Conditions: Pneumonia, Bacterial
Keywords: nemonoxacin community-acquired pneumonia quinolones
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 342
Healthy volunteers: no

Brief summary:
The primary objective of this study was to evaluate the clinical efficacy of treatment with Nemonoxacin compared with Tavanic® in patients with community-acquired pneumonia (CAP).

Detailed description:
Treatment-naive patients with CAP and patients with treatment failure were screened and if met the eligible criteria were randomized to receive either treatment with investigational product or comparator. Patients started to receive intravenous therapy with Nemonoxacin or Tavanic® and then upon a decision of investigator patients were switched to oral therapy with the same product.

Intravenous therapy included two consequence infusions (antibiotic solution and placebo solution) to maintain blinding. Intravenous therapy should have been given for at least 3 days and could have been prolonged by a decision of investigator up to 7 days. Then investigator switched a patient from intravenous to oral therapy on Day 4(8) of the study if the specific criteria of clinical stability were achieved. To maintain blinding during oral antibiotic therapy each Tavanic® tablet was placed into a capsule shell (over-encapsulated), that was identical in appearance to a Nemonoxacin-containing capsules.

The average duration of treatment (including intravenous and oral therapy) for each patient was 7(14) days and during this period patients should have stayed at hospital. After completion of the treatment patients could have been discharged from the hospital and returned for examinations within 1-2 days after the last dose (end of treatment visit). Then the patients attended the investigational site within 7-9 days after the last dose (test of cure visit). Then the investigator contacted the patients by phone within 21-23 days after the last dose (long-term follow-up visit).

Arms:
arm 1: Nemonoxacin solution for infusion, 500 mg (250 ml), daily, as single intravenous infusion over 90-110 minutes followed by infusion of Placebo (100 ml), solution for infusion, over a minimum duration of 60 minutes.

Then will be switched to oral therapy with Nemonoxacin capsules, 500 mg once daily (two 250 mg capsules). arm 2: Tavanic® solution for infusion, 500 mg (100 ml), daily, as single intravenous infusion over a minimum duration of 60 minutes with previous infusion of Placebo (250 ml), solution for infusion, over 90-110 minutes.

Then will be switched to oral therapy with Tavanic®, over-encapsulated film coated tablets, 500 mg once daily (two capsules each containing 250 mg film coated tablet).

Interventions: intervention 1: Nemonoxacin intervention 2: Nemonoxacin intervention 3: Tavanic intervention 4: Tavanic intervention 5: Placebo (250 ml) intervention 6: Placebo (100 ml)
Intervention descriptions: intervention 1: Solution for infusion, 500 mg (250 ml) intervention 2: Capsules, 250 mg intervention 3: Solution for infusion, 500 mg (100 ml) intervention 4: Film coated tablets (each tablet is placed into a capsule shell (overencapsulated) for blinding purposes), 250 mg intervention 5: 0.9% NaCl (250 ml), solution for infusion intervention 6: 0.9% NaCl (100 ml), solution for infusion

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
CLINICAL STUDY PROTOCOL 
 
An international, multicenter, randomized, double-blind, double-dummy, two-
way, parallel group, controlled study to compare the efficacy and safety of 
intravenous and oral Nemonoxacin versus Tavanic® in adult patients with 
community-acquired pneumonia. 
 
Test medicinal 
products 
Nemonoxacin 500mg (250 ml), solution for infusion 
Nemonoxacin 250 mg, capsules 
Indication 
Treatment of community-acquired pneumonia 
Protocol code 
CJ01060044 
Sponsor 
R-Pharm 
Legal address: 19/1, Berzarina str., 123154, Moscow, Russia 
Mailing address: 111B, Leninskiy Prospekt, 119421, Moscow, Russia. 
Tel: +7 (495) 956-79-37 
Fax: +7 (495) 956-79-38 
Phase 
III 
Version 
Final version 5.0 
Date 
26-Apr-2017 
Amendments 
Amendment No. 1 dated 17-Mar-2016 
Amendment No. 3 dated 26-Dec-2016  
Amendment No. 4 dated 26-Apr-2017 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT  
This document contains commercial secrets and commercial information, which is sensitive or confidential 
and will not be disclosed, if such disclosure is not stipulated by the legislation. In any case, persons, to whom 
such information has been disclosed, should be informed that such information is deemed sensitive or 
confidential and will not be disclosed by them further. Such limitations for disclosure will be equally 
applicable to all further information, provided to you and marked as sensitive or confidential. 
 


