
rate of 70% in both groups, non-inferiority margin δ = 20%, and ED rate not exceeding 10%, 
184 patients should be enrolled in the study at 1:1 ration (92 patients per treatment group). 
Assuming the screen-failure rate of about 20%, up to 230 patients will be screened in the 
study. 
Randomization: 
Patients will be randomly assigned into two equal groups (at 1:1 ratio). Randomization will 
be conducted with the use of Interactive Web Response System (IWRS). 
Number and version date of the protocol: 
Protocol LDP0114, Final Version 2.0 (Amendment 1) dated September 14, 2017  
 
 


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Table of Contents 
PAGE OF THE PROTOCOL APPROVAL .............................................................................. 2 
STATEMENT OF THE PRINCIPAL INVESTIGATOR ........................................................ 3 
CONTACT INFORMATION ON THE CLINICAL TRIAL ................................................... 4 
SYNOPSIS ................................................................................................................................ 7 
TABLES .................................................................................................................................. 17 
FIGURES ................................................................................................................................ 17 
ABBREVIATIONS AND TERMS DEFINITIONS ............................................................... 18 
1 
INTRODUCTION ........................................................................................................... 19 
1.1 
Acute respiratory infections of upper airways ....................................................... 19 
1.2 
Medical Therapy of Acute Non-Productive Cough in Acute Respiratory Infections of 
Upper Airways. ...................................................................................................... 19 
1.3 
Development of Levopront ® ................................................................................. 19 
2 
CLINICAL STUDY OBJECTIVES ................................................................................ 21 
2.1 
Primary objective ................................................................................................... 21 
2.2 
Secondary objectives ............................................................................................. 21 
3 
STUDY DESIGN ............................................................................................................ 22 
3.1 
Overall Study Design and Schedule ...................................................................... 22 
3.1.1 
Study Design ............................................................................................... 22 
3.2 
Justification of Study Design ................................................................................. 25 
3.3 
Study Duration and Dates ...................................................................................... 26 
3.3.1 
Preclinical Trials .......................................................................................... 26 
3.3.2 
Clinical Trials .............................................................................................. 27 
3.3.3 
Risk/Benefit Analysis .................................................................................. 28 
3.3.4 
Significant Potential Risks .......................................................................... 29 
4 
SELECTION OF STUDY POPULATION ..................................................................... 31 
4.1 
Study population .................................................................................................... 31 
4.2 
Inclusion Criteria ................................................................................................... 31 
4.3 
Exclusion criteria ................................................................................................... 31 
4.4 
Patient Withdrawal After Randomization ............................................................. 32 
5 
STUDY DRUG ............................................................................................................... 33 
5.1 
Study Drug Description ......................................................................................... 33 
5.2 
Administration of the Study Drug and Randomization ......................................... 33 
5.3 
Treatment Compliance .......................................................................................... 34 
5.4 
Packaging and labeling of the study drug .............................................................. 35 
5.5 
Storage and Account of the Study Drug ................................................................ 35 
5.6 
Concomitant Therapy ............................................................................................ 36 
5.7 
Prohibited Concomitant Therapy........................................................................... 36 
5.8 
Patient Nutrition and Activity Limitations ............................................................ 37 
6 
DESCRIPTION OF PROCEDURES .............................................................................. 38 
6.1 
Informed Consent .................................................................................................. 38 
6.2 
Patient Registration ............................................................................................... 38 


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6.3 
Demographic Data and Medical History ............................................................... 38 
6.4 
Physical Examination ............................................................................................ 38 
6.5 
Vital signs, height, weight ..................................................................................... 38 
6.6 
Electrocardiography............................................................................................... 38 
6.7 
Spirometry ............................................................................................................. 39 
6.8 
Six-point of daytime and nighttime cough assessment scale ................................ 39 
6.9 
Visual Analog Scale .............................................................................................. 39 
6.10 
Patient Diary .......................................................................................................... 40 
6.11 
Tests Performed at Local Laboratory .................................................................... 40 
6.11.1 
Laboratory Parameters ................................................................................. 40 
6.11.2 
Collection, Preparation, Storage and Delivery of Biological Samples ....... 41 
6.12 
Assessment of Adverse Events (AE) ..................................................................... 41 
6.12.1 
Definitions of AEs ....................................................................................... 41 
6.12.2 
Pregnancy .................................................................................................... 42 
6.12.3 
Reporting AEs and SAEs ............................................................................ 42 
6.12.4 
Assessment of AE Severity ......................................................................... 43 
6.12.5 
AE Relatedness to the Study Drug .............................................................. 43 
6.12.6 
Assessment of Expectedness ....................................................................... 44 
6.12.7 
Providing Reports about SAE/Pregnancy ................................................... 44 
6.12.8 
Overdose ...................................................................................................... 45 
6.12.9 
Emergency Procedures ................................................................................ 46 
6.12.10 Assessment of AE with concomitant therapy .............................................. 46 
6.12.11 Clinically Significant Laboratory Abnormalities ........................................ 46 
6.13 
Early Withdrawal of Patients from the Study or Discontinuation of Study Treatment
 ............................................................................................................................... 47 
6.14 
Validity of assessments ......................................................................................... 47 
7 
STUDY PROCEDURES ................................................................................................. 48 
7.1 
Screening and Randomization ............................................................................... 48 
7.1.1 
Visit 1, Day 1 ............................................................................................... 48 
7.2 
Study Therapy ....................................................................................................... 49 
7.2.1 
Visit 2, Day 4 ............................................................................................... 49 
7.2.2 
Visit 3, Day 8 ............................................................................................... 49 
7.3 
Follow up ............................................................................................................... 50 
7.3.1 
Telephone Contact, Day 10 ......................................................................... 50 
7.4 
Unscheduled Visits ................................................................................................ 50 
7.5 
Early Termination Visit ......................................................................................... 50 
8 
QUALITY ASSURANCE ............................................................................................... 51 
9 
STATISTICAL METHODS ........................................................................................... 52 
9.1 
General Provisions ................................................................................................. 52 
9.2 
Sample Size Determination ................................................................................... 52 
9.3 
Randomization ....................................................................................................... 53 
9.4 
Analyzed Populations ............................................................................................ 53 


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9.4.1 
Per Protocol Population ............................................................................... 53 
9.4.2 
Intent-to-Treat Population ........................................................................... 53 
9.4.3 
Safety Population ......................................................................................... 53 
9.5 
Patient Allocation, Demographic and Baseline Characteristics ............................ 53 
9.6 
Study Drug Administration ................................................................................... 53 
9.7 
Efficacy Analysis ................................................................................................... 53 
9.7.1 
Primary Efficacy Endpoint .......................................................................... 53 
9.7.2 
Secondary Efficacy Endpoints..................................................................... 54 
9.8 
Safety Analysis ...................................................................................................... 54 
9.9 
Procedures of Account of Missing, Non-Analyzable and Doubtful Data ............. 54 
9.10 
Procedures of Reporting of Deviations from Primary Statistical Plan .................. 54 
10 ADMINISTRATIVE PROCEDURES ............................................................................ 55 
10.1 
Legal Aspects ........................................................................................................ 55 
10.2 
Investigator’s Responsibilities ............................................................................... 55 
10.3 
Monitoring Procedures .......................................................................................... 55 
10.4 
Data Entry in CRF ................................................................................................. 55 
10.5 
Storage of Documentation ..................................................................................... 56 
10.6 
Ethical Aspects ...................................................................................................... 56 
10.6.1 
Independent Ethics Committee .................................................................... 56 
10.6.2 
Ethical Conduct of the Clinical Study ......................................................... 56 
10.6.3 
Informed Consent ........................................................................................ 56 
10.6.4 
Financing and insurance .............................................................................. 57 
11 REFERENCES ................................................................................................................ 58 
12 APPENDICES ................................................................................................................. 60 
 


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TABLES 
Table 1 
Study Schedule, Protocol LDP0114 ............................................................ 24 
Table 2. 
Laboratory Blood Test Parameters .............................................................. 40 
Table 3. 
Urine Laboratory Parameters....................................................................... 40 
Table 4. 
Causal Relationship to the Study Drug........................................................ 43 
 
FIGURES 
Figure 1. Study Diagram. .................................................................................................. 23 
Figure 2. Draft Label of the Study Drug, Trial LDP0114 ................................................. 35 
Figure 3. Draft of Label of Reference Drug, Trial LDP0114 ............................................ 35 


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ABBREVIATIONS AND TERMS DEFINITIONS 
ADR 
Adverse drug reaction 
AE 
Adverse events 
ALT 
Alanine transaminase 
ARVI 
Acute respiratory viral infection 
AST 
Aspartate transaminase 
BA 
Bronchial asthma 
BMI 
Body mass index 
BP 
Blood pressure 
CI 
Confidence Interval 
CNS 
Central nervous system 
COPD 
Chronic obstructive pulmonary disease 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CVS 
Cardiovascular system 
ECG 
Electrocardiogram/electrocardiography 
ED 
Early discontinuation (early discontinuation visit) 
ESR  
Erythrocyte sedimentation rate 
ET 
End of treatment 
ETV 
Early Termination Visit 
FEV1 
Forced expiratory volume per 1 second 
FS 
Food Supplement 
FVC 
Forced vital capacity 
GGT 
Gamma-glutamyl transferase 
GI tract 
Gastro-intestinal tract 
HDPE 
High density polyethylene 
HR 
Heart rate 
ICD 
International Classification of Diseases 
IEC 
Independent Ethics Committee (local) 
IP 
Investigational product 
IWRS 
Interactive Web Response System 
LDPE 
Low density polyethylene 
MoH RF 
Ministry of Healthcare of the Russian Federation 
NSAID 
Non-steroid anti-inflammatory drugs 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Polypropylene 
RBC 
Red blood cells 
RR 
Respiration rate 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOP 
Standard Operation Procedures 
TC 
Telephone contact 
WBC 
White Blood Cells 
WHO 
World Health Organization 


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1 
INTRODUCTION  
1.1 
Acute respiratory infections of upper airways 
According to International Classification of Diseases, 10th revision (ICD-10) acute 
respiratory infections of upper airways belong to class X, Diseases of the Respiratory System. In 
routine practice, the most common diagnosis corresponding to that complex of symptoms is 
acute respiratory viral infection (ARVI). ARVIs are clinically and morphologically similar acute 
inflammatory respiratory diseases caused by pneumotropic viruses. The epidemiology of ARVI 
is characterized by broad global incidence and includes influenza, para-influenza, respiratory 
syncytial infection, rhinoviral and adenoviral infections, and other catarrhal inflammations of 
upper respiratory tract.1  
Clinical signs of ARVI include typical symptoms, including nasal congestion, rhinorrhea, 
sneezing, throat ache and cough. Cough is one of the most common reasons for seeking 
outpatient medical aid. With estimated annual incidence of respiratory infections of 27.3 – 51.2 
mln cases, approximately ½ of patients of that numerous population seek medical aid for their 
cough symptoms.2  
In clinical practice cough is often classified depending on the underlying cause. Therefore 
high diagnostic value is attributed to information about the time of cough onset, its productivity, 
and related symptoms. 
The commonest causes of acute non-productive cough include ARVI, acute bacterial 
sinusitis, complications of chronic bronchitis, allergic rhinitis, pertussis. 
Cough associated with colds is generally caused by mechanic irritation of respiratory areas 
with secretions from upper airways (postnasal drip, sneezing). Cough may be of significant 
duration because of developing bronchial hyperreactivity. Moreover, acute cough may be a 
symptom of a more serious disease – pneumonia, cardiac failure, pulmonary artery 
thromboembolia (present in almost half of all cases, and being the sole respiratory symptom in 
individual patients), aspiration.3 
1.2 
Medical Therapy of Acute Non-Productive Cough in Acute Respiratory 
Infections of Upper Airways. 
After the nature of cough is determined, etiotropic or pathogenetic treatment of the 
underlying disease should be initiated. Concurrently symptomatic treatment of cough may be 
administered, with either antitussive agents, i.e. those preventing, managing and inhibiting 
cough; 
or 
expectorants 
(protussive) 
agents, 
providing 
more 
effective 
cough.  
  
Antitussive agents are recommended in cases when cough does not lead to clear airways. 
Possible measures include specific antitussive therapy, etiotropic or pathogenetic in nature 
(smoking cessation, removal of causes of postnasal drip). Non-specific antitussive therapy is 
rather symptomatic and is of limited use because of high probability of determining the cause of 
cough and initiation of targeted treatment.3  
1.3 
Development of Levopront ® 
Levopront® is a drug of Dompe farmaceutici S.p.A., Italy, authorized in European Union, 
and established within the past two decades as a reliable and safe cough agent. The active 
ingredient (Levodropropizine) is a levorotary isomer of the dropropizine racemic mixture, and it 
is registered as a non-narcotic anti-cough agent of predominantly peripheral action. 
Levodropropizine suppresses coughing by inhibiting the stimulation of peripheral sensorial 
nerves and modulations of the neuropeptides involved in the coughing reflex. At the same time, 
it does not modify the spirometry parameters, the rheology of the bronchial secretion and the 
ciliary activity of the bronchial epithelium. Levodropropizine does not bind to beta-adrenergic, 


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muscarine, and opioid receptors, it does not have the affinity to H1-histamine and alpha-
adrenergic receptors. The drug has less pronounced effect on the central nervous system, it has 
no effects on cardiovascular system and respiratory functional parameters, nor does it promote 
the development of drug dependence. The sedative effect of the drug is mild. 
This Phase 3 clinical trial is designed to assess the non-inferiority of the efficacy and safety 
of Levopront® (Levodropropizine) 30 mg/5 ml syrup in patients with non-productive cough 
associated with acute upper respiratory tract infection. 


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2 
CLINICAL STUDY OBJECTIVES  
2.1 
Primary objective  
To assess the efficacy of Levopront® in comparison with Libexin® based on daytime cough 
resolution rate by Day 8. 
The daytime cough symptoms resolution corresponds to 0 or 1 points on the "Six-point 
daytime and nighttime cough assessment scale". 
2.2 
Secondary objectives  
Secondary objectives of the study include treatment effect assessment in terms of the 
following efficacy and safety parameters: 
 
To assess the efficacy of Levopront® in comparison with Libexin® based on nighttime 
cough resolution rate by Day 8. 
 
Daytime and nighttime cough symptoms resolution according to "Six-point daytime and 
nighttime cough assessment scale" by Day 4. 
 
Change in severity and frequency of daytime and nighttime cough according to "Six-
point daytime and nighttime cough assessment scale" on Day 4 and Day 8 from baseline 
on Day 1. 
 
Cough intensity change according to the visual-analogue scale on Day 4 and Day 8 from 
baseline on Day 1. 
 
Change of FEV1 on Day 8 from baseline values on Day 1. 
 
Rate of Adverse events (AE) and Serious Adverse Events (SAE) of the various severity 
according to subjective complaints, laboratory test results, physical examination, vital 
signs and spirometry. 
 
 


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3 
STUDY DESIGN 
3.1 
Overall Study Design and Schedule  
This is a multicenter open-label randomized comparative Phase 3 clinical trial in parallel 
groups. The study will be conducted at 8 Russian sites. The total expected number of enrolled 
patients is 184 (92 per each group). Taking into account the possibility of 20% screen-failure 
rate, up to 230 patients will be screened in the study. 
3.1.1 Study Design  
The study will consist of 3 periods: screening and randomization, study therapy, follow-up. 
3.1.1.1 Screening and Randomization.  
At Visit 1, Day 1 after signing the Informed Consent Form, the patients will be screened for 
assessment of inclusion/exclusion criteria. Demography, medical history, and information on 
concomitant medications will be collected; physical examination, vital signs, weight and height 
measurements will be performed; blood and urine samples for laboratory tests will be collected; 
the cough severity and frequency rate will be assessed using the "Six-point daytime and 
nighttime cough assessment scale"; cough intensity will be assessed using the visual-analogue 
scale; ECG and spirometry will be performed (pre- and post-bronchodilator) along with the chest 
x-ray or fluorography. Women of childbearing potential will take the pregnancy test before 
conducting the chest x-ray or fluorography. 
According to the study schedule (considering acute condition of patients), screening and 
randomization will be performed in one day. Patients meeting all inclusion/exclusion criteria will 
be randomized into two groups (at a 1:1 ratio)  
 Levopront® syrup 30 mg/5 ml — 10 ml t.i.d. for 7 days  
 Libexin® 100 mg tablets — 1 tablet t.i.d. for 7 days 
3.1.1.2 Study Treatment Period 
The study drugs will be taken 3 times a day (with the interval of not less than 6 hours, 
between meals) during 7 days. The first study drug administration will be performed at the 
clinical site on the day of randomization; the last study drug administration will be performed in 
the evening before Day 8. 
During the study treatment period, patients will keep a diary on a daily basis and fill in the 
cough severity and frequency data, body temperature, study drug dosing, concomitant 
medications and adverse events. Cough severity and frequency assessment should be performed 
in the morning after waking up using the "Six-point daytime and nighttime cough assessment 
scale" provided in the Diary and in the evening before retiring to bed. Patients will visit the 
clinical site on Days 4 and 8 for assessment of efficacy and safety parameters. Patients should 
bring the completed Diary and the unused study drug at each visit. During the visits, physical 
examination will be performed, vital signs will be assessed, cough severity and frequency 
assessment will be performed using the "Six-point daytime and nighttime cough assessment 
scale", and also cough intensity assessment will be made using the visual-analogue scale. On 
Day 8, blood and urine samples for laboratory tests will be collected, spirometry (without-
bronchodilator) will be conducted, and then the study treatment period will be completed. If 
necessary, patients will continue treatment according to the local standards of medical care. 
 