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SPONSOR SIGNATURE PAGE 
I have read the protocol and agree that it contains all necessary details for conducting this 
clinical study in strict accordance with the specifications outlined herein. 
Sponsor Study Contact Person 
 
 
 
Medical Director of R-Pharm JSC 
Mikhail Samsonov, MD, PhD 
Legal address: 19/1, Berzarina str., 
123154, Moscow, Russia 
Mailing address: 111B, Leninskiy 
Prospekt, 119421, Moscow, Russia 
Tel: +7 (495) 956-79-37 
Fax: +7 (495) 956-79-38 
 
Date 
 
Study medical expert, appointed by the Sponsor 
 
 
 
Aleksandr  Chernavin 
Head of Medical Affairs Group, R-Pharm 
JSC 
Legal address: 19/1, Berzarina str., 
123154, Moscow, Russia. 
Mailing address: 111B, Leninskiy 
Prospekt, 119421, Moscow, Russia. 
Tel: +7 (495) 956-79-37 
Fax: +7 (495) 956-79-38 
 
Date 
 
 


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CONTRACT RESEARCH ORGANIZATION SIGNATURE PAGE 
 
 
 
General Director of OCT Rus Ltd. 
Dmitry Sharov 
Legal address/ postal address: 5, 
Kovensky lane, letter “B”, 191014, Saint 
Petersburg, Russia 
Tel.: +7 (812) 449-86-34 
Fax: +7 (812) 449-86-35 
 
Date 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
I have discussed the tasks of this study and contents of this protocol in detail with 
the Sponsor`s representative. 
I understand, that information in the protocol or relating to the protocol is 
confidential and without a written consent of the Sponsor will not be disclosed, except for 
its transfer to the employees, that directly participate in this study and in checks of its 
compliance with ethical norms. However, this information may to be provided to patients 
to receive their consent for participation in the study. 
I agree to conduct this study in accordance with the protocol, fulfill any 
requirements of the protocol and requirements of any provisions and directives related to 
ethics and safety, I also agree to conduct this research in accordance with the provisions 
of the Declaration of Helsinki, principles of GCP specified in Guidelines Е6 of the 
International Conference of Harmonisation, and all applicable local regulatory 
requirements. 
I agree to provide employees of the sponsoring company, its representatives and 
employees of regulating authorities with all documentation, related to the research in 
connection with my patients, with the aim to control the data I used to fill patients` 
individual electronic case report forms. I am aware of my duties as the principal 
investigator, reporter to me by the sponsor. 
I understand, that the sponsor is entitled to suspend or discontinue the study any 
time and for any reason; I will be informed of such decision in writing. On the other 
hand, if I decide to discontinue the study, I will forthwith notify the Sponsor’s 
representative thereof in writing. 
 
Name of Investigator: 
 
Affiliation: 
 
Name and address of Study 
center: 
 
 
 
Signature of Investigator: 
 
Date: 
 
 
 


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CONTACT INFORMATION 
 
Sponsor: 
 
R-Pharm JSC 
Legal address: 19/1, Berzarina str., 123154, 
Moscow, Russia 
Mailing address: 111B, Leninskiy Prospekt, 
119421. 
Tel: +7 (495) 956-79-37 
Fax: +7 (495) 956-79-38 
 
 
Medical Adviser: 
Alexander Chernavin 
Tel.: +7 (915) 085-66-29 
chernavin@rpharm.ru 
 
 
Contract Research Organization: 
OCT Rus Ltd. 
Legal address/ postal address: 5, Kovensky 
lane, letter “B”, 191014, Saint Petersburg, 
Russia 
Tel.: +7 (812) 449-86-34 
Fax: +7 (812) 449-86-35 
 
 
Central 
Microbiological 
Laboratory: 
Research Institute of Antimicrobial Therapy 
of Federal State Budget-funded Educational 
Establishment 
of 
Higher 
Education 
“Smolensk State Medical University of the 
Ministry 
of 
Health 
of 
the 
Russian 
Federation”. 
Legal / mailing address: 46A, Kirova Str., 
Smolensk, 214019, Russia. 
Telephone: +7 (4812) 45-06-02 
 
Central 
Pharmacokinetic 
Laboratory: 
Bioanalytical Laboratory “Exacte Labs” 
Legal / mailing address: 20, Nauchnyi 
Proezd, Bldg. 2, Moscow, 117246, Russia. 
Telephone: +7 (499) 963-90-01 
 


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INVESTIGATIONAL SITES 
List of Investigational Sites participating in this clinical study (name, address and 
telephone number of each site; name and title of the investigators) is provided in a 
separate List of Investigational Sites and Principal Investigators. 
  