 


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3.1.1.3 Follow-up Period 
On Day 10, patients will be contacted by the Investigator via the telephone to follow-up for 
possible adverse events. After that, the patient’s participation in the study will be over. 
3.1.1.4 Study Diagram and Study Procedure Schedule 
The summary of the study design and the study schedule are reported in Figure 1 and table 1, 
respectively 
Figure 1. Study Diagram. 
SCREENING AND 
RANDOMIZATION 
STUDY DRUG ADMINISTRATION 
FOLLOW-UP 
Levopront®, syrup 30 mg/5 mL (N=92) 
Libexin®, tablets 100 mg (N=92) 
VISIT (V) 
V1 (Randomization) 
V2 
V3 (ET or ED) 
TC 
DAY (D) 
D1 
D4 
D8 
D10 
 
 


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Table 1 
Study Procedure Schedule, Protocol LDP0114 
 
Screening and 
randomization 
Study treatment 
Follow-up 
Visit (V) 
V1 
V2 
V3 
ET or ED 
TC 
 
Day (D) 
D1 
D4 
D8 
D10 
Visit window 
 
± 1 day 
± 1 day 
± 1 day 
Informed consent 
 
 
 
 
Patient’s registration 
 
 
 
 
Demography data 
 
 
 
 
Medical history 
 
 
 
 
Physical examination 
 
 
 
 
Vital signs 
 
 
 
 
Body height and weight5 
 
 
 
 
Cough severity and frequency 
assessment with the "Six-point 
daytime and nighttime cough 
assessment scale" 
 
 
 
 
Cough intensity assessment with 
the visual-analogue scale. 
 
 
 
 
Laboratory testing: 
 
 
 
 
- hematology  
 
 
 
 
- biochemistry  
 
 
 
 
- urinalysis 
 
 
 
 
- pregnancy test1 
 
 
 
 
ECG 
 
 
 
 
Spirometry2 
 
 
 
 
Chest X-ray or fluorography3 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
Randomization4 
 
 
 
 
Study drug and Patient’s dairy 
distribution to patient4 
 
 
 
 
Return and accountability of the 
study drug, Patient’s dairy review 
 
 
 
 
Concomitant medications 
assessment 
 
 
 
 
AE assessment 
 
 
 
 
Abbreviations: ET — end of treatment, ED — early discontinuation, ECG — electrocardiography, AE — adverse 
events, TC – telephone contact 
Footnotes: 
1 Pregnancy test will be performed at the clinical site using the test-strip (only for the women of childbearing potential 
including the women in menopause of less than two years) before chest x-ray of fluorography. 
2 At visit Day 1 pre- and post-bronchodilator spirometry will be performed. At visit Day 8 only pre-bronchodilator 
spirometry will be performed. 
3 Results of the chest x-ray or fluorography performed before signing the Informed Consent Form as a part of routine 
patient’s examination for main disease (ARVI) can be used for the protocol purposes (if written conclusion report is 
available). 
4 Patient’s randomization and distribution of the study drug to the patient (along with the Patient’s dairy) on Day 1 will 
be performed only after assessment of all inclusion/exclusion criteria. The first dose of the study drug will be taken at 
the clinical site. 
5 The growth measure should be performed only during screening visit. For calculated values of lung function growth 
measured only at screening and weight measured during screening and Visit 3 (Day 8) should be used. 


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3.2 Justification of Study Design 
This is an open-label randomized comparative clinical trial of the efficacy and safety of 
Levopront, syrup 30 mg/5 mL and Libexin, tablets 100 mg in patients with dry non-productive 
cough associated with acute respiratory infection of upper airways. 
Patients from reference group will receive Libexin ®. The choice of Libexin® is based on the 
similarity of its mechanism of action (it is a peripheral antitussive drug) and on the fact that it 
belongs to the same group in the International anatomical therapeutic chemical classification. 
Open design was chosen because of differences in the pharmaceutical forms of the 
investigational drugs and technical problems with blinding process of investigational products. 
Study population includes patients with dry non-productive cough associated with non-
complicated acute respiratory infection of upper airways.  At Visit 1, Day 1 patients meeting 
inclusion/exclusion criteria will be enrolled into the study. During that period patients will 
receive either Levopront®, syrup 30 mg/5 mL or Libexin®, 100 mg tablets  along with 
standardized concomitant treatment allowed by this protocol for 7 days, if necessary. Patients 
will keep a diary where they will record their condition using a "Six-point daytime and nighttime 
cough assessment scale". Assessment of the cough intensity with the visual-analogue scale will 
be done on each visit of the patients at the clinical site.  
Patients with severe and chronic diseases of the respiratory system, burdened with smoking 
anamnesis, as well as patients who have indicated administration of the antibacterial therapy will 
not be included in the study. 
Study drug dosing regimen and treatment duration of 7 days were chosen according to the 
European label. The treatment duration is necessary and sufficient to establish control over 
efficacy of antitussive therapy (frequency of  resolution of cough symptoms) in acute respiratory 
infections of the upper respiratory tract. The intermediate evaluation of the efficacy will be held 
on Day 4. 
The proportion of patients who responded to treatment, i.e. daytime cough symptoms 
resolution by Day 8 Visit was chosen as the primary efficacy endpoint. Resolution of daytime 
cough symptoms corresponds to score 0 or 1 at the Six-point daytime and nighttime cough 
assessment scale. The choice of primary and secondary study endpoints was based on WHO 
recommendations15, national guidelines “Pulmonology. National Guidelines”, concise edition/ed. 
By A.G. Chuchalin. - М. : GEOTAR-Media, 201410, Guidelines for clinical trials ed. by A.N. 
Mironov7. 
Besides the study will assess secondary efficacy endpoints according to spirometry, Diary 
and visual-analog scale. At the end of treatment, all patients will undergo a three-day follow-up 
period to assess the safety parameters.  
The sample size is calculated for the primary efficacy endpoint - the proportion of patients 
with response to therapy (daily cough symptoms to visit Day 8), and the non-inferiority 
hypothesis to the efficacy19,22. 
The aim of this amended protocol  is to provide justification of the increasing of the 
patients number in this study based on the results of the analysis,  planned by the original 
protocol (Final version 1.0),  that showed lack of power due to lower efficacy rate in both 
treatment groups than had been projected initially. 
For this reason this analysis are considered interim analysis and an interim report will 
be issued to show these results. The full final report will be issued at the end of the study 
with the inclusion of the results of all patients. 


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The sample size estimation in the protocol amendment is based on the results of the study 
interim analysis that showed approximately 70% efficacy in both groups vs. 80% efficacy that 
had been projected initially. Thus the interim analysis at α = 0.05 (one-sided) showed lack of 
power for the hypothesis testing (< 80%).  
In order to achieve power 80%, with corrected α = 0.025 (one-sided), expected efficacy rate 
of 70% in both groups, non-inferiority margin δ = 20%, and ED rate not exceeding 10%, 
184 patients should be enrolled in the study at 1:1 ration (92 patients per treatment group).  
This approach complies with the general considerations for sample size re-estimation study 
designs (adaptive design used in both efficacy and BE studies). The alpha correction will provide 
the additional control over the type I error20,21. 
3.3 Study Duration and Dates 
The duration of participation of each patient in the study will be approximately 10 days and 
will include: screening and randomization (1 day), study treatment (7 days, including the day of 
randomization), follow-up (3 days). 
The first part of the study started on 09 November 2016 (First Visit First Patient) and it has 
been completed on 27 April 2017 (Last Visit Last Patient). For the second part of the study the 
start of patient enrollment is expected in November, 2017 and the completion of the study visits 
in February 2018.  
3.3.1 
Preclinical Trials 
Investigational studies of general toxicity (acute, subacute, chronic) of finished 
pharmaceutical form of Levopront® have shown that the drug at acute and chronic experimental 
conditions (3 months) does not exhibit toxic effects in warm-blooded laboratory animals (rodent 
and non-rodent species – rabbits), including at the stage of development. It is of note that 
planning and conduct of the study strictly met Russian MoH requirements and international 
standards in the field of preclinical study of safety of new pharmacological drugs – GLP (Good 
Laboratory Practice). 
Results of toxicometry, data of observations of test animals in postintoxication period of 
acute poisoning, and necropsy data suggest that Levopront (Levodropropizine syrup) belongs to 
class VI of relatively innocuous drugs (H. Hodge et al. Clinical Toxicology of Commercial 
Products. Acute Poisoning. Ed. IV, Baltimore, 1975, 427 p.; K.K. Sidorov, 1973).  
Condition of animals after acute intoxication suggests its good tolerability at doses 
exceeding human therapeutic doses (approximately 0.5 mL/kg) by several ten-fold. 
Subacute (30 days) daily intragastric administration of Levopront in sexually immature 
animals (rats, rabbits) and chronic (90 days) daily intragastric administration of Levopront in 
mature animals (rats, rabbits) had not  harmful effects on the key adaptive systems (nervous, 
cardiovascular, hematopoietic, excretory, respiratory), metabolism, general condition and 
development, key hemostatic body parameters. 
A lack of irritating effects on GI tissues should also be noted. It applies both to rodent and 
non-rodent species, suggesting of universal nature of innocuous properties of the drug. 
The drug has shown to be free of allergenic potential. 
According to Classification of hazardous drugs for clinical use (SI > 5) Levopront® belongs 
to class III of low toxic (low hazardous) drugs. 


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Results of Levopront ® toxicity tests in sexually immature animals supported its safety in 
pediatric population. 
Key pharmacokinetic parameters were defined, and analysis of pharmacokinetic response 
after oral administration of Levorpont® to dogs was performed. No evidence of drug 
accumulation in the body and possible cumulative effects were observed. 
Results of investigation of safety of Levopront (Dompe farmaceutici S.p.A., Italy) support 
low toxicity of the drug both in adult and pediatric populations. 
3.3.2 
Clinical Trials 
Efficacy: 
The administration of levodropropizine has been associated in all studies with a statistically 
significant decrease in cough starting from the first day of treatment, a finding that confirms that 
results may not be attributed to the natural course of the disease.  
Moreover, the observed statistically and clinically significant reduction in the number of 
cough-related night awakenings following levodropropizine treatment should translate into a 
better quality of life, both in children and in adults, particularly in neoplastic patients.  
The magnitude of the drug’s antitussive effect has been shown to be superimposable among 
the different underlying disease groups. This represents an advantage for the drug since use is 
not to be limited to specific etiologic diseases with non-productive cough, but can be extended to 
any lower and upper respiratory tract diseases, to cough associated with asthma, neoplasia, 
whooping cough (pertussis), cardiac cough, and can also be used in the prevention of cough 
during and after surgical interventions or fiberbronchoscopy.  
Types of diseases covered in the conducted trials can be considered representative of those 
present in the population that will receive cough-suppressing agents in clinical practice.  
Controlled studies, both placebo- and active-control, have shown levodropropizine to be 
more active than placebo and equally effective than tested reference drugs (i.e. 
dextromethorphan, clobutinol, dropropizine; dihydrocodeine, cloperastine and morclofone) in 
reducing the frequency of cough as measured by the number of coughing spells in the post-
treatment period in adult patients. Levodropropizine was also shown to be clinically as effective 
as dihydrocodeine in reducing the cough associated with thoracic neoplasia (particularly 
persistent, invalidating cough, resistant even to radiotherapy). 
In children, efficacy has been demonstrated both in a dose-finding study and in comparative 
and/or open-label clinical studies on a total of 608 subjects receiving levodropropizine.  
Finally, the results of a meta-analysis, carried out on an ITT sample rigorously selected 
across trials, and through appropriate patient stratifications, have confirmed the lack of influence 
of cough etiology or patients age on the efficacy of the medication.  
The level of clinical efficacy and substantial benefit from levodropropizine treatment has 
been recognized by the reference medical community and this is reflected in the article "Cough 
Suppressant and Pharmacologic Protussive Therapy: ACCP Evidence-Based Clinical Practice 
Guidelines" published in Chest (Bolser, 2006), where the drug is recommended as the treatment 
of choice, amongst the peripheral cough suppressants, for the short-term symptomatic relief of 
cough in patients with chronic or acute bronchitis. 
Safety: 


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The safety of levodropropizine has been studied in clinical pharmacology and clinical studies 
comprising 107 healthy volunteers and 2868 patients, 788 of whom were under 14 years of age.  
Out of the 2868 subjects exposed to 1-22 days of levodropropizine in clinical studies, 
suspected ADRs have been reported in as few as 60 patients (2.1%) without any excess risk for 
paediatric patients.  
Amongst the reported ADRs, CNS effects, such as cephalalgia, somnolence, 
fatiguability/asthenia accounted for 25 events (0.9%); gastrointestinal events, such as nausea, 
diarrhoea, abdominal cramps, pyrosis/dyspepsia, gastralgia and vomiting for 31 events (1.1%). 
In 1 case dyspnea was reported, but the relationship to levodropropizine administration was not 
assessed.  
Allergic reactions were evident in 7 cases. Cardiovascular organ system was involved in 3 
cases with palpitations and in 1 case with precordial pain; in none of these cases was a 
relationship to study drug considered.  
Tolerability data from clinical studies confirm results from animal experiments with regard 
to the lack of CNS effects of levodropropizine. Indeed, no changes in the EEG pattern or 
significant modifications of the psychomotor performance have been observed. Comparative 
clinical studies have shown that the frequency of somnolence reported with the reference drugs 
(dihydrocodeine, dextromethorphan, clobutinol, dropropizine) was more than double that 
reported with levodropropizine, and at times statistically significant 
Neither age nor concomitant therapies did modify the safety profile, even when 
benzodiazepines were concomitantly administered (Bejor et al., 1988; Arrigo et al., 1988; Bejor 
et al., 1990; Fiocchi et al., 1989; 1991).  
As levodropropizine does not interfere with the respiratory center and with the clearance 
capacity of the lung, drug administration can be considered safe also in patients with severe 
respiratory insufficiency (Bossi et al., 1988).  
Results from special population studies, such as mild to moderate renal impaired and hepatic 
impaired patients, do not contraindicate the use of levodropropizine in such patients. Post 
marketing studies and spontaneous reporting confirmed the frequency and type of AEs observed 
in clinical trials.  
3.3.3 
Risk/Benefit Analysis 
This study is aimed at collecting data on efficacy and safety of Levopront ® in patients with 
acute non-productive cough associated with acute respiratory infection of upper airways. It is 
suggested that study subjects receiving Levopront® for 7 days could be achieved a high 
frequency resolution of cough due to stimulation of peripheral ends of sensitive nerves and 
modulation of neuropeptides involved into the cough reflex. 
According to results of previous preclinical trials, Levopront® was free of allergenic, 
immunotoxic, cancerogenic, mutagenic potential, did not affect respiratory, cardiovascular, 
urinary system, blood hematology and biochemistry parameters. 
Preclinical studies have shown that the drug , both in terms of acute administration, and 
prolonged use for 3 months did not have a toxic effect on the body of warm-blooded laboratory 
animals ( rodents and non-rodents - rabbits ) , including on growing organisms. 
In bioequivalence studies of two pharmaceutical forms of levodropropizine, the drug 
demonstrated good tolerability and safety at single doses. 


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Efficacy and safety of levodropropizine was also evidenced in multiple Phase II and III 
trials, including studies in pediatric populations. 
3.3.4 Significant Potential Risks 
Levopront® is a drug of Dompe Farmaceutici S.p.A., Italy, authorized in European Union 
and in extra European countries (Brazil, Mexico, Chile Columbia, Costa Rica, Ecuador, El 
Salvador, Guatemala, Honduras, Indonesia, Nicaragua, Panama, Philippines, Thailand, 
Venezuela, Turkey, South Korea), and established within the past two decades as a reliable and 
safe cough agent. Potential risks (known side effects) of Levopront include:  
 Eye disorders: Mydriasis, bilateral blindness. 
 Immune system disorders: Allergic and anaphylactoid reactions, eyelid edema, 
angioneurotic edema, urticaria. 
Psychiatric disorders: Nervousness, drowsiness, personality change, or personality 
disorder. 
Nervous system disorders: Syncope, dizziness, vertigo, tremor, paraesthesia, tonic-
clonic seizures and attacks of petit mal, hypoglycemic coma. 
Cardiac disorders: Palpitations, tachycardia, atrial bigeminy. 
Vascular disorders: Hypotension. 
Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, edema of the 
respiratory tract. 
Gastrointestinal disorders: Gastric pain, abdominal pain, nausea, vomiting, diarrhea. 
Hepatobiliary disorders: Cholestatic hepatitis. 
Skin and subcutaneous tissue disorders: Urticaria, erythema, rash, pruritus, 
angioedema, skin reactions, aphthous stomatitis and glossitis. Epidermolysis. 
Musculoskeletal and connective tissue disorders: Weakness of the lower limbs. 
General disorders and conditions regarding the side of administration: General 
malaise, generalized edema, asthenia. 
Preclinical study results have shown that the drug after acute and chronic dosing for 3 
months has no toxic effects in warm-blooded laboratory animals (rodent and non-rodent species 
– rabbits), including developing organisms. 
Potential risks of Libexin include: hypersensitivity reactions: bronchospasm, skin rash, 
angioedema; GI tract disorders: dry mouth and throat, transient numbness and loss of sensitivity 
of the oral mucosa, stomach ache, predisposition to constipations, nausea; nervous system 
disorders: light sedative effect, fatigue (sedative effect and fatigue are observed at doses 
exceeding therapeutic, and all symptoms spontaneously resolve within several hours after drug 
discontinuation). 
The study will include only the patients who agree to use adequate contraception measures 
for the whole study period.  
Particular attention in the study will be paid to adverse events on the part of essential organs 
according to subjective complaints, physical examination, vital signs, laboratory test results, and 
ECG. 
 