 
 
  


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DESCRIPTION OF THE PROTOCOL CHANGES 
 
The changes introduced into the Protocol by Amendment No. 4 dated 26 April 
2017 are listed below:  
Appendix 1 contains Intensive Care Unit admission criteria that have been 
corrected on the basis of the “Clinical guidelines for the diagnosis, treatment, and 
prevention of severe community-acquired pneumonia in adult patients of 2014” (referred 
to further in the protocol changes description as the “2014 Clinical Guidelines”). These 
criteria have been brought into agreement with the Infectious Diseases Society of 
America / American Thoracic Society criteria referenced by the 2014 Clinical Guidelines.  
Section 11.5 now contains clarified requirements for the registration of 
pregnancies in the course of the study.  
Sections 12.1 and 12.2 contain clarified requirements for the enrollment of 
subjects in the Clinically Evaluable (CE) population.  
Section 13.3 now provides information on the financing and insurance of the 
study.  
Minor formatting changes and correction of misprints in the protocol were 
performed as well. 
 
The principal changes introduced into the Protocol by Amendment No. 3 dated 26 
December 2016 are listed below.  
The following changes were made in the inclusion criteria:  
• 
Inclusion criterion No. 2 was modified: the maximum age of patients that 
can be enrolled in the study was increased to 70 years inclusive. This 
change was due to a significant proportion of such patients in the overall 
population of patients admitted to hospital with a diagnosis of 
“community-acquired pneumonia”, and was aimed to enlarge the study 
population.  
• 
Inclusion criterion No. 3 was clarified (the need to meet the requirements 
of Appendix 1 “Criteria for hospitalization” was again underlined). 
• 
For Inclusion criterion No. 4, a clearer definition of required symptoms / 
signs was included: the terms “dyspnea” and “rigors” were excluded to 
avoid misunderstanding. 
  
The following change was made in the exclusion criteria:  
• 
For Exclusion criterion No. 4, a clearer definition of QT prolongation was 
included: QTc(F) interval more than 450 ms.  
          
In the “Contact information” section, information on the Central Microbiological 
Laboratory and the Central Pharmacokinetic Laboratory was added.  
Section 8.6 “Blinding” now contains a modified description of the package 
labeling, which will allow masking of blinding packages right at the investigational sites 
for more convenience of the investigational site personnel.  


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            Section 8.7 “Prior and concomitant therapy” now contains a clarification that the 
eCRF documents information on previous drugs and treatments used from the onset of 
community-acquired pneumonia until the enrollment in the study (signing of the 
Informed Consent Form).  
          Section 9.1 “Schedule of study procedures” now includes, in the interests of study 
subjects, clarified requirements for the time frame of Visit 3, which should be conducted 
at least 24 hours after the last dose of the study drug.  
           The description of the screening procedures and Sections 10.3.4, 10.3.5, 10.3.6 
now include information that the Investigator may use laboratory test results obtained at 
the laboratory of the investigational site within 24 hours of study enrollment (Signing of 
the Informed Consent Form) if he / she considers that available data are sufficient to 
permit a decision on whether the subject meets the selection criteria. In this case, another 
blood sampling procedure has to be conducted in the period from the signing of the 
Informed Consent Form to the start of treatment in order to evaluate all other laboratory 
parameters that have to be determined on Day 1 in accordance with the study protocol. 
This amendment was done in the interests of study subjects, in order to rule out more 
unnecessary material collection procedures, as well as to shorten the time to start of 
treatment.  
The description of the screening procedures (9.2.1) now provides clarifying 
information that prior therapy should be evaluated for the 30 days preceding the Visit and 
treatment, from the onset of community-acquired pneumonia.  
For all study visits including an ECG recording (Visit 1 “Screening procedures”, 
Visit 2 “Switch to oral therapy”, Visit 3, Visit 4), an opportunity was added, for more 
convenience of patients and investigators, to have an ECG recording not only before the 
blood sampling procedure, but also 30 minutes after it.                                                               
The description of the Visit 2 procedures (9.2.2) now provides clarifying 
information that, in the event intravenous therapy is prolonged, the overall duration of 
treatment within this study will not exceed 14 days.            
Section 10.2.1 "Chest X-ray / Chest Computed Tomography” now includes 
clarifying information that only one radiological method (X-ray imaging only or CT 
imaging only for all visits) should be used for a patient throughout the study to ensure 
unified and improved quality of analysis.          
Section 10.3.7 “Documentation of adverse events” now contains clarified 
requirements for the documentation of adverse events.  
Section 11.1.1 “Adverse event (AE)” now provides clarifying information in 
order to improve the adverse event reporting procedure: any worsening of symptoms of 
the primary disease (as compared with estimates made during the screening procedures) 
should also be registered as an AE; there is now also information that the Investigator 
will record all available information on each occurring SAE in the source 
documentation.  
            The title of Section 11.4  “ Management of Non Serious Adverse Events (NSAEs) 
and/or laboratory abnormalities” was changed to 11.4 “Management of adverse events 
not classified as serious”. A requirement was also included to record information about 
adverse events in the source documentation.  
Clarifying information was included in Appendix 1:  


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• 
Clearer criteria for preferred in-patient treatment and for hospitalization in 
an intensive care unit were included.  
• 
One of the criteria for hospitalization in an intensive care unit was better 
defined: Respiratory rate ≥ 30 movements per minute.  
 
 
       Minor formatting changes and correction of misprints in the protocol were performed 
as well.  
  
The changes introduced into the Protocol by Administrative Amendment No. 1 
dated 17 March 2016:  
The mailing address of the Study Sponsor was changed to 111B, Leninskiy 
Prospekt, 119421, Moscow, Russia.  
Section 8.9 “Treatment compliance” now mentions that the volume (mL) of the 
infusion (instead of the dose) will be recorded in the eCRF.  
Information was added in Section 9.3 “Unscheduled visits” that, if the 
Investigator makes a decision to withdraw a subject from the study during an 
unscheduled visit (a so-called “early termination visit”), the minimal number of 
completed procedures should correspond to that of the “End of treatment visit”. For 
more information on discontinuation of therapy and early withdrawal of subjects from 
the study, see Section 7  
Section 10.3.2  “Vital signs” now contains clarifying information that both 
systolic and diastolic blood pressure should be measured.  
The contact details for SAE reporting was changed in Section 11.3.1 “Reporting 
duties of the Investigator”.  
 
No changes were made in the study protocol following Amendment No. 2 dated 
05 September 2016. Amendment No. 2 dated 05 September 2016 was abolished and was 
not used.  
 


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TABLE OF CONTENTS 
Sponsor Signature Page ...................................................................................................... 2 
Contract Research Organization Signature Page ................................................................ 3 
Investigator Signature Page ................................................................................................ 4 
Contact information ............................................................................................................ 5 
Investigational Sites ............................................................................................................ 6 
Table of Contents .............................................................................................................. 10 
1 
ABBREVIATIONS ..................................................................................... 14 
2 
SYNOPSIS .................................................................................................. 16 
3 
INTRODUCTION ....................................................................................... 23 
3.1 
Background information ............................................................................. 23 
3.2 
Investigational products .............................................................................. 24 
3.3 
Preclinical and clinical studies of Nemonoxacin ........................................ 25 
3.3.1 
Preclinical studies of Nemonoxacin ............................................................ 25 
3.3.1.1 
In vitro studies on antibacterial activity of nemonoxacin ........................... 25 
3.3.1.2 
Efficacy of nemonoxacin in pulmonary model of infection ....................... 25 
3.3.1.3 
Animal pharmacokinetics and metabolism ................................................. 26 
3.3.1.4 
Toxicological studies ................................................................................... 26 
3.3.1.5 
Interaction with cytochrome P450 .............................................................. 27 
3.3.2 
Clinical studies of nemonoxacin ................................................................. 27 
3.3.2.1 
Phase I clinical trials ................................................................................... 27 
3.3.2.2 
Phase II clinical trials .................................................................................. 29 
3.3.2.3 
Phase III clinical trials ................................................................................. 29 
3.4 
Assessment of Potential risks and benefits for participants ........................ 30 
3.5 
Dose, route, regimen and treatment period rationale .................................. 30 
4 
STUDY OBJECTIVES ............................................................................... 31 
4.1 
Primary Objective ....................................................................................... 31 
4.2 
Secondary Objectives .................................................................................. 31 
5 
CLINICAL STUDY ENDPOINTS ............................................................. 31 
5.1 
Efficacy endpoints ....................................................................................... 31 
5.1.1 
Primary efficacy endpoint ........................................................................... 31 
5.1.2 
Secondary efficacy endpoints ...................................................................... 32 
5.2 
Safety endpoints .......................................................................................... 32 
5.3 
Pharmacokinetic parameters ....................................................................... 32 
6 
STUDY DESIGN ........................................................................................ 32 
6.1 
Design Summary ......................................................................................... 32 