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4 
SELECTION OF STUDY POPULATION 
4.1 Study population 
Patients from 18 to 65 years old with dry non-productive cough associated with acute 
respiratory infection of upper airways. Up to 230 patients will pass screening procedures to 
randomize 184 patients into one of two study groups at a ratio of 1:1 
 Levopront® syrup 30 mg/5 ml — 10 ml t.i.d. for 7 days  
 Libexin® 100 mg tablets — 1 tablet t.i.d. for 7 days 
4.2 Inclusion Criteria 
Subjects should meet the following inclusion criteria to be included into this clinical trial: 
1. Signed Informed Consent Form 
2. Male or female aged from 18 to 65 (inclusive) 
3. Dry non-productive cough as a symptom of acute upper respiratory infection (IDC codes 
J00-J06) 
4. Daytime cough symptom score ≥ 3 points according to the "Six-point daytime and 
nighttime cough assessment scale"  
5. Pre-bronchodilator FEV1 ≥ 70% of the predicted values, post-bronchodilator FEV1 
increase of ≤ 12% or ≤ 200 ml compared to the baseline, FEV1/FVC (Tiffeneau index) 
≥ 0.7 
6. Patient's consent to follow the protocol procedures, including the completion of the 
patient’s diary 
7. Patient’s consent to use the adequate contraception methods throughout the study period. 
The adequate birth control methods are as follows: 
o Oral or transdermal contraceptives 
o Condoms or diaphragms (barrier method) with spermicide 
o Intrauterine contraceptive devices 
4.3 Exclusion criteria 
Subjects with any of the following conditions will be excluded from the study: 
1. Hypersensitivity or individual contraindications to Levodropropizine, Prenoxdiazine or 
additives of the study drug 
2. Hereditary fructose intolerance, glucose-lactose malabsorption, lactase deficiency, 
sucrose-isomaltose deficiency 
3. Tuberculosis, bronchial asthma, malignant tumors of lungs or bronchi, COPD, severe 
respiratory failure (cyanosis, need for respiratory support) or other lung pathology at 
screening or in history 
4. Inhalation anesthesia within 3 months before screening 
5. Smoking history of more than 10 pack-years 
6. Previous use of cough medicines, ACE inhibitors or amiodarone within 30 days before 
screening 


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7. Contraindications or inability to perform spirometry 
8. Necessity (in the Investigator’s opinion) of prescribing mucolytic agents, expectorants, 
antibiotics or other medications prohibited by the protocol during the study 
9. Excessive mucous excretion which (in the Investigator’s opinion) could be a 
contraindication to prescribing anti-cough medicines; decreased mucociliary function 
(Kartagener's syndrome, ciliary dyskinesia) 
10. Malignant tumors in the past 5 years (except for the basal cell carcinoma) 
11. Serious cardiovascular disease at the moment or within 12 months prior to screening, 
including: Chronic heart failure class III or IV (according to the classification of the New 
York Heart Association), severe arrhythmias requiring treatment with antiarrhythmic 
drugs class Ia, Ib, Ic or III, unstable angina, myocardial infarction, heart surgery and 
coronary arteries, serious valvular heart disease, transient ischemic attack or stroke, 
uncontrolled hypertension with systolic blood pressure > 180 mmHg and diastolic blood 
pressure > 110 mmHg, pulmonary embolism or deep vein thrombosis 
12. Gastric or duodenal ulcers, gastroesophageal reflux disease within a period of 12 months 
before screening  
13. Systemic autoimmune disorders and connective tissue diseases that require (currently or 
previously) administration of systemic glucocorticosteroids, cytostatic medications or 
penicillamine 
14. Signs of intensive non-controlled concurrent disease, including disorders of the nervous 
system, endocrine system, kidneys, liver or gastrointestinal tract, which (in the 
Investigator’s opinion) could prevent the patient’s participation in the study 
15. History of alcohol or drug abuse at screening or in the past, which results in the inability 
of the patient to participate in the study at the Investigator’s discretion 
16. Taking part in another clinical trial or use of study drug within 30 days before screening  
17. Pregnant or breast-feeding women or women planning pregnancy during the clinical trial; 
women of childbearing potential (including not sterilized operatively and in 
postmenopausal period of less than 2 years), not using appropriate methods of 
contraception 
18. Inability to read or write; unwillingness to understand and follow the procedures of the 
study protocol; violation of the drug administration regimen or procedure execution that, 
at the discretion of the Investigator, can impact he results of the study or safety of the 
patient and interfere his further participation in the study; any other concomitant medical 
or serious mental conditions that make the patient unsuitable for participation in the 
clinical study, limit the validity of receiving an informed consent or may affect the 
patient's ability to participate in the study. 
4.4 
Patient Withdrawal After Randomization 
The randomization procedure will be performed before laboratory test results are available. 
In case of significant abnormalities that in the Investigator’s opinion interfere with the patient’s 
participation in the study, the patient should be withdrawn from the study. 


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5 
STUDY DRUG 
5.1 Study Drug Description 
Study Drug: 
Levopront® 
Active substance: 
Levodropropizine 
Pharmacological Group: 
Antitussive drug with peripheral action 
 
Pharmaceutical form and 
composition: 
syrup 30 mg/5 mL 
Active substance: Levodropropizine 
Excipients: Saccharose, Methyl-p-hydroxybenzoate, Propyl-p-
hydroxybenzoate,Monohydrate citric acid, Sodium hydroxide, 
Cherry flavour, Purified water 
Presentation: 
Package 220 ml brown glass bottle containing 200 ml of 
solution and closed   with an HDPE child-proof cap, complete 
with an LDPE seal and a PP measuring cap. 
Daily dose 
180 mg or 30 mL 
Dosing regimen: 
Orally 10 mL (60 mg) t.i.d. at intervals of at least 6 hours, 
between meals 
Storage conditions: 
Keep in a place, out of reach of children 
Keep at a temperature below 25° С 
Manufacturer: 
Dompe farmaceutici S.p.A. (Italy) 
 
Comparator product:: 
Libexin® 
Active substance: 
Prenoxdiazine 
Pharmacological Group: 
Antitussive drug with peripheral action 
Pharmaceutical form and 
composition: 
100 mg tablets  
Active substance: prenoxdiazine hydrochloride - 100 mg. Other 
ingredients: glycerol (glycerin), magnesium stearate, talc, 
povidone, corn starch, lactose monohydrate. 
Presentation: 
20 tablets in a blister, one blister per 1 carton 
Daily dose 
300 mg 
Dosing regimen: 
orally 1 tablet (100 mg) 3 times a day, no chewing 
Storage conditions: 
Keep at a temperature below 25° С 
Keep in a place, out of reach of children 
Manufacturer: 
Chinoin Pharmaceutical and Chemical Works Private CJSC 
(Hungary) 
NB: Libexin® Prescribing Information are reported in Appendix 1 
5.2 Administration of the Study Drug and Randomization 
At Visit 1, Day 1 all patients complying with selection criteria will be randomized into one of 
the two study groups at 1:1 ratio using an Interactive Web-Response System (IWRS): 
- The group receiving the study drug Levopront ®, syrup 30 mg/5 mL - 92 patients 
- The group, receiving reference drug Libexin®, tablets 100 mg - 92 patients.  


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Randomization and the first intake of study drug at the center is carried out after all the 
procedures for screening and confirmation of the presence of all the inclusion criteria and the 
absence of criteria for exclusion. 
 
Further, patients will take investigational products three times a day at intervals of not less than 6 
hours, between meals. 
The investigational product Levopront® syrup is dispensed by a measuring cup. 
 
Reference drug Libexin®, tablets are swallowed without chewing, with appropriate amount of 
drinking water at room temperature (200-250 mL).  
Overall duration of treatment with the study drug within the study treatment will take 7 days ± 1 
day.  
5.3 Treatment Compliance 
The first dose of the study drug should be taken by patient at the study site under 
Investigator’s control (Visit 1, Day 1). Compliance with guidelines on self-administration of 
study drugs will be checked by Investigator at Visit 2 and 3 based on account of returned study 
drug with the diary filled in by the patient. It should be strictly monitored that patient takes 30 
mL of the study drug or 3 tablets of reference drug daily. 
NB: Patients must take the last dose of the study drug in the evening before Visit 3 (i.e. in 
the evening of Day 7(±1)) because the patients should submitted to the examinations 
requested by the protocol for Day 8 (±1) without having taken the study drug. 
Compliance with the test drug treatment Levopront® will be assessed by the Investigator at 
Visits 2 and 3. All study sites will be provided with certificated scales.  The bottles with syrup 
will be weighted at the study sites before and after dispensing. The Investigator will measure the 
difference between initial and final weight. The density of Levopront® is known (indicated in IP 
documentation), after that calculation of compliance for the syrup will be calculated according to 
the following formula: 
 
Compliance (ml) = 
(m disp. – m return.) 
х 100% 
ρ (g/ml)*V calc.(ml) 
 
where m disp. = the m (g) of dispensed syrup, m (g) return. = the number of returned syrup, 
ρ (g/ml) - density, V (ml) calc. = calculated ml of syrup that the patient had to take from the time 
of previous visit. 
Calculation of compliance for the reference drug will be calculated according to the 
following formula:  
Compliance = (N disp. – N return.)/N calc. х 100% 
where N disp. = the number of dispensed tablets, N return. = the number of returned tablets, 
N calc. = calculated number of tablets that the patient had to take from the time of previous visit. 
Patient compliance for each drug should be similar and be within the interval of 80% to 
120%. In case of need patient should be additionally instructed to take the drug. 
 


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5.4 Packaging and labeling of the study drug 
The study drug will be provided by Sponsor. The study drug will be packed and labeled 
according to the current legislation and applicable requirements, in particular, Federal Law of the 
Russian Federation of April 12, 2010 No 61 FZ On Drug Circulation, current edition.17 
Labeling of the study drugs is shown in Figure 2, 3. 
Figure 2. Draft Label of the Study Drug, Trial LDP014 
 
 
Figure 3. Draft Label of Reference Drug, Trial LDP0114 
 
5.5 Storage and Account of the Study Drug 
Investigator will be responsible for ensuring adequate acceptance, storage, distribution and 
return of the study drug, as well as keeping records of its account and registration in IWRS. 
Limited access and suitable temperature regimen should be ensured. Temperature control 
should be performed using thermometers, registering minimum and maximum temperature in the 
 
For clinical trial only 
Clinical trial N° LDP0114 
Patient n° - 
Visit No __________    KIT XXX* 
Dosage: Take 1 tablet 3 times per day 
Date dispensed __________ 
For clinical trial only 
Clinical trial N° LDP0114 
Patient n° - 
Visit No __________    KIT  XXX* 
Levopront (Levodropropizine), syrup 30 mg/5 mL - 200 ml for oral use 
Dosage: Take 10 mL three times per day. between food intakes 
Keep in a dry, dark place at a temperature below 25° С 
Manufacturer Dompe Farmaceutici S.p.A. (Italy); 
Study sponsor Dompé farmaceutici S.p.A. 
Local contact: IPHARMA LLC Russia, tel. + 7 (495) 276-1143 
Date dispensed __________ 
Batch: ХХХХХХ 
  Expiry date: ХХХХХХХ 
Keep out of reach of children 


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reporting period. Information of temperature monitoring should be regularly included into the 
temperature monitoring log every day at least two times a day.  
Patients will be instructed to return to the study site bottles with the study drug or blisters 
with reference drug at Visit 2 (Day 4) to assess patient compliance. If the study drugs are lost by 
the patient a corresponding record should be made in the source documentation and in the study 
drug log. At the end of the trial after final calculation the study drugs should be returned to 
Sponsor or to its representative. 
5.6 Concomitant Therapy 
Patients may receive symptomatic treatment of the main disease. 
For allowed symptomatic treatment are permitted antipyretics - NSAIDs: Paracetamol 
(maximum single dose of 2 g, the maximum daily dose of 4 g); ibuprofen (200 mg 3-4 times a 
day), acetylsalicylic acid (a single dose of 0.5-1 g, maximum single dose of 1 g, the intervals 
between doses of the drug for at least 4 hours, the maximum daily dose of 3 g). To improve nasal 
breathing may be used vasoconstrictor nasal drops and sprays. In case of appearing of any 
symptoms of laryngotracheitis it is permitted to use local antiseptics. 
The decision on the appointment of concomitant therapy in each case takes the Investigator. 
All basic and concomitant drugs, including food supplements (FS) should be recorded in the 
source documents and in Case Report Form (CRF). It includes all drugs and food supplements 
except the study therapy taken by patients within three months before screening and at any time 
during the clinical trial. Name (predominantly name of the active substance), dosage, frequency 
of dosing, route of administration, indications for use (including underlying disease, concomitant 
conditions, adverse events or prevention), dates of start and completion of the study drug intake 
should be reflected in the source documentation and in CRF. If study therapy intake was ongoing 
at the time of study completion, an appropriate remark should be made in the CRF.  
5.7 
 Prohibited Concomitant Therapy 
During the study treatment with other investigational products and drugs listed below is not 
permitted: 
 Expectorant drugs (Farfara, violet, licorice, marjoram, inula, hormopsis, polygala, althea, 
herpinhydrate, lycorine, ether oil preparations)  
 Mucolytics: 
enzymes 
(trypsin, 
chemotrypsin, 
ribonuclease), 
sulfur-containing 
compounds (acetylcysteine, carbocysteine), vasicine alkaloid derivatives (bromhexine, 
ambroxol)  
 Antitussive agents of central and peripheral action, expect the study IMPs  provided for 
by the study 
 Antibiotics  
 Combined "anti-commoncold" drugs 
 Antihistamines  
 Drugs that have a sedative effect and reinforcing the depressive effect on the central 
nervous system, as well as other cough suppressants, except for the study drugs. 
 Antiviral drugs (except Arbidol®) 


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5.8 Patient Nutrition and Activity Limitations 
Patients should maintain usual diet and limit physical exercise, refrain from alcohol and 
smoking for the whole period of the study. 
For the whole duration of the study, subjects must agree to use adequate contraception measures.  
Adequate birth control measures include:  
 oral or transdermal contraceptives, 
 condom or diaphragm (barrier method) with spermicide or 
 intrauterine device. 


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6 
DESCRIPTION OF PROCEDURES 
All study procedures will be performed according to the requirements and recommendations 
of the Good Clinical Practice guidelines of International Conference for Harmonization (ICH 
GCP) and Eurasian Economic Union (EAEU), principals outlined in the Declaration of Helsinki, 
as well as according to the current legislation and applicable regulations of Russian Federation. 
The Investigator must consent to accept monitoring, audits and inspections at the clinical site and 
provide direct access to the study materials to the Sponsor and its representatives, Independent 
Ethics Committee and regulatory authorities. 
6.1 Informed Consent 
Informed consent will be obtained at screening before any study-related procedures are 
made. 
6.2 Patient Registration  
Each patient signing Patient Information Leaflet and Informed Consent Form will be 
assigned an individual registration number consisting of four digits: 
-
 - the first two 
digits denote the site number, the last two digits – the number of patient at the site (01, 02, 03 
etc.). Guidelines for patient registration in the IWRS will be provided to the Investigator before 
the study. 
6.3 Demographic Data and Medical History  
To asses patient compliance to inclusion/non-inclusion criteria, patient demographic data 
(sex, date of birth/age, race) and full medical history, including significant acute and chronic 
disorders and conditions (e.g. menopause), surgical interventions and allergic reactions should be 
collected. Besides, patient should be asked about hospitalizations and/or surgical interventions 
scheduled within the study period (if applicable). All new diagnoses and conditions detected at 
screening (including results of laboratory and instrumental studies) should be attributed to the 
patient’s medical history. 
History of smoking is assessed by the pack/year index according to the following formula: 
Pack/year index =  
No. of cigarettes per day х Smoking experience (years) 
20 
6.4 Physical Examination 
Physical examination includes assessment of general appearance, condition of skin, mucous 
membranes, neck (including thyroid gland), eyes, ears, nasopharynx, lungs, heart, abdomen, 
lymph nodes and neurological status. 
Changes versus baseline characteristics, determined to be AEs should be appropriately 
reported in the source documentation and in CRF. 
6.5 Vital signs, height, weight 
The examination includes measurement of body temperature in the armpit, sitting blood 
pressure, pulse, respiratory rate. Changes of vital signs versus baseline values, regarded as AEs, 
should be appropriately reported in the source documentation and in CRF. 
Weight and height of patients are measured with shoes off. Body mass index (BMI) is 
calculated according to the following formula: BMI = mass/height2 (kg/m2), where mass is 
measured in kilograms, and height in meters. 
6.6 Electrocardiography 
12-lead electrocardiography (ECG) is performed in supine position. Investigator should 
review the ECG record, assess deviations (if any), sign and date the report. 


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6.7 Spirometry 
Lung function assessment will be performed using regularly calibrated spirometric 
equipment according to the Federal clinical guidelines on spirometry by Russian Respiratory 
Community, 2013. 13 
To assess lung function and whether it meets study inclusion criteria, at Visit 1, Day 1 
spirometry is performed pre- and post-bronchodilator, and registered spirometry parameters shall 
include: 
 Pre-bronchodilator FEV1 ≥ 70% of the predicted values, 
 Post-bronchodilator FEV1 increase of ≤ 12% or ≤ 200 ml compared to the baseline,  
 FEV1/FVC (Tiffeneau index) ≥ 0.7 
At visit on Day 8, spirometry is performed without bronchodilator, spirometry values will 
include FEV1. 
The growth measure should be performed only during screening visit. For calculated values 
of lung function growth measured only at screening and weight measured during screening and 
Visit 3 (Day 8), should be used.  
Tests should meet quality criteria for technical suitability and repeatability. To obtain 
reproducible results, at least three technically satisfying tests corresponding to acceptance 
criteria should be obtained; the best (maximum) result should be reported in the CRF. 
Investigator should review the report of spirometry, assess test results, sign and date the 
report. Change of spirometry values versus baseline determined to be AEs should be 
appropriately reported in the source documentation and in CRF. 
6.8 Six-point of daytime and nighttime cough assessment scale 
Assessment of the severity and frequency of daytime and nighttime cough will be conducted 
with the "Six-point daytime and nighttime cough assessment scale" on visits to the center. Also, 
the patient will independently evaluate the severity and frequency of daytime cough (evening 
before retiring to bed) and nocturnal cough (in the morning after waking up) and enter the data in 
the patient diary. 
"Six-point scale assessment of daytime and nighttime cough" is presented in Appendix 2. 
The patient will choose the most appropriate answer to the question and the corresponding points 
for the daytime and nighttime cough. 
The investigator will record the results of the evaluation of severity  and frequency of 
daytime and nighttime cough in the primary documentation and CRF. 
6.9 Visual Analog Scale 
The cough intensity will be assessed with Visual Analog Scale  (Appendix 3).Visual analog 
scale is a 100 mm line where patient needs to mark cough intensity, where the extreme left point 
corresponds to no cough, and the extreme right point corresponds to severe cough of high 
intensity, significantly impairing daily activities. Investigator will measure the number of 
millimeters reported by patient with a ruler and report results in the source documentation and in 
CRF. 


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6.10 Patient Diary 
During the period of study therapy, patients are on a daily basis to keep a diary in which to 
record the severity and frequency of daytime and nighttime cough, the investigational product 
intake, concomitant treatment, and adverse events occurred.  
Also, patients will be advised to the measurement of body temperature twice a day: in the 
morning after waking and at night before retiring to bed. 
6.11 Tests Performed at Local Laboratory 
Local laboratory will be used for laboratory tests. Collection, preparation and storage of 
biological samples will meet requirements of the study site local laboratory. 
At baseline, all local laboratories will provide the required certificates and laboratory 
reference values. Local laboratory is responsible for sending laboratory reports to the 
Investigator, and for reporting abnormal laboratory values to the Investigator. Investigator should 
review the laboratory report, all abnormal values should be assessed, signed and dated. 
Deviations of laboratory values from baseline, reported as AEs should be appropriately reported 
in the source documentation and in CRF. 
Patient randomization is performed before laboratory test results are available. In case of 
significant abnormality which, at the Investigator’s opinion, could interfere with patient’s 
participation in the study or impact interpretation of efficacy or safety parameters, the patient 
should be withdrawn from the study. 
6.11.1 Laboratory Parameters  
Laboratory tests will be performed at predefined visits (D1 and D8) according to the Study 
Procedure Schedule (Table 1). Table 2 shows laboratory parameters which will be assessed in 
this clinical trial. 
Table 2. 
Laboratory Blood Test Parameters 
Blood 
Hematology 
Blood Biochemistry 
 
Hemoglobin 
Hematocrit 
RBC 
WBC 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Bazophils 
Platelets 
ESR 
Total Protein 
Albumin 
 
Total cholesterol 
Total bilirubin 
Сonjugated bilirubin 
ALT 
AST 
 
Serum 
creatinine 
GFR 
Abbreviations: ESR – erythrocyte sedimentation rate, ALT – alanine transpherase, AST – aspartate 
transaminase, RBC - red blood cells, WBC - white blood cells, GFR - Glomerular filtration rate  
Table 3 shows laboratory parameters of urine to be assessed in this clinical trial. 
Table 3. 
Urine Laboratory Parameters 
Clinical Urine Test 
Special Tests 
General properties: color, clarity, specific gravity, pH, protein, 
glucose, 
bilirubin, 
urobilinogen, 
ketone 
bodies, 
nitrites, 
Pregnancy test (only for women of childbearing potential, 
including women at menopause of less than two years) 


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Clinical Urine Test 
Special Tests 
hemoglobin 
Sediment microscopy: epithelium, erythrocytes, leukocytes, 
casts, bacteria, salts 
6.11.2 Collection, Preparation, Storage and Delivery of Biological Samples 
Collection, preparation, storage and delivery of biological samples will be performed 
according to normative regulations and local laboratory guidelines. The overall volume of blood 
collected from each patient during the study will be approximately 20 mL.  
6.12 Assessment of Adverse Events (AE) 
6.12.1 Definitions of AEs  
Adverse Event (AE) – is any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product which does not necessarily have a causal 
relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, complaint or disorder. In 
this study AEs will be reported from the moment of signing Informed Consent Form (prior to 
administration of the first dose of the study drug) to Day 30 after the last visit of the patient or 
last procedure per protocol. 
Adverse Drug Reaction (ADR) – any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. “Reasonable possibility" means there is 
evidence to suggest a causal relationship between the drug (at any dose) and the adverse event. 
Serious Adverse Event (SAE) and/or Serious Adverse Drug Reaction (SADR) – Any 
adverse medical event which, irrespective of the dose of the study drug: 
- results in death; 
- is life-threatening; 
- requires hospitalization (initial or prolonged); 
- results in significant, persistent or permanent impairment or disability; or 
- is a congenital anomaly or birth defect 
- is an important medical event that may be not immediately life threatening or result in death 
or hospitalization but, based upon appropriate medical judgment, may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
definition above. 
Significant medical events that do not pose an immediate threat to life, do not result in death 
or hospitalization, but put patients at risk or require interventions aimed at the prevention of the 
above outcomes can also be included in SAE/SADR. Examples of such events may include 
bronchospasm of allergic genesis, convulsions, malignant neoplasms. 
NOTE: Hospitalization for social reasons, visits to day patient facility, hospitalization or 
operation preplanned prior to patient enrollment into the study for treatment of underlying 
condition, are not to be considered SAEs. 
Unexpected ADR – ADR of nature and severity not corresponding to the known 
information about the product (e.g. to the Investigator’s Brochure for unauthorized 
investigational product or to the prescribing information for authorized product). The group also 
includes ADRs specified in the investigator’s brochure as characteristic for the class of products 


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or expected as related to the pharmacological properties of the study product, but which had not 
been observed earlier. 
Serious and Unexpected Suspected Adverse Reaction: Any suspected adverse reaction 
that is both serious and unexpected (SUSAR). 
6.12.2 Pregnancy 
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant.  
For the whole duration of the study, subjects must agree to use adequate contraception measures. 
Adequate birth control measures include:  
 oral or transdermal contraceptives, 
 condom or diaphragm (barrier method) with spermicide or 
 intrauterine device. 
Pregnancy is not a SAE, but refers to events that require an urgent reporting to the Sponsor. 
In case of pregnancy during the study, either occurring in a female patient or in a male patient’s 
partner, the pregnancy status should immediately be reported to the Sponsor. Female patient will 
be withdrawn from the study and will be monitored throughout pregnancy and up to 30 days 
after its outcome. Health conditions of any newborn who was conceived during the study will 
also be followed up to 30 days after birth (including pregnancy of patient’s partner). Relevant 
information will be recorded in source documents, CRF and Pregnancy Report Form. Pregnancy 
reports should be completed and e-mailed/faxed following the procedure described in Paragraph 
6.12.7. 
6.12.3 Reporting AEs and SAEs 
At every visit, patients should report any AEs, responding to open, non-probing questions 
(e.g. How have you been doing since the last visit?). For each AE/SAE reported by a patient, the 
Investigator should collect and document in source documents and CRF all the needed 
information, including diagnosis and symptoms, date of onset and date of resolution, outcome, 
severity, criteria of seriousness, circumstances, that may denote possible relatedness to the study 
drug and concomitant therapy, underlying diseases or concomitant conditions, study procedures 
or other causes, actions related to the study drug, pharmaceutical treatment, medical 
interventions, results of laboratory and instrumental tests for AE, other circumstances, which 
may add to comprehensive description of the event 
Within the period of self-administration of the study drug, patients will enter information 
about possible adverse events in a diary. 
Increase in severity of the ongoing adverse event shall be considered a new AE. The date of 
further worsening in severity will be the start date of the new AE, and the previous day shall be 
the end date of the original AE. 
The date of onset of SAE is the date of onset of the seriousness criterion. The preceding 
condition, if applicable, should be reported as a non-serious AE. 
If an AE is serious, Investigator should also promptly submit a SAE report (specifying the 
seriousness criteria), within 24 hours from first knowledge to the IPHARMA Medical Monitor. 
New information about SAE which becomes known later, should be reported to the Sponsor in 
the same way and in the same time.  Besides, the Sponsor should be provided with certified 


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copies of source documents for that SAE (hospital discharge summary, autopsy report, death 
certificate etc.). Data in source document and SAE form shall be duly anonymized. 
AEs should be followed up and reported from the date of signing informed consent to the 
last visit or study related procedure (teleconference at follow-up). Any AE or SAE which is 
spontaneously reported by a patient within 30 days after the last study visit, will be reported and 
assessed in the same way as AEs occurring during the study. AEs should be reported until 
resolution or stabilization of patient’s condition. 
In line with ICH E2A provisions on Post-Study events, although such information is not 
routinely sought or collected by the Sponsor, serious adverse events that occurred after the 
patient had completed a clinical study (including any protocol-required post-treatment follow-
up) will possibly be reported by the Investigator to the Sponsor. Such “post-study cases” should 
be regarded for expedited reporting purposes as though they were study reports. Therefore, a 
causality assessment and determination of expectedness are needed for a decision on whether or 
not expedited reporting is required. 
Monitor is responsible for verifying compliance of CRF and SAE reports to the source 
documentation. 
6.12.4 Assessment of AE Severity 
For each AE, the Investigator will assess the severity grade. For that purpose the following 
severity grading scale is used: 
1. Mild 
Grade 1 - does not interfere with patient’s usual function (awareness of 
symptoms or signs, but easily tolerated [acceptable]). 
2. Moderate 
Grade 2 - interferes to some extent with patient’s usual function 
(enough discomfort to interfere with usual activity [disturbing]). 
 3. Severe 
Grade 3 - interferes significantly with patient’s usual function 
(incapacity to work or to do usual activities [unacceptable]) 
 
For each episode, the highest severity grade attained should be reported. 
It should be noted that severe AEs not always comply with criteria of seriousness, while 
SAE is not always severe. The urgency of reporting of SAE does not depend on the severity of 
the event. 
6.12.5 AE Relatedness to the Study Drug  
For each AE the Investigator should assess its possible causal relationship to the study drug 
according to the Modified WHO scale/ICH E2B, shown in Table 4. 
Table 4. 
Causal Relationship to the Study Drug 


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AE Category 
Definition 
1. None 
(Intercurrent Event) 
An event that is not and cannot be related to the Investigational Product, 
e.g. patient is a passenger in a road traffic accident.  
2. Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test 
abnormality with temporal relationship to drug administration which makes 
a causal relationship improbable and in which other drugs, chemicals or 
underlying disease provide more plausible explanations 
3. Possible 
Relationship may exist, but could have been produced by the patient’s 
condition or treatment or other cause 
4. Probable 
Relationship is likely, the AE abates upon discontinuation of 
Investigational Product and cannot be due to the patient’s condition 
5. Highly Probable 
Strong 
relationship, 
the 
event 
abates 
upon 
discontinuation 
of 
Investigational Product and, if applicable, re-appears upon repeat exposure 
6.12.6 Assessment of Expectedness 
Expectedness will be determined based on the contents of the Investigators’ Brochure/SmPC 
as applicable for the suspected drug. Please also refer to Section 3.4.4 "Significant Potential 
Risks". 
Expected 
An adverse reaction, the nature or severity of which is consistent 
with the applicable product information (e.g. Investigators’ 
Brochure)  
Unexpected 
An adverse reaction, the nature or severity of which is not 
consistent with information in the relevant source document (e.g. 
Investigators’ Brochure) 
 
6.12.7  Providing Reports about SAE/Pregnancy 
All SAE irrespective of severity and relatedness to the study drug, as well as pregnancy 
cases should be reported to IPHARMA Medical Monitor and the Dompé Pharmacovigilance, by 
fax or e-mail, within 24 hours from the moment of first knowledge by the Investigator. 
Information about SAE should be sent in the form of SAE report. Information about pregnancy 
should be sent in the form of pregnancy report. In case of need Investigator may contact with 
Medical Monitor for consultation or explanations. 
Reporting about SAE/pregnancy 
IPHARMA LLC Medical department: 
Medical Monitor: Dmitry Davydov 
Tel+7 (495) 276-1143 
Fax: +7 (495) 276-1147 
Mob.: +7 (915) 397-3447 
e-mail: SAE@ipharma.ru 
 
Dompé Pharmacovigilance: 
Laura Boga, Safety Manager 


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Direct line: +39 02 58383462; Mobile: +39 335 219580 
Fax: +39 02 36026913 
E-mail: farmacovigilanza@dompe.com 
 
IPHARMA Medical Monitor will be then responsible for verifying consistence of 
information reported and data included in SAE/Pregnancy Report Form, obtaining and reporting 
any additional information received from the Investigators, and forwarding fully completed 
SAE/Pregnancy Report Forms to the Dompé Pharmacovigilance, by e-mail immediately and 
anyway within 24 hours of knowledge of event. SAE reports with fatal outcome shall be 
transmitted to the Dompé Pharmacovigilance as soon as possible, and within a maximum 
of 12 hours from the time IPHARMA has knowledge of the death. 
Investigator should instruct each patient to report SAE or pregnancy during study and 30 
days after the last visit to the study site or last study procedure. Investigator should provide in the 
SAE/pregnancy report form all information about the event. Each SAE report form should 
include at least the following information: patient details, event title, seriousness criterion, 
relatedness to the study drug, and outcome at the time of report. 
For primary report the Investigator makes the following remark to the SAE report – 
“Primary report”. If additional information about SAE (for example, new information about 
patient condition or results of laboratory tests) occurs Investigator should fill in a new form of 
SAE report with “Additional report” mark. Original of SAE report form should be kept in 
Investigator File. 
The Investigator (or an authorized staff member) will be responsible for reporting any 
SAEs/SUSARs to the Local Ethics Committee and local institutions in accordance with local 
regulations and requirements.  
The Sponsor shall be responsible to prepare and approve Periodic safety reports and SUSAR 
report and to forward them the IPHARMA for submission. IPHARMA will be responsible 
Periodic safety reporting to the Regulatory Authorities in the Russian Territory and Investigators, 
and expedited reporting of SUSARs to the local Regulatory Authorities, in accordance with local 
regulations and requirements. The Sponsor will be responsible for regulatory reporting outside 
the Russian Territory, as applicable. 
6.12.8 Overdose  
Cases of overdose (accidental or intentional) which may or may not result in serious adverse 
reactions are to be reported by Investigator to IPHARMA and Sponsor Pharmacovigilance, 
following the same procedure for SAE, within 24 hours from the Investigator’s knowledge of its 
occurrence. This includes reports related to drug intake with suicidal intentions and consequent 
drug overdose. 
An overdose of LEVOPRONT  is defined as the administration of more than 30 ml (180 mg)  
on any given treatment day (with allowances of 120% compliance). An overdose of LIBEXIN  is 
defined as the administration of more than 900 mg  on any given treatment day, according 
prescribing information for LIBEXIN. 
The Investigator shall provide in the SAE form information about symptoms, corrective 
treatment and outcome of overdose. 


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6.12.9 Emergency Procedures 
Investigator is responsible for obtaining information about all emergency medical conditions 
of patients in the study. The Patient information leaflet and Informed consent form contains 
contact details of Investigator. Patients will be recommended to contact the Investigator in case 
of any emergencies during the study.  
6.12.10 Assessment of AE with concomitant therapy 
To assess relatedness of AE to concomitant therapy please refer to prescribing information 
for the drugs (State Register of Medicinal Drugs http://grls.rosminzdrav.ru/GRLS.aspx). 
6.12.11 Clinically Significant Laboratory Abnormalities 
Any clinically significant abnormalities of laboratory parameters or results of the 
instrumental methods of examination noted at screening shall be registered in the patient's 
medical history. After screening, new or worsened clinically significant abnormalities shall be 
reported as adverse events in source documents and CRF. 
 


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6.13 Early Withdrawal of Patients from the Study or Discontinuation of Study 
Treatment 
The patient has the right to refuse to take part in the study at any stage without giving 
reasons. 
The patient should be withdrawn from the clinical study if: 
 Investigator considers it important from the medical point of view 
 Patient withdraws his consent 
 Patient does not comply with the study drug dosing regimen or study related procedures 
 AE or SAE which may impact safety or well-being of patient 
 Infection of lower respiratory tract 
 Patient is included into the study with violation of inclusion/exclusion criteria 
In the following cases immediate discontinuation of the study drug is required: 
 Patient starts administration of another study drug 
 Pregnancy in a study subject 
 Significant protocol deviations that may impact patient’s safety and integrity of the study 
data 
 Use of prohibited drugs  
If possible, the Investigator should discuss the need to withdraw the patient with the Medical 
Monitor or inform about patient withdrawal from the study within 48 hours. The reason for 
patient withdrawal should be specified in the source documents and in CRF. If a patient 
discontinues from the study for more than one reason, only the main reason should be specified. 
If a patient withdraws consent because of AE or SAE, the AE or SAE should be specified as the 
reason for patient withdrawal. 
Besides, the Sponsor may terminate the study at any time. The Investigator has the right to 
terminate the study at any time for medical or regulatory reasons. Study may only be terminated 
after mutual consultations between the Investigator and the Sponsor. 
If the study is terminated early, all patients should undergo procedures of early termination 
and all study materials should be returned to the Sponsor or his/her representative. 
Follow up of AEs, SAEs and pregnancy ongoing at the time of study termination should be 
continued per protocol if not agreed otherwise between the Investigator and the Sponsor. 
6.14 Validity of assessments 
Efficacy and safety assessments in patients with dry non-productive cough associated with 
acute respiratory infection of upper airways are standard and well-characterized. Patients will 
receive stable symptomatic treatment for the whole study period. Open, randomized, clinical 
study in parallel groups will enable receiving maximum objective data about efficacy and safety 
of the study drug. 