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7 
SELECTION OF STUDY POPULATION ................................................. 35 
7.1 
Inclusion Criteria ......................................................................................... 35 
7.2 
Exclusion Criteria ........................................................................................ 35 
7.3 
Discontinuation of Therapy and Withdrawal of the Patients from the 
Study ............................................................................................................ 36 
8 
TREATMENT ............................................................................................. 37 
8.1 
Treatments Administered ............................................................................ 37 
8.2 
Investigational Medicinal Products (IMPs) ................................................. 38 
8.3 
Non-Investigational Medicinal Products ..................................................... 39 
8.4 
Packaging, labeling and storage of IMPs .................................................... 39 
8.5 
Method of Assigning Patients to Treatment Groups ................................... 40 
8.6 
Blinding ....................................................................................................... 40 
8.7 
Prior and Concomitant therapy ................................................................... 41 
8.7.1 
Permitted concomitant therapy .................................................................... 42 
8.7.2 
Prohibited and limited in use therapy .......................................................... 42 
8.8 
Contraception .............................................................................................. 42 
8.9 
Treatment compliance ................................................................................. 43 
9 
STUDY VISITS AND PROCEDURES ..................................................... 43 
9.1 
Schedule of study procedures ...................................................................... 43 
9.2 
Description of visits .................................................................................... 48 
9.2.1 
Visit 1 (screening /randomization and intravenous therapy, Days 1-3(7) 
of the study) ................................................................................................. 48 
9.2.2 
Visit 2 (switch to oral therapy/oral therapy, Days 4(8)-7(14) of the study) 49 
9.2.3 
Visit 3 (end of treatment visit, within 1-2 days after the last dose) ............ 50 
9.2.4 
Visit 4 (test of cure visit, within 7-9 days after the last dose) ..................... 51 
9.2.5 
Visit 5 (long-term follow-up visit, within 21-23 days after the last dose) .. 51 
9.3 
Unscheduled Visits ...................................................................................... 51 
10 
ASSESSMENTS ......................................................................................... 52 
10.1 
Initial assessments ....................................................................................... 52 
10.1.1 
Demographic data and other baseline characteristics.................................. 52 
10.1.2 
Medical history ............................................................................................ 52 
10.1.3 
Pregnancy test ............................................................................................. 52 
10.1.4 
Pulse oximetry ............................................................................................. 52 
10.2 
Assessment of efficacy ................................................................................ 53 
10.2.1 
Chest X-ray / Chest Computed Tomography .............................................. 53 
10.2.2 
Clinical response assessment ...................................................................... 53 
10.2.3 
Bacteriological study ................................................................................... 54 
10.2.4 
Infection relapse assessment ....................................................................... 54 


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10.3 
Assessment of Safety .................................................................................. 55 
10.3.1 
Physical Examination .................................................................................. 55 
10.3.2 
Vital Signs ................................................................................................... 55 
10.3.3 
Electrocardiography .................................................................................... 56 
10.3.4 
Haematology test ......................................................................................... 56 
10.3.5 
Biochemical assay ....................................................................................... 56 
10.3.6 
Urinalysis .................................................................................................... 57 
10.3.7 
Documentation of adverse events ............................................................... 58 
10.4 
Drug Concentration Measurements for Assessment of Pharmacokinetic 
Parameters ................................................................................................... 58 
11 
ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS 
(SAE) ........................................................................................................... 59 
11.1 
Definitions ................................................................................................... 59 
11.1.1 
Adverse Event (AE) .................................................................................... 59 
11.1.2 
Drug Relationship ....................................................................................... 59 
11.1.3 
Adverse Drug Reactions .............................................................................. 60 
11.1.4 
Seriousness .................................................................................................. 60 
11.1.5 
Adverse Event (AE) / Adverse Drug Reaction (ADR) severity .................. 60 
11.1.6 
Adverse Event (AE) / Adverse Drug Reaction (ADR) expectedness ......... 61 
11.1.7 
Suspected Unexpected Adverse Drug Reaction (SUSAR) ......................... 61 
11.2 
Monitoring and Recording of Adverse Events ............................................ 61 
11.3 
Management of Serious Adverse Events (SAE) ......................................... 61 
11.3.1 
Reporting duties of the Investigator ............................................................ 61 
11.3.2 
Reporting duties of the Sponsor .................................................................. 62 
11.4 
Management of adverse events not classified as serious ............................ 62 
11.5 
Pregnancy .................................................................................................... 62 
12 
STATISTICAL METHODS ....................................................................... 63 
12.1 
Analysis populations ................................................................................... 63 
12.2 
Exclusion of Patients from Analysis ........................................................... 63 
12.3 
Criteria for termination of the study ............................................................ 64 
12.4 
General considerations ................................................................................ 64 
12.5 
Procedure for accounting for missing, unused, and spurious data .............. 65 
12.6 
Efficacy evaluation ...................................................................................... 65 
12.6.1 
Efficacy endpoints ....................................................................................... 65 
12.6.2 
Primary efficacy analysis ............................................................................ 65 
12.6.3 
Secondary efficacy analyses ........................................................................ 66 
12.7 
Safety evaluation ......................................................................................... 67 
12.8 
Pharmacokinetic parameters ....................................................................... 67 