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7 
STUDY PROCEDURES  
7.1 
Screening and Randomization 
7.1.1 Visit 1, Day 1 
 
Procedure of obtaining Informed Consent 
 
Patient registration  
 
Collection of demographic data, medical history and concomitant therapy 
 
Assessment of the severity  and frequency of daytime and nighttime cough according to 
"Six-point daytime and nighttime cough assessment scale" 
 
Assessment of the cough intensity with the visual-analogue scale 
 
Physical examination 
 
Vital signs 
 
Height, weight 
 
ECG (12 leads) 
 
Collection of blood samples for blood hematology and biochemistry 
 
Collection of urine sample for clinical urine analysis and pregnancy test (women of 
childbearing potential, including women at menopause of less than two years) 
 
Spirometry (pre- and post-bronchodilator use) 
 
Chest X-ray or fluorography 
 
Inclusion/exclusion criteria 
 
Assessment of adverse events  
 
Patient enrolment (After examination, obtaining ECG results, spirometry, fluorography 
(or X-ray) or confirming compliance to all inclusion/exclusion criteria patients will be 
randomized) 
Patients not meeting all inclusion/exclusion criteria will not be included into the study. 
Patients not included into the study for manageable reasons, may once pass re-screening on 
agreement with the Sponsor or his/her representative. 
Randomization 
 
Prescription and dispensing of the study drug (administration of the first dose of the 
study drug at the site) 
 
Assessment of adverse events  
 
Dispensing patient diaries 
Patient randomization is performed before laboratory test results are available. In case of 
significant abnormality which, at the Investigator’s, opinion could interfere with patient’s 
participation in the study or impact interpretation of efficacy or safety parameters, the patient 
should be withdrawn from the study. 


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7.2 
Study Therapy 
7.2.1 Visit 2, Day 4 
(Visit Window Day ±1) 
 
Assessment of adverse events and concomitant therapy 
 
Physical examination 
 
Vital signs 
 
Account of the study drug, compliance assessment 
 
Review of patient diaries  
 
Assessment of the severity and frequency of daytime and nighttime cough according to 
"Six-point daytime and nighttime cough assessment scale" 
 
Assessment of the cough intensity with the visual-analogue scale 
 
Dispensing of the study drug and patient diaries 
 
7.2.2 Visit 3, Day 8  
(Visit Window Day ±1) 
 
Assessment of adverse events and concomitant therapy 
 
Return and account of the study drug, compliance assessment 
 
Review of patient diaries 
 
Assessment of the severity and frequency of daytime and nighttime cough according to 
"Six-point daytime and nighttime cough assessment scale" 
 
Assessment of the cough intensity with the visual-analogue scale  
 
Spirometry 
 
Physical examination 
 
Vital signs 
 
Collection of blood samples for blood hematology and biochemistry 
 
Collection of urine sample for clinical urine analysis and pregnancy test (women of 
childbearing potential, including women at menopause of less than two years) 
NB: Patients must take the last dose of IP in the evening before Visit 3 (i.e. last dose should 
be taken in the evening on Day 7(±1)). On the day of Visit 3 (Day 8 ±1) patients must not take 
the study drug because they will be submitted to the last examinations requested by the 
protocol. Patients must be instructed accordingly. 
 
 
 
 
 


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7.3 
Follow up 
7.3.1 Telephone Contact, Day 10 
(Visit window ± 1 day) 
 
Assessment of adverse events 
7.4 
Unscheduled Visits 
At the Investigator’s discretion patients may be invited to an unscheduled visit at any time 
during clinical trial for safety reasons, should repeated examination or procedure be required. At 
unscheduled visits the Investigator may perform the required procedures, including laboratory 
and instrumental studies. Unscheduled visits should be documented in the source documentation 
and CRF. Unscheduled visits should not modify the preplanned visit schedule per protocol. 
7.5 
Early Termination Visit 
In case of early withdrawal from the study after Visit 1 (Randomization) and before Visit 3 
(Day 8) the patient should be invited to the study site for early termination visit (ETV). 
Investigator should make all reasonable efforts to perform all the required assessments at the 
ETV. Early termination visit should occur not later than on Day 3 after the last dose of the study 
drug. 
ETV should include all procedures of Visit 3, (Day 8). If ETV cannot be performed in full 
volume, the Investigator should agree his/her actions with the Medical Monitor. 
At ETV the patient should return to the site all used and unused packages of the study drug. 
The patient will be given recommendations for further treatment within standard ARVI treatment 
options. 
If possible, the Investigator should discuss patient withdrawal with Medical Monitor in 
advance. Otherwise, the Investigator should contact the Medical Monitor within 24 hours 
after the early termination visit. 


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8 
QUALITY ASSURANCE  
This clinical trial will be performed according to Standard Operating Procedures (SOPs) of 
Sponsor and/or its representative, according to the Good Clinical Practice Guidelines of 
International Conference on Harmonization (ICH GCP) and Eurasian Economic Union (EAEU), 
principles outlined in the Declaration of Helsinki, and applicable regulations of Russian 
Federation. The compliance will be assured by auditing the clinical sites, study data and study 
relevant documents. 
 


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9 
STATISTICAL METHODS 
9.1 
General Provisions 
This is comparative clinical study of efficacy and safety of Levopront®, syrup 30 mg/5 mL 
and Libexin®, 100 mg tablets in patients with drug non-productive cough associated with acute 
respiratory infection of upper airways. 
Statistical analysis described below will be performed according to the statistical analysis 
plan (SAP) created and finalized before database lock. SAP will be included into the clinical 
study report for the present protocol. 
9.2 
Sample Size Determination 
 
The sample size is calculated for the primary efficacy endpoint - the proportion of patients 
with response to therapy (daily cough symptoms permission to visit Day 8) and non-inferiority 
hypothesis. 
According to available data in the literature (Schroeder K., Fahey T. Over-the-counter 
medications for acute cough in children and adults in ambulatory settings) in clinical studies 
antitussives difference between the active treatment group and the placebo group was about 
44%. In the placebo-controlled study (Smith SM, Schroeder K., Fahey T. Over-the-counter 
(OTC) medications for acute cough in children and adults in community settings) the difference 
between the active treatment groups and the placebo group was 25% and 35%. According to the 
meta-analysis of clinical trials of levodropropizine in two placebo-controlled studies the 
difference between the efficacy of the study drug and placebo was 45% in the pediatric 
population of patients (study Fiocchi) and 39% in the adult population of patients (study Allegra, 
where efficacy of levodropropizine was about 80% 17,18). 
According to ICH guideline, the selected non-inferiority margin (non-inferiority margin) 
should not exceed the minimum difference between the performance indicators of the active drug 
and placebo19. Based on the above data, non-inferiority margin δ = 20% was chosen for the 
study. 
The sample size estimation in the protocol amendment is based on the results of the study 
interim analysis that showed approximately 70% efficacy in both groups vs. 80% efficacy that 
had been projected initially. Thus the interim analysis at α = 0.05 (one-sided) showed lack of 
power for the hypothesis testing (< 80%).  
The sample size was calculated using the formula for non-inferiority for comparison of two 
independent proportions: 
n = (Zα/2+Zβ)2 × [p1 × (100% - p1) + p2 × (100% - p2)] / (p1 - p2 - δ)2 
where n – sample size for each group, p1 - success rate in the control group, p2 – success rate 
in the treatment group, δ – non-inferiority margin, Zα/2 is 1.96 for one-sided α = 0.025 and Zβ is 
0.84 for 80% power.In order to achieve power 80%, with corrected α = 0.025 (one-sided)20,21, 
expected efficacy rate of 70% in both groups, non-inferiority margin δ = 20%, and ED rate not 
exceeding 10%, 184 patients should be enrolled in the study at 1:1 ration (92 patients per 
treatment group). 
Assuming the screen-failure rate of about 20%, up to 230 patients will be screened in the 
study. 


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9.3 
Randomization 
Randomization will be performed at Visit 1 with Interactive Web Response System (IWRS). 
Patients will be randomly distributed into one of two study groups at 1:1 ratio (92 patients per 
group). No stratification will be performed. 
9.4 
Analyzed Populations 
9.4.1 Per Protocol Population 
Per-protocol population includes all randomized patients completing treatment with the 
study drug, having primary efficacy analysis assessment done and considered to be compliant. 
Patients without serious deviations from protocol during the study will be considered compliant. 
The key protocol deviations will be discussed in more detail in the SAP and will be determined 
before the date of database lock.. PP population is the primary population for the primary 
endpoint (Non-inferiority) analysis22. 
9.4.2 Intent-to-Treat Population 
The population of patients is based on the initial treatment assignment and not on the 
treatment eventually received (ITT).. 
9.4.3  Safety Population 
All patients who received at least one dose of the study drug will be included into the safety 
population. 
9.5 
Patient Allocation, Demographic and Baseline Characteristics 
Patient distribution, demographic and baseline characteristics will be provided using 
descriptive statistics. The number and per cent of patients taking concomitant drugs will be 
provided in the frequency tables for ATC class, international non-proprietary name (INN). 
Besides, the number of patients with concomitant disorders and underlying conditions will be 
provided. 
9.6 
Study Drug Administration 
Information about dosing, including daily doses, duration of exposure and total doses, will 
be provided descriptively for treatment groups. 
9.7 
Efficacy Analysis 
9.7.1 Primary Efficacy Endpoint  
Primary endpoint: : The main efficacy analysis population includes all randomized patients 
completing treatment with the study drug (PP population) 
Study statistical testing hypothesis will be expressed as: 
H0: Lower bound of the 97.5% one-sided CI (p1-p2) ≤ -20%  Non-inferiority rejected 
H1: Lower bound of the 97.5% one-sided CI (p1-p2) > -20%  Non-inferiority accepted 
The primary objective is to demonstrate the "non-inferiority" of Levopront® comparing to 
Libexin® with regards to the primary endpoint. For this purpose, the one-sided 97.5% CI will be 
calculated for the two proportions difference — the rate of patients who responded to treatment 
by Day 8 in the study treatment group and in the control group with a non-inferiority margin of 
δ = 20%. The null hypothesis (H0) that in the study treatment group the rate of treatment 
responders is less than in the control group, will be declined if the lower bound of the 97.5% 


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one-sided CI for the two proportions difference is located to the right of the  
-0.20, with the final conclusion of non-inferiority of Levopront® versus Libexin®. 
9.7.2 Secondary Efficacy Endpoints 
For the secondary efficacy endpoints analysis, the descriptive statistic methods will be used 
along with calculating the 95% CI and independence testing. To compare the dynamic changes 
of the parameters obtained for the study groups, independent samples T-test will be used. 
9.8 
Safety Analysis 
All patients who receive at least one dose of the study drug will be included into the safety 
population. 
The number and percentage of the patients with AE and SAE for every treatment group 
(along with the total numbers) will be summarized in tables by system organ class and preferred 
term, relationship to the study drug and severity; the laboratory results will be summarized in 
tables with change from baseline. The vital signs, laboratory and spirometry results will be 
summarized by means of descriptive statistics. 
9.9 
Procedures of Account of Missing, Non-Analyzable and Doubtful Data 
Missing data will not be substituted. For analysis of efficacy end points the last observation 
carried forward method (LOCF) will be used. For sensitivity assessment will be used sensitivity 
analyses: first the patients with missing data as failure will be analysed and second the patients 
without substitution of missing data 
9.10 Procedures of Reporting of Deviations from Primary Statistical Plan  
In case of deviations from the planned statistical analysis all changes versus methods 
described in the protocol should be identified. Similarly, if there is a need for some additional 
modifications after analysis, these should be reflected in the study report. 


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10 ADMINISTRATIVE PROCEDURES 
10.1 Legal Aspects 
Names of all patients should be kept strictly confidential. Patient identification is performed 
by assigned number and date of birth. Patients should be informed that any information stored at 
the study site, with the Sponsor or his/her representatives, will be kept in strict compliance with 
confidentiality requirements according to regulatory norms.  
10.2 Investigator’s Responsibilities  
The Investigator shall perform the clinical trial according to the terms specified in this 
Protocol, Guidelines on Good Clinical Practice of the International Conference on 
Harmonization (ICH GCP) and Eurasian Economic Union (EAEU), Helsinki Declaration 
principles, and applicable regulations of the Russian Federation.  
The Investigator shall give his/her consent for monitoring, audits and inspections of the 
study site at any time, and provide direct access to the study materials for the Sponsor and 
his/her representatives, Independent Ethics Committee and authorized bodies at their request. 
The Investigator shall keep originals of all signed Informed Consent Forms and full list of 
study patients specifying their full name, personal number, date of birth, address and telephone 
number to enable their identification. These documents should not be copied for transfer to 
Sponsor or his/her representatives. 
The Investigator shall ensure security of study materials, including source documentation, 
copies of CRF and Investigator File for at least 15 years after study completion or to the time 
specified by the Sponsor.  
10.3 Monitoring Procedures 
The Investigator shall provide direct access to source documentation, CRF and Investigator 
File to Sponsor and his/her representatives, IEC and authorized bodies. Source documentation 
includes primary documents, data and records, including medical history, outpatient records, 
laboratory records, notes, diaries, questionnaires, drug dispensing logs, automatic records, 
verified and certified copies or extracts, photonegatives, microfilms or magnet carriers, X-ray 
images, any records related to patient, including records kept in the pharmacy, in laboratories 
and instrumental diagnostic departments used in clinical study. 
Monitoring will be performed by Sponsor or his/her representative according to Standard 
operation procedures and Study monitoring plan. 
10.4 Data Entry in CRF 
The Investigator should transfer clinical data from source documents to the CRFs. CRF 
completion training for the Investigator will be conducted at the Investigators Meeting and at/or 
during the Site Initiation Visit. If the Investigator delegates the CRF completion responsibility to 
other site employees, their names, positions, initials and signatures should be listed in the 
Delegation of Responsibilities Form and provided to the Sponsor or its representative.  
All changes in CRFs should be made with audit trail; that means that data before and after 
correction should be seen, along with the reason of correction, date and initials of a person who 
made correction. Completed CRFs should be signed by the Investigator. 
The Investigator must transfer the data obtained during clinical trial from the source 
documentation into CRF. The Investigator will review the rules of data entry into CRF during 
investigator meeting and/or during initiation visit. If the Investigator authorizes filling CRF to 


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another member of personnel of the study site, the name, position, signature and initials of such 
persons should be included into the list of distribution of study site personnel responsibilities, 
which is to be provided to the Sponsor or his/her representative.  
If corrections are made in the CRF, physical traces of corrections should be left, i.e. data 
before and after corrections should be kept visible, the reason for correction (if applicable) 
should be available, the date and initials of the person making amendments should be 
documented. Completed CRFs must be electronically signed by the Investigator.  
10.5 Storage of Documentation 
Source documentation, copies of CRF and Investigator File must be stored at the study site 
or in a specially reserved archiving area with limited access for at least 15 years after completion 
of the study or for another term specified by the Sponsor. The Sponsor must be informed in case 
of documentation transfer to other persons or to another institution. Study related materials will 
be kept by the Sponsor and his/her representatives according to the normative regulations.  
10.6 Ethical Aspects 
10.6.1 Independent Ethics Committee 
Prior to clinical study initiation, written approvals of Independent ethics committees (IEC) 
will be obtained according to the Guidelines on Good Clinical Practice of the International 
Conference on Harmonization (ICH GCP) and Eurasian Economic Union (EAEU), Helsinki 
Declaration principles, and applicable regulations of the Russian Federation. The following 
documents should be submitted to IEC: study protocol with amendments, patient information 
leaflet and Informed Consent Form, written materials to be provided to patients, investigator 
brochure, safety information of the study drug, information about payments and compensations 
to patients, academic CV of Investigator, and other documents as required. 
A list of IEC members and declaration of conformity of its organization and operations to 
Good Clinical Practice principles and normative guidelines should be provided to the Sponsor. 
10.6.2 Ethical Conduct of the Clinical Study  
Procedures described in the clinical study protocol, related to its conduct, assessment and 
documentation of results, were developed to guarantee that Sponsor or Investigator comply with 
the Guidelines on Good Clinical Practice of the International Conference on Harmonization 
(ICH GCP) and Eurasian Economic Union (EAEU) and applicable regulations of the Russian 
Federation. This clinical trial will be performed according to the current legislation and 
applicable guidelines. It includes potential audits and inspections of representatives of the 
Sponsor and/or authorized bodies. The Investigator must give consent to monitoring, audits and 
inspections at the study center and provide direct access to study materials to Sponsor and his/her 
representatives, Independent Ethics Committee and authorized bodies. 
10.6.3 Informed Consent  
Prior to clinical study initiation written approvals by Independent Ethics Committee (IEC) 
should be obtained for Patient Information Leaflet and Informed Consent Form as well as any 
other written information which can be provided to patients. Written approval by IEC and 
approved documents will be kept in the Investigator File. 
The process of obtaining informed consent should occur according to the Guidelines on 
Good Clinical Practice of the International Conference on Harmonization (ICH GCP) and 
Eurasian Economic Union (EAEU), Helsinki Declaration principles, and applicable regulations 
of the Russian Federation. Informed Consent Form must be personally signed and dated by the 


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patient before study initiation or any of the study procedures performed. The procedure for 
obtaining informed consent must be described in detail in the source documentation, including 
the fact of patient consent for participation in the clinical study and the date of signing and the 
version of the Informed Consent Form. 
10.6.4 Financing and insurance 
Financing conditions are described in a separate document drawn up between the organizer 
and the research center for the study. 
Participation in the study does not require any financial expenses. The conduct of the clinical 
study is completely sponsored by Dompé farmaceutici s.p.a. (Italy). All clinical study 
procedures, including the administration of the investigational drug, clinical visits, laboratory 
tests and assessments, will be free.  
In the course of the study patients will receive the drugs for treatment of dry cough that will 
be assigned during the study and thermometer for free. 
Participation in this study does not suggest payments to patients. 
Patient’s life and health as a participant of a clinical study is insured according to the 
legislation of the Russian Federation (article 44 of the Federal Law on Drugs Circulation No 61-
FZ of April 12, 2010 and other regulatory requirements in force). Mandatory insurance of the 
clinical study participants will be provided by «INGOSSTRAKH» Insurance Company. The 
address of the insurance company, insurance terms, information about payments and 
compensations is provided in the insurance policy. 


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11 REFERENCES 
1. N.I. Nisevich, V.F. Uchaikin. Infections in Children. — 1st edition. — М.: Medicine, 1990. - 
P. 71-113. - 624 p.  
2. Cough: approaches to diagnostics and treatment. Polyclinic Doctor’s Guide. 2015; 10: 15 
3. А. I. Sinopalnikov, I.L. Kliachkina Central Military Clinical Hospital named after N.N. 
Burdenko, Pulmonology Department State Extension Course Institute for Medical 
Practitioners of the Ministry of Defense of the Russian Federation, Moscow. 
DIFFERENTIAL DIAGNOSIS. Cough. Consilium Medicum. 2004; 1 
4. Register of Drugs RLS, Patient 2003. Moscow, Register of Drugs, 2002. 
5. R.N. Karapetian. Preclinical trials of drugs. Specific pharmacological activity of biologically 
active substance based on bronchial asthma model. Preclinical study report REP-BL-13-1, 
JSC IICR. 
6. T.A. Guskova. Toxicology of Medicines. 2nd Edition, Amended. – М.: МDV., 2008 
7. Guidelines for clinical trials of drugs. Part one. – M: Grif and Co, 2012. – p. 244. 
8. Federal Law of the RF of April 12, 2010 No 61-FZ On Drug Circulation. 
9. National standard of the Russian Federation GOST R 52379-2005. Good Clinical Practice. – 
Moscow, 2005 
10. Pulmonology. National Guidelines. Concise Edition/Ed. By A.G. Chuchialin – M. – 
GEOTAR Media, 2014. – p. 800. 
11. Pulmonology. National Guidelines. Ed. by A.G. Chuchialin. GEOTAR Media, 2009.  
12. Scientific-Practical Edition. Clinical Guidelines. Pulmonology. Ed. by A.G. Chuchialin. 
2005-2006 
13. Russian Respiratory Society. Federal Clinical Guidelines on Spirometry. 2013 
14. H. Hodge et al. Clinical Toxicology of Commercial Products. Acute Poisoning. Ed. IV, 
Baltimore, 1975, 427 p.; K.K. Sidorov, 1973 
15. «WHO Guidelines for Pharmacological Management of Pandemic Influenza A(H1N1) and 
other Influenza Viruses Revised February 2010» 
16. «Guidelines for the management of adult lower respiratory tract infections» G. Huchon, M. 
Woodhead and the ERS TASK FORCE, Eur Respir J 2005; 26: 1138–1180 
17. Allegra L, Bossi R. Clinical trials with the new antitussive levodropropizine in adult 
bronchitic patients.  Arzneimittelforschung. 1988 Aug;38(8):1163-6 
18. Zanasi et al. Levodropropizine for treating cough in adult and children: a meta-analysis of 
published studies Multidisciplinary Respiratory Medicine (2015) 10:19 
19. EMA 
CHMP 
Guideline 
on 
the 
choice 
of 
the 
non-inferiority 
margin 
EMEA/CPMP/EWP/2158/99, 2005 
20. Talibov O.B. Аdaptive design in bioequivalence studies (a review) Vestnik Roszdravnadzora 
#2-2015  
21. Yili L. Pritchett et al. Sample Size Re-estimation Designs In Confirmatory Clinical Trials—
Current 
State, 
Statistical 
Considerations, 
and 
Practical 
Guidance. 
Statistics 
in 
Biopharmaceutical Research Volume 7, 2015 - Issue 4 


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22. FDA Non-Inferiority Clinical Trials to Establish Effectiveness Guidance for Industry, 2016. 


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12 APPENDICES 
Appendix 1  
Libexin® Prescribing Information 
П N015126/01-291008 
 
LIBEXIN PRESCRIBING INFORMATION 
 
Marketing Authorization Number: 
Trade Name: Libexin 
International Non-Proprietary Name: prenoxdiazine 
Pharmaceutical form: tablets. 
Composition 
Active ingredient: prenoxdiazine hydrochloride – 100 mg 
Excipients: glycerol (glycerine), magnesium stearate, talc, povidone, maize starch, lactose 
monohydrate. 
 
Appearance: round, flat, white to off-white tablets beveled at both sides. LIBEXIN 
engraved on one side and a scoreline dividing the tablet into quarters – on the other side of the 
tablet 
 
Pharmacotherapeutic group: antitussive drug of peripheral action. 
ATC code: R05DB18 
 
Pharmacological Properties 
Pharmacodynamics 
Prenoxdiazine is an antitussive drug of peripheral action. The drug inhibits peripheral links 
of cough reflex for the following effects: 
- 
Local anesthetic effect decreasing irritability of peripheral sensitive (cough) airway 
receptors; 
- 
Bronchodilatory activity, blocking stretch receptors involved in cough reflex; 
- 
Slight inhibition of respiratory center activity (without respiratory distress). 
The antitussive effect of the drug is approximately similar to that of codeine. 
Prenoxdiazine does not cause addiction or drug dependence. Anti-inflammatory action of 
prenoxdiazine occurs in chronic bronchitis. 
Prenoxdiazine does not affect the central nervous system function except possible 
indirect anxiolytic action. 
 
Pharmacokinetics 
Prenoxdiazine is quickly and largely absorbed from the gastrointestinal tract. 
Maximum plasma concentration of prenoxdiazine is achieved 30 minutes after drug 
intake, its therapeutic concentration is maintained for 6-8 hours. 
55-59% of the drug is bound to plasma proteins. 
Half-life is 2.6 hours. 
Most part of the dose is metabolized in liver, just about 1/3 of the dose is excreted 
unchanged, the rest of the drug is excreted in the form of metabolites (4 metabolites of 
prenoxdiazine are known). 


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In the first 12 hours of metabolism of prenoxdiazine, biliary excretion of prenoxdiazine 
and its metabolites plays the most important role. 93% of the drug is excreted within 24 
hours after intake. 72 hours after oral intake 50-74% of the dose is excreted with feces and 
26-50% with urine. 
 
Therapeutic Indications 
Non-productive cough of any nature (respiratory catarrh, influenza, acute and chronic 
bronchitis, pneumonia, emphysema, night cough in patients with cardiac failure, patient 
preparation for bronchoscopy or bronchography). 
 
Contraindications 
Hypersensitivity to the drug 
Conditions associated with excessive bronchial secretion. 
Condition after inhalation anaesthesia. 
Galactose intolerability, lactase deficiency or glucose-galactose malabsorption. 
With caution: children. 
 
Pregnancy and lactation 
Libexin use by pregnant and nursing women is only possible if potential benefit for the 
mother outweighs potential risk for fetus and baby. 
 
Posology and Method of Administration 
The mean adult dose is 100 mg three or four times daily (1 tablet 3-4 times a day). In 
more complicated cases the dose may be increased to 200 mg three-four times or 300 mg 
three times daily (2 tablets 3-4 times daily or 3 tablets 3 times daily) 
Mean dose for children depending on age and body weight: 25-50 mg three or four times 
daily (¼– ½ tablets 3-4 times daily). 
Maximum single dose for children is 50 mg (½ tablet) for adults – 300 mg (3 tablets). 
Maximum daily dose for children is 300 mg (2 tablets), for adults – 900 mg (9 tablets). 
As preparation for bronchoscopy the dose of 0.9 – 3.8 mg/kg body weight is combined 
with 0.5 – 1 mg atropine 1 hour before the procedure. 
Tablets need to be swallowed without chewing (to avoid anesthesia of oral mucosa). 
 
Side Effects 
Allergic Reactions 
Rare: - skin rash; 
- 
Angioedema 
Gastrointestinal tract disorders 
Rare: - dry mouth or throat; 
- 
Anesthesia (temporary numbness and loss of sensitivity) of oral mucosa; 
Less than in 10% cases: 
- 
Gastric pain; 
- 
Disposition to constipations; 
- 
Nausea 
Nervous system disorders (at high doses) 
- 
Mild sedative effect; 
- 
Fatigue. 


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Sedative effect and fatigue occur at doses exceeding therapeutic, all symptoms 
spontaneously resolve within a few hours after drug discontinuation. 
 
 
 
Overdosage 
No data about overdosage in humans are available. Sedative effect and fatigue may develop 
if taken at doses exceeding therapeutic. 
 
Drug Interactions 
It is not recommended to combine the drug with mucolytic or expectorant agents, as it may 
inhibit expectoration, fluidified by the latter.  
There are no preclinical or clinical data available on interaction with other drugs. 
 
Special Warnings 
The drug may cause gastrointestinal problems in patients with lactose intolerability, as 
tablets contain lactose (0.38 mg lactose in each tablet). 
 
Effects on Ability to Drive and Perform Operations Associated with Increased Hazard: 
Product intake at high doses may affect the speed of reaction, that is why when the drug is 
taken at high doses, the possibility of driving or performing operations associated with increased 
hazard should be assessed individually. 
 
Presentation 
Tablets 100 mg 
20 tablets in a blister of polyvinylchloride film and Alu foil. 
1 blister and a package insert in a carton pack. 
 
Storage Conditions 
Keep at a temperature below 25 °C. 
Keep out of reach of children. 
 
Shelf Life 
5 years. 
Do not use after the expiry date specified on the package. 
 
Rx Status: 
Over the counter drug 
 
Manufacturer 
CHINOIN Pharmaceutical and Chemical Works, JSC 
1045 Budapest, To U 1-5, Hungary. 
 
Consumer claims are to be sent to the following address: 
115035 Moscow, ul. Sadovnicheskaya, 82, bld. 2 
Tel. (495) 721-14-00, fax (495) 721-14-11. 
 
Acting Director of the Institute of Preclinical and Clinical Drug Expertise  
(signature) 
A.N. Vasiliev 


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(stamp) 
FEDERAL STATE INSTITUTION * MOSCOW 
Scientific Center of Expertise of Medicinal Drugs 
Ministry of Healthcare of the Russian Federation 
Institute of Preclinical and Clinical Drug Expertise 
 
For Copies and Instructions 
Company Representative  
 
 
(signature)  
A.B. Raskurazhev 
(stamp) 
Representation of joint stock company * Permission of State Register under the Ministry of 
Justice of the Russian Federation No 11772 * Moscow 
Sanofi-aventis groupe (France) 
 
 
 


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(stamp) 
RUSSIAN MINISTRY OF HEALTHCARE 
П N015126/01 – 19.07.13 
APPROVED 
 
MINISTRY OF HEALTHCARE OF THE RUSSIAN FEDERATION 
 
PRESCRIBING INFORMATION 
For a medicinal drug 
 
Libexin 
Name of the medicinal drug 
 
Tablets 
Pharmaceutical form, dosage 
 
CHINOIN Pharmaceutical and Chemical Works, JSC, Hungary 
Manufacturer name, country 
 
Amendment No 1 
 
Date of amendment: 19/07/13 
 
Previous Version 
Current Version 
Side effects 
Allergic Reactions 
Rare: - skin rash; 
- 
Angioedema 
 
Gastrointestinal tract disorders 
- 
Rare: - dry mouth or throat; 
- 
Anesthesia (temporary numbness and 
loss of sensitivity) of oral mucosa; 
- 
Less than in 10% cases: 
- 
Gastric pain; 
- 
Disposition to constipations; 
- 
Nausea 
Nervous system disorders (at high doses) 
- 
Mild sedative effect; 
 
Side effects 
Allergic Reactions 
Rare: - skin rash; 
- 
Angioedema 
Frequency unknown: bronchospasm 
Gastrointestinal tract disorders 
- 
Rare: - dry mouth or throat; 
- 
Anesthesia (temporary numbness and 
loss of sensitivity) of oral mucosa; 
- 
Less than in 10% cases: 
- 
Gastric pain; 
- 
Disposition to constipations; 
- 
Nausea 
Nervous system disorders (at high doses) 
Mild sedative effect 
 
 


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Appendix 2 
Six-point daytime and nighttime cough assessment scale  
 
Score 
Daytime cough 
Score Nighttime cough 
0 
No cough 
0 
No cough 
1 
Single cough impulses 
1 
Cough does not interfere with sleep 
2 
Rare cough at daytime 
2 
Cough interrupting sleep not more 
than 2 times in a night 
3 
Frequent cough not interfering with 
daily activities 
3 
Cough interrupting sleep over 2 
times in a night 
4 
Frequent 
cough 
impairing 
daily 
activities 
4 
Frequent sleep interruption caused 
by cough 
5 
Severe cough, impossible to maintain 
daily activities 
5 
Cough precluding sleep 
 
 


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Appendix 3 
 
Visual analog scale 
 
Please mark on the scale below your cough intensity. 
 
 
 
NB: Please use only VAS provided by IPHARMA and avoid to perform any copy of the form.  
 
In case, for any reason, you need to perform a reproduction of the form, after any reproduction 
verify the length of the VAS: the line must be 100 mm 
 Cough Intensity 
 
 
                        no cough                                                                                                                            Heavy, Severe cough 

SAP_001.pdf: 


LDP0114 Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS 
5 
2. 
INTRODUCTION 
6 
2.1 
Study Design 
6 
2.2 
Sample Size 
7 
2.3 
Study Objectives 
8 
3. 
INTERIM ANALYSIS, FINAL ANALYSIS AND UNBLINDING 
9 
4. 
ENDPOINTS AND COVARIATES 
9 
4.1 
Efficacy endpoints 
9 
4.2 
Safety endpoints 
9 
5. 
ANALYSIS SETS 
9 
5.1 
Per Protocol Population 
9 
5.2 
Intent-to-Treat Population 
9 
5.3 
Safety Analysis Set 
9 
5.4 
Protocol Deviations 
9 
6. 
HANDLING OF MISSING VALUES 
10 
6.1 
Efficacy Parameters 
10 
6.2 
Safety Parameters 
10 
6.2.1 
Missing onset dates in AE 
10 
7. 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
10 
7.1 
Statistical Methods 
10 
7.2 
Statistical Analyses 
10 
7.2.1 
Disposition of Subjects 
10 
7.2.2 
Demographic and baseline characteristics 
10 
7.2.3 
Primary Efficacy Analysis 
11 
7.2.4 
Secondary Efficacy Analyses 
11 
7.3 
Safety Analysis 
12 
7.3.1 
Adverse Events 
12 
7.3.2 
Laboratory Data 
12 
7.3.3 
Compliance 
12 
7.3.4 
Vital Signs Data 
12 
7.3.5 
Physical Examination Data 
12 
7.3.6 
Concomitant Treatments 
13 
7.3.7 
Listings 
13 
7.4 
Changes in the planned analyses 
13 
8. 
REFERENCES 
13 
9. 
TABLE EXAMPLES 
14 
9.1 
Demographics and baseline 
14 
9.2 
Efficacy 
16 
9.3 
Safety 
19 
 


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LIST OF TABLE’S SHELLS 
Table 2.1 
Study procedure Schedule 
7 
Table 9.1 
Disposition 
14 
Table 9.2 
Demographic and other baseline characteristics.  ITT analysis set. Screening 
(baseline). N = xx 
14 
Table 9.3 
Medical history. ITT analysis set. Screening (baseline). N = xx 
15 
Table 9.4 
Ongoing diseases/diagnosis/abnormalities. ITT analysis set. Screening 
(baseline). N = xx 
15 
Table 9.5 
Previous medication. ITT analysis set. 
15 
Table 9.6 
Physical examination. ITT analysis set. Screening. N = xx 
16 
Table 9.7 
Vital signs. ITT analysis set. Screening. N = xx 
16 
Table 9.8 
Primary efficacy. Daytime cough resolution. 
16 
Table 9.9 
Primary efficacy. Daytime cough resolution. 
17 
Table 9.10 
Secondary efficacy. Nighttime cough resolution. 
17 
Table 9.11 
Secondary efficacy. Daytime and Nighttime cough resolution. 
17 
Table 9.12 
Change in severity and frequency of daytime and nighttime cough on Day 4 and 
Day 8 from baseline on Day 1. ITT population. N = xx 
17 
Table 9.13 
Cough intensity change according to the visual-analogue scale on Day 4 and Day 
8 from baseline on Day 1. ITT population. N = xx 
18 
Table 9.14 
Change of FEV1 on Day 8 from baseline values on Day 1. 
19 
Table 9.15 
Physical examination. Safety population. N = xx 
19 
Table 9.16 
Vital signs. Safety population. N = xx 
20 
Table 9.17 
Urine pregnancy test (females only). Safety population. N = xx 
21 
Table 9.18 
Concomitant medication. Safety population. 
21 
Table 9.19 
Laboratory parameters. Hematology. Deviation from normal values. Safety 
population. N = xx 
21 
Table 9.20 
Laboratory parameters. Hematology. CS deviations only. Safety population. N = 
xx 
21 
Table 9.21 
Laboratory parameters. Biochemistry. Deviation from normal values. Safety 
population. N = xx 
21 
Table 9.22 
Laboratory parameters. Biochemistry. CS deviations only. Safety population. N = 
xx 
22 
Table 9.23 
Laboratory parameters. Urinalysis. Deviation from normal values. Safety 
population. N = xx 
22 
Table 9.24 
Laboratory parameters. Urinalysis. CS deviations only. Safety population. N = xx 
22 
Table 9.25 
Laboratory parameters. Microscopic urine examination. Deviation from normal 
values. Safety population. N = xx 
23 
Table 9.26 
Laboratory parameters. Microscopic urine examination. CS deviations only. 
Safety population. N = xx 
23 
Table 9.27 
Laboratory parameters. Hematology. Absolute values. 
23 
Table 9.28 
Laboratory parameters. Biochemistry. Absolute values. 
23 
Table 9.29 
Laboratory parameters. Urinalysis. Absolute values. 
23 
Table 9.30 
Laboratory parameters. Microscopic urine examination. 
24 
Table 9.31 
Compliance. Safety population. N = XX 
24 
Table 9.32 
Adverse Events (including SAE) started before the first dose of the study drug(s). 
Safety population. N = xx 
24 