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12.9 
Procedures for reporting any deviations from the original statistical plan. 68 
12.10 
Sample size calculation ............................................................................... 68 
13 
ETHICAL AND LEGAL CONSIDERATIONS ........................................ 68 
13.1 
Informed Consent Form .............................................................................. 68 
13.2 
Information Confidentiality ......................................................................... 69 
13.3 
Financing and Insurance coverage .............................................................. 69 
14 
ADMINISTRATIVE OBLIGATIONS ....................................................... 70 
14.1 
Data collection ............................................................................................. 70 
14.2 
Data handing ............................................................................................... 70 
14.3 
Storage and archiving of Data ..................................................................... 70 
15 
QUALITY CONTROL AND QUALITY ASSURANCE .......................... 70 
16 
PUBLICATIONS ........................................................................................ 71 
17 
REFERENCES ............................................................................................ 72 
APPENDIX 1: CRITERIA FOR HOSPITALIZATION* ................................................ 74 
APPENDIX 2: ASSESSMENT OF CLINICAL STABILITY (POSSIBILITY OF 
SWITCH TO ORAL TREATMENT)* ....................................................... 76 
APPENDIX 3: DRUGS THAT MAY PROLONG THE QT INTERVAL WITH 
KNOWN RISK OR POSSIBLE RISK OF TORSADES DE POINTES 
(TDP) ........................................................................................................... 77 
APPENDIX 4: DECLARATION OF HELSINKI ............................................................ 82 
 
LIST OF TABLES 
Table 6-1 Summary of treatment groups .......................................................................... 33 
Table 8-1 Investigational Medicinal Products (IMPs) ...................................................... 38 
Table 9-1 Schedule of procedures/assessments ................................................................ 44 
Table 10-1 Criteria for evaluation of clinical response .................................................... 53 
 
LIST OF FIGURES 
Figure 6-1 Study design .................................................................................................... 34 
Figure 10-1 Schedule for blood sample collection for the PK at Visit 1 ........................ 58 
 
 


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1 ABBREVIATIONS 
ADR 
Adverse drug reaction 
AE 
Adverse event/experience 
ALP 
Alkaline phosphatase  
ALT 
Alanine aminotransferase (alanine transaminase) 
AST 
Aspartate aminotransferase (aspartate transaminase) 
BLNAR 
β-lactamase negative ampicillin-resistant  
CAP 
Community-acquired pneumonia 
CAPRIE 
Community-Acquired Pneumonia Recovery in the Elderly 
C. pneumoniae 
Chlamydophila pneumoniae 
CNS 
Central nervous system  
CRA 
Clinical research associate 
CRO 
Contract research organization 
CT 
Computed tomography 
DBP 
Diastolic blood pressure 
DNA 
Deoxyribonucleic acid 
DRSP 
Drug-resistant S.pneumoniae  
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
ESR 
Erythrocyte sedimentation rate 
GCP 
Good Clinical Practice 
GGTP 
Gamma-glutamyl transpeptidase  
GI 
Gastrointestinal system 
H. influenzae 
Haemophilus influenzae 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC  
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INN 
International Non-proprietary Name 
ISF 
Investigator Site File 
i.v. 
Intravenous 
IWRS 
Interactive Web Response System 
K. pneumoniae 
Klebsiella pneumoniae 
L. pneumophila 
Legionella pneumophila 
LRTI 
Lower respiratory tract infection 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MRSA 
Methicillin-resistant Staphylococcus aureus  
M. pneumoniae 
Mycoplasma pneumoniae 
NSAE 
Non Serious Adverse Events 
NFQ 
Non-fluorinated quinolone 
PISP 
Penicillin-intermediate S. pneumonia 
PRSP 
Penicillin-resistant S. pneumonia 
P. aeruginosa 
Pseudomonas aeruginosa 
pH 
Hydrogen ion concentration 
PQ 
Cardiac PQ interval 
QRS 
Cardiac QRS interval 
QT  
Cardiac QT interval 
QTc 
Cardiac QT interval corrected for heart rate 
SAE 
Serious Adverse Event/experience 
S. aureus 
Staphylococcus aureus 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOPs 
Standard Operating Procedures  
S. pneumoniae 
Streptococcus pneumoniae 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMP-SMX 
Trimethoprim-sulfamethoxazole  
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
 