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Table 9.33 
Adverse events. Summary table. Safety population. N = XX 
24 
Table 9.34 
Adverse Events (including SAE). Safety population. N = xx 
24 
Table 9.35 
Adverse Events (including SAE) and severity. 
25 
Table 9.36 
Adverse Events (including SAE) and relation to study drug(s). 
25 
Table 9.37 
Serious Adverse Events (only). Safety population. N = xx 
25 
Table 9.38 
Serious Adverse Events (only) and severity. 
25 
Table 9.39 
Serious Adverse Events (only) and relation to study drug(s). 
25 
 


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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AP 
Arterial Pressure 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CLcr 
Creatinine Clearance 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Clinically Significant 
ECG 
Electrocardiogram 
ESR 
Erythrocyte Sedimentation Rate 
FEV1 
Forced Expiratory Volume for a second 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
HBV, HCV 
Hepatitis B and C  
IC 
Informed Consent 
ICH 
International Conference on Harmonization 
ICH GCP 
Guidelines for Good Clinical Practice of the International 
Conference on Harmonization 
IEC 
Independent Ethics Committee  
ITT 
Intent-to-treat 
LME 
Linear Mixed Effect Model 
Mean 
Mean value 
N 
Number of observations 
PP 
Per Protocol 
PTT 
Prothrombin Time 
p-value 
p-value for H0 of test performed 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
TESS 
Treatment Emergency Sign and Symptom 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION 
This document contains further details to the statistical analyses described in the 
protocol LDP0114 and is the primary source of all statistical analyses for the study. 
2.1 
STUDY DESIGN 
The present study is a multicenter open-label randomized comparative Phase 3 clinical 
trial in parallel groups. The study will be conducted at 8 Russian sites. The total 
expected number of enrolled patients is 184 (92 per each group). Taking into account 
the possibility of 20% screen-failure rate, up to 230 patients will be screened. 
The study will consist of 3 periods: screening and randomization, study therapy, follow-
up. 
Patients meeting all inclusion/exclusion criteria will be randomized into two groups (at 
a 1:1 ratio): 
 Levopront® syrup 30 mg/5 ml — 10 ml t.i.d. for 7 days 
 Libexin® 100 mg tablets — 1 tablet t.i.d. for 7 days 
The study drugs will be taken 3 times a day (with the interval of not less than 6 hours, 
between meals) during 7 days. The first study drug administration will be performed at 
the clinical site on the day of randomization; the last study drug administration will be 
performed in the evening before Day 8. 
Figure 2.1 Study diagram 
 


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Table 2.1 
Study procedure Schedule 
 
 
 
2.2 
SAMPLE SIZE1 
The sample size is calculated for the primary efficacy endpoint - the proportion of 
                                            
1 Citation from the protocol 


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patients with response to therapy (daily cough symptoms permission to visit Day 8) 
and non-inferiority hypothesis. 
According to available data in the literature (Schroeder K., Fahey T. Over-the-counter 
medications for acute cough in children and adults in ambulatory settings) in clinical 
studies antitussives difference between the active treatment group and the placebo 
group was about 44%. In the placebo-controlled study (Smith SM, Schroeder K., 
Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in 
community settings) the difference between the active treatment groups and the 
placebo group was 25% and 35%. According to the meta-analysis of clinical trials of 
levodropropizine in two placebo-controlled studies the difference between the efficacy 
of the study drug and placebo was 45% in the pediatric population of patients (study 
Fiocchi) and 39% in the adult population of patients (study Allegra, where efficacy of 
levodropropizine was about 80%1,2). 
According to ICH guideline, the selected non-inferiority margin (non-inferiority margin) 
should not exceed the minimum difference between the performance indicators of the 
active drug and placebo3. Based on the above data, non-inferiority margin       
was chosen for the study. 
The sample size estimation in the protocol amendment is based on the results of the 
study interim analysis that showed approximately 70% efficacy in both groups vs. 80% 
efficacy that had been projected initially. Thus, the interim analysis at α = 0.05 (one-
sided) showed lack of power for the hypothesis testing (< 80%). 
The sample size was calculated using the formula for non-inferiority for comparison of 
two independent proportions: 
     
     
 
                                        
where   – sample size for each group,    - success rate in the control group,    – 
success rate in the treatment group,   – non-inferiority margin,   
  is 1.645 for one-
sided        and    is 0.84 for 80% power. 
In order to achieve power 80%, with corrected α = 0.025 (one-sided), expected efficacy 
rate of 70% in both groups, non-inferiority margin δ = 20%, and ED rate not exceeding 
10%, 184 patients should be enrolled in the study at 1:1 ration (92 patients per 
treatment group).  
Assuming the screen-failure rate of about 20%, up to 230 patients will be screened in 
the study. 
2.3 
STUDY OBJECTIVES 
To assess the efficacy of Levopront® in comparison with Libexin® based on daytime 
cough resolution rate by Day 8. 
The daytime cough symptoms resolution corresponds to 0 or 1 points on the "Six-point 
daytime and nighttime cough assessment scale". 
                                            
1 Allegra L, Bossi R. Clinical trials with the new antitussive levodropropizine in adult bronchitic patients. 
Arzneimittelforschung. 1988 Aug;38(8):1163-6 
2 Zanasi et al. Levodropropizine for treating cough in adult and children: a meta-analysis of published studies 
Multidisciplinary Respiratory Medicine (2015) 10:19 
3 EMA CHMP Guideline on the choice of the non-inferiority margin EMEA/CPMP/EWP/2158/99, 2005 


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3. 
INTERIM ANALYSIS, FINAL ANALYSIS AND UNBLINDING 
No interim analysis is planned. 
There is open-label study. No unblinding required. 
4. 
ENDPOINTS AND COVARIATES 
4.1 
EFFICACY ENDPOINTS 
Primary efficacy endpoint 
 To assess the efficacy of Levopront® in comparison with Libexin® based on 
daytime cough resolution rate by Day 8. 
Secondary efficacy endpoints 
 To assess the efficacy of Levopront® in comparison with Libexin® based on 
nighttime cough resolution rate by Day 8 
 Daytime and nighttime cough symptoms resolution according to “Six-point 
daytime and nighttime cough assessment scale” by Day 4 
 Change in severity and frequency of daytime and nighttime cough according to 
“Six-point daytime and nighttime cough assessment scale” on Day 4 and Day 8 
from baseline on Day 1 
 Cough intensity change according to the visual-analogue scale on Day 4 and 
Day 8 from baseline on Day 1 
 Change of FEV1 on Day 8 from baseline values on Day 1 
4.2 
SAFETY ENDPOINTS 
Rate of Adverse events (AE) and Serious Adverse Events (SAE) of the various severity 
according to subjective complaints, laboratory test results, physical examination, vital 
signs and spirometry. 
5. 
ANALYSIS SETS 
5.1 
PER PROTOCOL POPULATION 
Per-protocol population includes all randomized patients completing treatment with the 
study drug, having primary efficacy analysis assessment done and considered to be 
compliant. Patients without serious deviations from protocol during the study will be 
considered compliant. The key protocol deviations will be determined before the date 
of database lock. PP population is the primary population for the primary endpoint 
(Non-inferiority) analysis  
5.2 
INTENT-TO-TREAT POPULATION 
The population of patients is based on the initial treatment assignment and not on the 
treatment eventually received (ITT). 
5.3 
SAFETY ANALYSIS SET 
All patients who received at least one dose of the study drug will be included into the 
safety population. 
5.4 
PROTOCOL DEVIATIONS 
A full list of protocol deviations will be compiled and reviewed to identify major and 


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minor deviations prior to database lock. 
6. 
HANDLING OF MISSING VALUES 
6.1 
EFFICACY PARAMETERS 
Replacement of missing data is not planned for efficacy parameters. 
6.2 
SAFETY PARAMETERS 
6.2.1 
Missing onset dates in AE 
AE with missing onset date will be counted as TESS (Treatment Emergency Sign and 
Symptom). 
In case of AE date is incomplete following rules will be used: 
Day 
Month 
Year 
Condition 
Missing 
Missing 
In place 
In case of month and year of onset > date of 
start study time (IC date) - TESS 
Missing 
Missing 
In place 
In case of year of onset > year of start study 
time (IC date) - TESS 
Missing 
Missing 
Missing 
TESS 
Missing 
In place 
Missing 
TESS 
Missing 
Missing 
In place 
Year of onset > year of start study time (IC 
date) - TESS 
 
7. 
STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
7.1 
STATISTICAL METHODS 
Statistical analysis will be done using statistical software R (www.r-project.org). 
For the statistical analysis is planned to use descriptive statistics, confidence intervals 
for difference in proportion (See section 8 [1]), mixed-effect model, two sample t-test, 
one-sample t-test, Wilcoxon test, Mann-Whitney test, Fisher exact test, Shapiro-Wilk 
test and permutation tests (See section 8 [2]). 
7.2 
STATISTICAL ANALYSES 
7.2.1 
Disposition of Subjects 
Disposition of all subjects (enrolled, randomized, discontinued) in analyzed population 
will be presented.  
7.2.2 
Demographic and baseline characteristics 
This data will be presented for ITT population by treatments group at baseline (Day 1). 
Continuous data will be presented with number of non-missing values, mean, standard 
deviation, median, minimal and maximal values.  
Nominal data will be presented with absolute and relative (percent) frequencies. 
Between groups continuous data will be compared using unpaired Student’s t-test (for 
normally distributed data) or Mann-Whitney test (for free distribution data). Between 
groups binominal data will be compared using Fisher exact test, for categorical data 
Mann-Whitney test will be used. 


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7.2.3 
Primary Efficacy Analysis 
According to the Guideline EMA/EWP-482 (Superiority-non-inferirority and switching), 
in non-inferiority study primary analysis must be performed on Per-Protocol population 
(see chapter IV.1.4 Choice of analysis set of the guideline). 
The main efficacy analysis population is defined as Per-Protocol (PP). 
Study statistical testing hypothesis is expressed as: 
H0: Lower bound of the 97.5% one-sided CI (p1-p2) ≤ -20% => Non-inferiority rejected  
H1: Lower bound of the 97.5% one-sided CI (p1-p2) > -20% => Non-inferiority 
accepted 
The primary objective is to demonstrate the "non-inferiority" of Levopront® comparing 
to Libexin® with regards to the primary endpoint. For this purpose, the one-sided 
97.5% Confidence Interval (CI) will be calculated for the two proportions difference — 
the rate of patients who responded to treatment (cough absents, when score is 0 or 1 
at “six-point cough scale” vs. cough presents, when score is ≥ 2 at “six-point cough 
score”) by Day 8 in the study treatment group and in the control group with a non-
inferiority margin of δ = 20%. The null hypothesis (H0) that in the study treatment 
group the rate of treatment responders is less than in the control group, will be 
declined if the lower bound of the 97.5% one-sided CI for the two proportions 
difference 
is 
located 
to 
the 
right 
of 
the  
-0.20, with the final conclusion of non-inferiority of Levopront® versus Libexin®. 
The proportion difference will be calculated using Newcombes Hybrid Score method 
(1998). See 8 [1]. 
7.2.4 
Secondary Efficacy Analyses 
Secondary efficacy analysis will be performed on the ITT population. 
7.2.4.1 
Nighttime cough resolution rate by Day 8 
Nighttime cough symptoms will be classified as Absent (<2 at six-point cough scale) or 
Present (≥2 at six-point cough scale). For such derivation treatment groups will be 
compared using the Fisher exact test. 
7.2.4.2 
Daytime and nighttime cough symptoms resolution by Day 4 
Daytime and Nighttime cough symptoms will be classified as Absent (<2 at sit-point 
cough scale) or Present (≥2 at six-point cough scale). Resolution Daytime (<2 at 
scale) and Nighttime (<2 at scale) symptoms at Day 4 will be described by treatment 
groups. Treatment groups will be compared using the Fisher exact test. 
7.2.4.3 
Change in severity and frequency of daytime and nighttime cough on Day 4 
and Day 8 from baseline on Day 1 
Scores from the six-point cough scale will be described by visits and treatment groups 
together with changes from baseline (Day 1). Within group change will be tested using 
paired t-test (normal data) or Wilcoxon sign test (violation of normality), between 
groups test – two sample t-test (normal data) or Mann-Whitney test (violation of 
normality). Test for normality – Shapiro-Wilk. 
Treatment groups will be also compared at baseline (Day 1). In case of significant 
difference (statistically) in scores\values at baseline a mixed-effect model will be 


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discussed. 
Parameter dynamics also will be presented with graphics (see Figure 9.1).  
7.2.4.4 
Cough intensity change according to the visual-analogue scale on Day 4 and 
Day 8 from baseline on Day 1 
Analysis is similar to 7.2.4.3. 
7.2.4.5 
Change of FEV1 on Day 8 from baseline values on Day 1 
Analysis is similar to 7.2.4.3. 
7.3 
SAFETY ANALYSIS 
Analysis will be performed for the safety population. 
7.3.1 
Adverse Events 
Adverse Events will be summarized by treatment groups. Relation of AE to the therapy 
will be defined by AE onset date and period start date for the patient. All AEs will be 
coded with MEDDRA dictionary. AEs will be summarized by SOC (System Organ 
Class) and PT (Preferred Terms). 
Adverse Events (if any) started before the first dose of the study drug(s) will be 
presented in the separate table. 
AE frequencies will be compared between treatment groups. For such comparisons 
MedDRA Preferred Terms (PT) will be used. Treatment groups will be compared by set 
of frequencies of PT terms using permutation tests. One p-value will be provided (H0: 
treatment groups are equal in set of AE frequencies). 
7.3.2 
Laboratory Data 
Laboratory data will be summarized by treatment group as clinical relevance 
(normal/abnormal, without clinical relevance/ abnormal, with clinical relevance) and as 
continuous data (absolute values).  
All laboratory data and changes from baseline will be described as continuous 
variables at each visit. 
Treatment groups will be compared for the set of parameters (hematology set, 
biochemistry set, urinalysis set and microscopic urine examination set). Only clinically 
significant deviations (CS) will be taken into account. Permutation test will be used see 
8 [2]. 
7.3.3 
Compliance 
Patient’s compliance will be described by treatment groups. 
7.3.4 
Vital Signs Data 
Vital signs data such as blood pressure, heart rate and body temperature will be 
summarized as continuous data by treatment group.  
All vital signs data and changes from baseline will be described at each visit.  
7.3.5 
Physical Examination Data 
Physical examination data will be summarized as normal/abnormal data. 
Physical examination data will be compared between treatment groups as each time 


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point using permutation tests. 
7.3.6 
Concomitant Treatments 
Concomitant therapy and immunosuppressive therapy during the study time will be 
summarized by treatment groups. Drugs will be presented by ATC groups as nominal 
data (absolute and relative frequencies).  
7.3.7 
Listings 
Additionally, combined listings from the database will be presented for: 
 Laboratory data 
 Adverse events and serious adverse events data. 
Laboratory data listings will be presented with patient number, age of patient, study 
period, group of treatment and laboratory data with units and flag of clinically 
significant abnormalities. Separately the same format listing will be presented for 
laboratory data but for patients who had abnormal values. 
7.4 
CHANGES IN THE PLANNED ANALYSES 
Any changes in the planned statistical methods will be documented and justified in the 
Clinical Study Report. 
8. 
REFERENCES 
1. Newcombes Hybrid Score method: Schuirmann, D. J. (1999), “Confidence 
Interval Methods for Bioequivalence Testing with Binomial Endpoints,” in 
Proceedings of the Biopharmaceutical Section, 227–232, Alexandria, VA: 
American Statistical Association. 
2. Permutation Tests methodology: 
 Helmut Strasser & Christian Weber (1999). On the asymptotic theory of 
permutation statistics. Mathematical Methods of Statistics *8*, 220-250. 
 Torsten Hothorn, Kurt Hornik, Mark A. van de Wiel & Achim Zeileis (2006). A 
Lego System for Conditional Inference. The American Statistician, *60*(3), 
257-263. 
 Torsten Hothorn, Kurt Hornik, Mark A. van de Wiel & Achim Zeileis (2008). 
Implementing a class of permutation tests: The coin package, Journal of 
Statistical Software, *28*(8), 1-23. http://www.jstatsoft.org/v28/i08 
 


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9. 
TABLE EXAMPLES1 
9.1 
DEMOGRAPHICS AND BASELINE 
Table 9.1 
Disposition 
 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
Enrolled subject 
xx 
xx 
Randomized subjects 
xx (xx.x%) 
xx (xx.x%) 
ITT Analysis Set 
xx (xx.x%) 
xx (xx.x%) 
Safety Analysis Set 
xx (xx.x%) 
xx (xx.x%) 
Completed Study per protocol 
xx (xx.x%) 
xx (xx.x%) 
Discontinued prematurely 
xx (xx.x%) 
xx (xx.x%) 
   Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
   Death 
xx (xx.x%) 
xx (xx.x%) 
   Infection of lower respiratory tract 
xx (xx.x%) 
xx (xx.x%) 
   Lost to follow-up 
 
 
   Consent withdrawn 
xx (xx.x%) 
xx (xx.x%) 
   Investigator decision 
xx (xx.x%) 
xx (xx.x%) 
   Protocol violation, including non-compliance 
xx (xx.x%) 
xx (xx.x%) 
   Protocol entry criteria not met 
xx (xx.x%) 
xx (xx.x%) 
   Study is stopped by Sponsor decision 
xx (xx.x%) 
xx (xx.x%) 
   Study is stopped by regulatory authorities / ethics committee 
xx (xx.x%) 
xx (xx.x%) 
   Other 
xx (xx.x%) 
xx (xx.x%) 
   Pregnancy 
xx (xx.x%) 
xx (xx.x%) 
 
Table 9.2 
Demographic and other baseline characteristics.  
ITT analysis set. Screening (baseline). N = xx 
Parameter 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
p-value 
Age (years) 
 
 
 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Gender 
 
 
 
   Male 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
   Female 
xx (xx.x%) 
xx (xx.x%) 
 
   No data2 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Race 
 
 
 
   Caucasian 
xx (xx.x%) 
xx (xx.x%) 
 
   Other 
xx (xx.x%) 
xx (xx.x%) 
 
   No data3 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Height (cm) 
 
 
 
   N 
xx 
xx 
--- 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Weight (kg) 
 
 
 
   N 
xx 
xx 
--- 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min – Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Duration of the acute upper respiratory infection (days)1 
                                            
1 Tables in the report may differ from this templates but meaning and information presented should be kept 
2 if any 
3 if any 


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Parameter 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
p-value 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Duration of dry non-productive cough (days)2 
 
 
 
   N 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
   Median 
xx.x 
xx.x 
 
   Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
Smoking history 
 
 
 
   Never smoked 
 
 
 
   Currently smokes 
 
 
 
      Duration 
 
 
 
         N 
xx 
xx 
--- 
         Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
         Median 
xx.x 
xx.x 
 
         Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
   Smoked in the past 
 
 
 
      Duration 
 
 
 
         N 
xx 
xx 
--- 
         Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
         Median 
xx.x 
xx.x 
 
         Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
   Not known 
 
 
 
 
Table 9.3 
Medical history. ITT analysis set. Screening (baseline). N = xx 
  MedDRA System Organ Class term 
 
MedDRA Preferred term 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
x (%) 
 
Y 
x (%) 
 
Y 
BODY SYSTEM CODE 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 1 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 2 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
 
Table 9.4 
Ongoing diseases/diagnosis/abnormalities. ITT analysis set. 
Screening (baseline). N = xx 
  MedDRA System Organ Class term 
 
MedDRA Preferred term 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
x (%) 
 
Y 
x (%) 
 
Y 
BODY SYSTEM CODE 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 1 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Term 2 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
 
Table 9.5 
Previous medication. ITT analysis set. 
Screening (baseline). N = xx 
ATC code 
   Drug 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
  
 
  
Group 
 
 
   Total 
xx (xx.x%) 
xx (xx.x%) 
   DRUG (ATC) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
                                                                                                                                           
1 Relative to the informed consent date 
2 Relative to the informed consent date 


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Table 9.6 
Physical examination. ITT analysis set. Screening. N = xx 
Category 
Levopront® (T) 
n (%) 
N = XX 
Libexin® (C) 
n (%) 
N = XX 
p-value 
Screening (baseline). Day 1 
 
 
0.xxx 
   General appearance 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
   Eyes, ears, nose, throat 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
   Neck (including thyroid) 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
.. 
 
 
 
 
Table 9.7 
Vital signs. ITT analysis set. Screening. N = xx 
 
Levopront® (T) 
n (%) 
N = XX 
Libexin® (C) 
n (%) 
N = XX 
p-value 
Screening (baseline) 
 
 
 
   Body temperature (°C) 
 
 
0.xxx 
      N 
xx 
xx 
 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
   Pulse (beats/min) 
 
 
0.xxx 
      N 
xx 
xx 
 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
 
 
 
   Respiratory rate (/min) 
 
 
0.xxx 
      N 
xx 
xx 
 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
 
 
 
   Systolic blood pressure (Hg mm) 
 
 
0.xxx 
      N 
xx 
xx 
 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
 
 
 
   Diastolic blood pressure (Hg mm) 
 
 
0.xxx 
      N 
xx 
xx 
 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
 
      Median 
xx.x 
xx.x 
 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
9.2 
EFFICACY 
Table 9.8 
Primary efficacy. Daytime cough resolution.  
PP analysis set. N = xx 
 
Levopront® (Test) 
n (%) 
N = XX 
Libexin® (Control) 
n (%) 
N = XX 
Daytime cough resolution 
   Ongoing (≥2) 
xx (xx.x%) 
xx (xx.x%) 
   Resolved (<2) 
xx (xx.x%) 
xx (xx.x%) 
   Test – Control (resolved)   
xx (xx.x%) 97.5% CI [xx.x%; --] 
 
 
 
 


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Table 9.9 
Primary efficacy. Daytime cough resolution.  
ITT analysis set. N = xx 
 
Levopront® (Test) 
n (%) 
N = XX 
Libexin® (Control) 
n (%) 
N = XX 
Daytime cough resolution 
   Ongoing (≥2) 
xx (xx.x%) 
xx (xx.x%) 
   Resolved (<2) 
xx (xx.x%) 
xx (xx.x%) 
   Test – Control (resolved)   
xx (xx.x%) 97.5% CI [xx.x%; --] 
 
 
 
 
 
Table 9.10 Secondary efficacy. Nighttime cough resolution. 
ITT population set. N = xx 
 
Levopront® (Test) 
n (%) 
N = XX 
Libexin® (Control) 
n (%) 
N = XX 
Nighttime cough resolution 
   Ongoing (≥2) 
xx (xx.x%) 
xx (xx.x%) 
   Resolved (<2) 
xx (xx.x%) 
xx (xx.x%) 
   p-value (Fisher) 
0.xxx 
 
 
 
 
 
Table 9.11 Secondary efficacy. Daytime and Nighttime cough resolution. 
ITT population set. N = xx 
 
Levopront® (Test) 
n (%) 
N = XX 
Libexin® (Control) 
n (%) 
N = XX 
Daytime & Nighttime cough resolution 
   Ongoing (≥2) 
xx (xx.x%) 
xx (xx.x%) 
   Resolved (<2) 
xx (xx.x%) 
xx (xx.x%) 
   p-value (Fisher) 
0.xxx 
 
 
 
 
 
Table 9.12 Change in severity and frequency of daytime and nighttime cough 
on Day 4 and Day 8 from baseline on Day 1. ITT population. N = xx 
 
Day 1 (baseline) 
Day 4 
Change at Day 4 
Day 8 
Change at Day 8 
Levopront® 
 
 
 
 
 
   Daytime cough 
 
 
 
 
 
      N 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
0.xxx 
 
 
 
 
 
 
Libexin® 
 
 
 
 
 
   Daytime cough 
 
 
 
 
 
      N 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
0.xxx 
 
 
 
 
 
 
p-between 
0.xxx 
 
0.xxx 
 
0.xxx 
 
 
 
 
 
 
Levopront® 
 
 
 
 
 
   Nighttime cough 
      N 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
0.xxx 
 
 
 
 
 
 
Libexin® 
 
 
 
 
 


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 18 of 25 
 
Day 1 (baseline) 
Day 4 
Change at Day 4 
Day 8 
Change at Day 8 
   Nighttime cough 
      N 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
0.xxx 
 
 
 
 
 
 
p-between 
0.xxx 
 
0.xxx 
 
0.xxx 
 
Figure 9.1 Graphics example 
 
 
Table 9.13 Cough intensity change according to the visual-analogue scale on 
Day 4 and Day 8 from baseline on Day 1. ITT population. N = xx 
 
Day 1 (baseline) 
Day 4 
Change at Day 4 
Day 8 
Change at Day 8 
Levopront® 
 
 
 
 
 
   Cough intensity. VAS 
      N 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
0.xxx 
 
 
 
 
 
 
Libexin® 
 
 
 
 
 
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
1
2
3
Visit
Scale
group
G1
G2
Graphics example


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 19 of 25 
 
Day 1 (baseline) 
Day 4 
Change at Day 4 
Day 8 
Change at Day 8 
   Cough intensity. VAS 
      N 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
0.xxx 
 
 
 
 
 
 
p-between 
0.xxx 
 
0.xxx 
 
0.xxx 
 
Table 9.14 Change of FEV1 on Day 8 from baseline values on Day 1.  
ITT population. N = xx 
 
Day 1 (baseline) 
Day 8 
Change at Day 8 
Levopront® 
 
 
 
   FEV1 (liters) 
 
 
 
      N 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
 
 
 
Libexin® 
 
 
 
   FEV1 (litres) 
 
 
 
      N 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
 
 
 
p-between 
0.xxx 
 
0.xxx 
 
 
 
 
Levopront® 
 
 
 
   FEV1 (%) 
 
 
 
      N 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
 
 
 
Libexin® 
 
 
 
   FEV1 (%) 
 
 
 
      N 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
 
 
0.xxx 
 
 
 
 
p-between 
0.xxx 
 
0.xxx 
 
 
 
 
 
9.3 
SAFETY 
Table 9.15 Physical examination. Safety population. N = xx 
Category 
Levopront® (T) 
n (%) 
N = XX 
Libexin® (C) 
n (%) 
N = XX 
p-value 
Screening (baseline). Day 1 
 
 
0.xxx 
   General appearance 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
   Eyes, ears, nose, throat 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 
   Neck (including thyroid) 
 
 
 
      Normal 
xx (xx.x%) 
xx (xx.x%) 
 
      Abnormal 
xx (xx.x%) 
xx (xx.x%) 
 
      Not done 
xx (xx.x%) 
xx (xx.x%) 
 


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 20 of 25 
Category 
Levopront® (T) 
n (%) 
N = XX 
Libexin® (C) 
n (%) 
N = XX 
p-value 
.. 
 
 
 
Day 4 
 
 
0.xxx 
… 
 
 
 
Day 8/ET or ED 
 
 
0.xxx 
… 
 
 
 
 
Table 9.16 Vital signs. Safety population. N = xx 
 
Levopront® (T) 
N = XX 
Libexin® (C) 
N = XX 
Day 1 (baseline) 
 
 
   Body temperature (°C) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
   Heart rate (beats/min) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
   Respiratory rate (/min) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
   Systolic blood pressure (Hg mm) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
   Diastolic blood pressure (Hg mm) 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
 
 
Day 4 
 
 
… 
 
 
Day 4. Change from baseline 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min - Max 
xx.x – xx.x 
xx.x – xx.x 
      p-change 
0.xxx 
0.xxx 
 
 
 
Day 8/ET or ED 
 
 
… 
 
 
Day 8/ET or ED. Change from baseline 
 
 
… 
 
 
 


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 21 of 25 
Table 9.17 Urine pregnancy test (females only). Safety population. N = xx 
 
Levopront® (T) 
n (%) 
N = XX 
Libexin® (C) 
n (%) 
N = XX 
Screening (Day 1) 
 
 
      Positive 
xx (xx.x%) 
xx (xx.x%) 
      Negative 
xx (xx.x%) 
xx (xx.x%) 
      No data 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Day 8/ED 
 
 
      Positive 
xx (xx.x%) 
xx (xx.x%) 
      Negative 
xx (xx.x%) 
xx (xx.x%) 
      No data 
xx (xx.x%) 
xx (xx.x%) 
 
Table 9.18 Concomitant medication. Safety population.  
During the study. N = xx 
ATC code 
   Drug 
Levopront® (T) 
n (%) 
N = XX 
Libexin® (C) 
n (%) 
N = XX 
  
 
  
Group 
 
 
   Total 
xx (xx.x%) 
xx (xx.x%) 
   DRUG (ATC) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
Table 9.19 Laboratory parameters. Hematology. Deviation from normal values. 
Safety population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Hemoglobin 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Hematocrit 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
Parameters to be presented: Hemoglobin, Hematocrit, RBC, WBC, Neutrophils (abs), Lymphocytes (abs), Monocytes (abs), 
Eosinophils (abs), Basophils (abs), Platelets, ESR, Neutrophils (%), Lymphocytes (%), Monocytes (%), Eosinophils (%), Basophils 
(%). 
 
Table 9.20 Laboratory parameters. Hematology. CS deviations only. Safety 
population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Hemoglobin 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Hematocrit 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
p-value1 
 
0.xxx 
 
0.xxx 
 
Table 9.21 Laboratory parameters. Biochemistry. Deviation from normal 
values. Safety population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Total protein 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
                                            
1 For the set of parameters at visit 


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 22 of 25 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Albumin 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
Parameters to be presented: Total protein, Albumin, Total cholesterol, Total bilirubin, Сonjugated bilirubin, ALT, AST, Serum 
creatinine, Glomerular filtration rate. 
 
Table 9.22 Laboratory parameters. Biochemistry. CS deviations only. Safety 
population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Total protein 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Albumin 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
p-value 
 
0.xxx 
 
0.xxx 
 
Table 9.23 Laboratory parameters. Urinalysis. Deviation from normal values. 
Safety population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Color 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Clarity 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
Parameters to be presented: Color, Clarity, Specific gravity, pH, Protein, Glucose, Bilirubin, Urobilinogen, Ketone bodies, Nitrites, 
Hemoglobin. 
 
Table 9.24 Laboratory parameters. Urinalysis. CS deviations only. Safety 
population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Color 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Clarity 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
p-value 
 
0.xxx 
 
0.xxx 
 


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 23 of 25 
Table 9.25 Laboratory parameters. Microscopic urine examination. Deviation 
from normal values. Safety population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Epithelium 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Erythrocytes 
 
 
 
 
   No data 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CNS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
   Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
Parameters to be presented: Epithelium, Erythrocytes, Leukocytes, Casts, Bacteria, Salts. 
 
Table 9.26 Laboratory parameters. Microscopic urine examination. CS 
deviations only. Safety population. N = xx 
Parameter 
Day 1 
Day 8\ET 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Epithelium 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Erythrocytes 
 
 
 
 
   CS deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
p-value 
 
0.xxx 
 
0.xxx 
 
Table 9.27 Laboratory parameters. Hematology. Absolute values.  
Safety population. N = xx 
 
Day 1 (baseline) 
Day 8/ET or ED 
Change at Day 8 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Levopront® 
Libexin® 
Hemoglobin 
 
 
 
 
 
 
      N 
xx 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
Hematocrit 
 
 
 
 
 
 
      N 
xx 
xx 
xx 
xx 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
xx.x – xx.x 
… 
 
 
 
 
 
 
Parameters to be presented: Hemoglobin, Hematocrit, RBC, WBC, Neutrophils (abs), Lymphocytes (abs), Monocytes (abs), 
Eosinophils (abs), Basophils (abs), Platelets, ESR, Neutrophils (%), Lymphocytes (%), Monocytes (%), Eosinophils (%), Basophils 
(%). 
Table 9.28 Laboratory parameters. Biochemistry. Absolute values.  
Safety population. N = xx 
Similar 
Parameters to be presented: Total protein, Albumin, Total cholesterol, Total bilirubin, Сonjugated bilirubin, ALT, AST, Serum 
creatinine, Glomerular filtration rate. 
 
Table 9.29 Laboratory parameters. Urinalysis. Absolute values.  
Safety population. N = xx 
Similar 
Parameters to be presented: Color, Clarity, Specific gravity, pH, Protein, Glucose, Bilirubin, Urobilinogen, Ketone bodies, Nitrites, 
Hemoglobin. 
 


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 24 of 25 
Table 9.30 Laboratory parameters. Microscopic urine examination. 
Absolute values. Safety population. N = xx 
Similar 
Parameters to be presented: Epithelium, Erythrocytes, Leukocytes, Casts, Bacteria, Salts. 
 
Table 9.31 Compliance. Safety population. N = XX 
 
Levopront®  
N = XX 
Libexin® 
N = XX 
Compliance 
 
 
      N 
xx 
xx 
      Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
      Median 
xx.x 
xx.x 
      Min – Max 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
 
Table 9.32 Adverse Events (including SAE) started before the first dose of 
the study drug(s). Safety population. N = xx 
MEDDRA System Organ Class term 
   MEDDRA Preferred term 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
x (%) 
 
Y 
x (%) 
 
Y 
SOC term 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 1 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 2 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
X = Number of subjects having at least one AE from the group.  
% = Percent of patients having at least one AE from the group 
Y = Total number of events 
 
Table 9.33 Adverse events. Summary table. Safety population. N = XX 
Parameter 
Levopront®  
N = XX 
Libexin® 
N = XX 
p-value 
Fisher test 
Patients with AE/SAE 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Patients with SAE 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Patients with death outcome AE/SAE  
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Patients with mild and moderate AE/SAE 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Patients with severe AE/SAE 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Patients with related (possible probable or highly probable) AE/SAE 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Patients with AE/SAE leaded to discontinuation 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
 
Table 9.34 Adverse Events (including SAE). Safety population. N = xx 
MEDDRA System Organ Class term 
   MEDDRA Preferred term 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
x (%) 
 
Y 
x (%) 
 
Y 
SOC term 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 1 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 2 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
X = Number of subjects having at least one AE from the group.  
% = Percent of patients having at least one AE from the group 
Y = Total number of events 
p-value = 0.xxx 
 


LDP0114 Statistical Analysis Plan 
 
Final version 2.0 
Page 25 of 25 
Table 9.35 Adverse Events (including SAE) and severity. 
Safety population. N = xx 
MEDDRA System Organ Class term 
   MEDDRA Preferred term 
Severity 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
 
x (%) 
 
Y 
x (%) 
 
Y 
SOC term 
 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 1 
Mild 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 2 
Moderate 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
 
X = Number of subjects having at least one AE from the group.  
% = Percent of patients having at least one AE from the group 
Y = Total number of events 
 
Table 9.36 Adverse Events (including SAE) and relation to study drug(s).  
Safety Set. N = xx 
Similar 
Table 9.37 Serious Adverse Events (only). Safety population. N = xx 
MEDDRA System Organ Class term 
   MEDDRA Preferred term 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
x (%) 
 
Y 
x (%) 
 
Y 
SOC term 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 1 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 2 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
X = Number of subjects having at least one AE from the group.  
% = Percent of patients having at least one AE from the group 
Y = Total number of events 
Table 9.38 Serious Adverse Events (only) and severity. 
Safety population. N = xx 
MEDDRA System Organ Class term 
   MEDDRA Preferred term 
Severity 
Levopront® (T) 
n (%) 
Libexin® (C) 
n (%) 
 
x (%) 
 
Y 
x (%) 
 
Y 
SOC term 
 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 1 
Mild 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
   Preferred term 2 
Moderate 
xx (xx.x) 
xx 
xx (xx.x) 
xx 
… 
 
 
 
 
 
X = Number of subjects having at least one AE from the group.  
% = Percent of patients having at least one AE from the group 
Y = Total number of events 
 
Table 9.39 Serious Adverse Events (only) and relation to study drug(s).  
Safety Set. N = xx 
Similar