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2 SYNOPSIS 
Title of Study: 
An international, multicenter, randomized, double-blind, double-
dummy, two-way, parallel group, controlled study to compare 
the efficacy and safety of intravenous and oral Nemonoxacin 
versus Tavanic® in adult patients with community-acquired 
pneumonia. 
Protocol code: 
CJ01060044 
Sponsor: 
R-Pharm JSC 
Medical condition 
or disease under 
investigation: 
Community-acquired pneumonia (CAP) 
Objectives: 
 
Primary objective 
• 
To evaluate the clinical efficacy of treatment with 
Nemonoxacin compared with Tavanic® in patients with 
CAP. 
Secondary objectives 
• 
To evaluate the clinical efficacy of treatment with 
intravenous Nemonoxacin compared with intravenous 
Tavanic® in patients with CAP 
• 
To assess the safety of treatment with Nemonoxacin 
compared with Tavanic® in patients with CAP 
• 
To assess the pharmacokinetic parameters of intravenous 
Nemonoxacin in adult patients with CAP 
• 
To evaluate the microbiological efficacy of treatment 
with Nemonoxacin compared with Tavanic® in patients 
with CAP. 
Study design: 
This is an international, multicenter, randomized, double-
blind, double-dummy, controlled, parallel group study of 
efficacy and safety. 
Treatment-naive 
patients 
with 
community-acquired 
pneumonia (non-nosocomial pneumonia) and patients with 
treatment failure will be screened and if eligible will be 
randomized to receive either treatment with Nemonoxacin or 
Tavanic® in a ratio of 1:1. 
Patients will stay at hospital (non-intensive care unit) and 
receive daily i.v. treatment with either invesigational product 
(Nemonoxacin 500 mg (250 ml), solution for infusion) with 
Placebo (100 ml), solution for infusion, or comparator (Tavanic® 
500 mg (100 ml), solution for infusion) with Placebo (250 ml), 
solution for infusion, for at least 3 days. The i.v. treatment may 
be prolonged by decision of investigator until and including Day 
7 of the study. 
Thus the investigator will switch a patient from i.v. to 


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oral therapy at Day 4(8) of the study if the specific criteria of 
clinical stability are achieved. The treatment will be continued 
with appropriate oral therapy. If the patient receives i.v. therapy 
with Nemonoxacin he/she will continue oral therapy with 
Nemonoxacin 250 mg, 2 capsules per day. If the patient receives 
i.v. therapy with Tavanic® he/she will continue oral therapy with 
Tavanic® 250 mg, 2 over-encapsulated film coated tablets per 
day. 
The duration of oral therapy will be judged by 
investigator and oral therapy will last until and including Day 
7(14) of the study. 
The study includes 5 visits:  
1. Visit 1 (Screening /randomization/ intravenous therapy, 
Days 1-3(7) of the study ) 
2. Visit 2 (Switch to oral therapy /oral therapy, Days 4(8)-
7(14) of the study) 
3. Visit 3 (End of treatment visit, within 1-2 days after the 
last dose) 
4. Visit 4 (Test of cure visit, within 7-9 days after the last 
dose) 
5. Visit 5 (Long-term follow-up visit; within 21-23 days 
after the last dose). 
Number of 
Subjects: 
A total of 342 eligible patients (171 patients per test group) will 
be enrolled and randomized in the study. Presumably screening 
of 382 patients will allow randomization of 342 patients. 
Inclusion Criteria: 
1. Written informed consent obtained from the patient. 
2. Female and male patients aged between 18 and 70 years 
inclusive.  
3. Patients with moderate to severe community-acquired 
pneumonia who need inpatient treatment (correspodence 
to at least one of the criteria for hospitalization / preferred 
hospitalization described in the Appendix 1 of this 
protocol) but do not need ICU treatment (in case of 
correspondence to at least one «major» or three «minor» 
criteria for hospitalization in intensive care unit described 
in Appendix 1 of this protocol, patient should not be 
enrolled in the study). 
4. The presence of at least 
3 of the following 
symptoms/signs: 
• 
Cough 
• 
Purulent sputum production 
• 
Tachypnea (respiratory rate > 24 breaths/minute) 
• 
Chills 
• 
Fever (rectal/ tympanic temperature ≥ 38.5°C or 
axillary/ oral/ cutaneous temperature ≥ 38.0°C) 
• 
WBC count of ≥10.0 x 109/L or ≥15% immature 


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neutrophils (bands; regardless of peripheral WBC 
count). 
5. Radiological evidence of (a) new infiltrate(s) consistent 
with bacterial pneumonia at baseline. 
6. Treatment-naive patients or patients who have received 
single dose of a short-acting antibacterial drug within 24 
hours of enrollment or patients with treatment failure who 
have received antibiotics (with the exception of 
quinolones or fluoroquinolones) for less than 72 hours. 
7. Consent to use contraception during participation in the 
study (for women of childbearing potential and men). 
Exclusion Criteria: 
1. Known hypersensitivity to quinolones, fluoroquinolones 
or any of the excipients. 
2. Female patients who are pregnant or nursing. 
3. History of tendon disease/disorder related to quinolone 
treatment. 
4. Known congenital or documented-acquired QT/QTc(F) 
prolongation on ECG (QTc(F) interval more than 450 
ms); concomitant use of drugs, reported to increase the 
QT interval; uncorrected hypokalaemia and uncorrected 
hypomagnesemia; 
clinically 
relevant 
bradycardia; 
clinically relevant heart failure with reduced left-
ventricular 
ejection 
fraction; 
previous 
history 
of 
symptomatic arrhythmias. 
5. History of bronchiectasis, cystic fibrosis, bronchial 
obstructions excluding chronic obstructive pulmonary 
disease. 
6. History of epilepsy and/or history of psychotic disorder. 
7. Patients with history of myasthenia gravis. 
8. Patients with diabetes mellitus. 
9. Known glucose-6-phosphate dehydrogenase deficiency. 
10. Active hepatitis or decompensated cirrhosis. 
11. Alanine transaminase or aspartate transaminase increase 
> 3 fold ULN. 
12. Patients with creatinine ≥ 1.1 fold ULN. 
13. Patients requiring concomitant systemic or inhaled 
antibiotics (e.g., tobramycin). 
14. Known or suspected active tuberculosis or endemic 
fungal infection. 
15. Concomitant immunosuppressive therapy including a 
long-term (more than 2 weeks) treatment with oral or 
intravenous glucocorticoids at doses of 20 mg and higher 
of prednisone daily or an equivalent dose of other 
glucocorticoids. 
16. Patients known to have HIV-positive status or AIDS or 
known to have other disease that seriously affects the 


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immune system such as active haematological or solid 
organ malignancy, or splenectomy. 
17. History of drug or alcohol abuse. 
18. Patients have received quinolones or fluoroquinolones 
within 14 days before enrollment. 
19. Previous enrolment in this study or participation in 
another study within the previous 4 weeks. 
20. Patients with any severe medical condition as determined 
by medical history that, in the opinion of the investigator, 
does not allow the patient to carry out all planned 
procedure of the protocol. 
Investigational 
products, dosage 
and mode of 
administration: 
• Investigational product 1: Nemonoxacin 500 mg (250 ml), 
solution for infusion. 
Dosage and mode of administration: 500 mg (250ml) daily 
administered as single intravenous infusion over 90-110 
minutes. 
 
• Investigational product 2: Nemonoxacin 250 mg, capsules. 
Dosage and mode of administration: a dose of 500 mg (two 250 
mg capsules) will be administered orally once a day. 
Comparators, 
dosage and mode 
of administration: 
• Comparator 1: Tavanic® 500 mg (100 ml), solution for 
infusion. 
Dosage and mode of administration: 500 mg (100 ml) daily 
administered as single intravenous infusion over a minimum 
duration of 60 minutes. 
 
• Comparator 2: Tavanic® 250 mg, film coated tablets. 
Each tablet is placed into a capsule shell (over-
encapsulated) for blinding purposes. 
Dosage and mode of administration: a dose of 500 mg (two  250 
mg over-encapsulated film coated tablets) will be administered 
orally once a day. 
Placebo, dosage 
and mode of 
administration: 
• Placebo (100 ml), solution for infusion. 
Dosage and mode of administration: 100 ml of solution will be 
administered daily as single intravenous infusion over a 
minimum duration of 60 minutes after the infusion of 
Nemonoxacin, solution for injection. 
 
• Placebo (250 ml), solution for infusion. 
Dosage and mode of administration: 250 ml of solution will be 
administered daily as single intravenous infusion over 90-110 
minutes before the infusion of Tavanic®, solution for infusion. 
Duration of 
treatment: 
For each patient treatment duration will be approximately 7 – 14 
days. 
 


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Endpoints: 
Efficacy endpoints: 
Primary endpoint: 
• Proportion of patients with clinical success as judged by 
the investigator at the test of cure visit (Visit 4). 
Secondary endpoints: 
• Proportion of patients with clinical success as judged by 
the investigator at the Visit 2 (switch to oral therapy) and 
Visit 3 
• Proportion of patients with infection relapse at Visit 5 
• Time to switch therapy from i.v. to oral therapy 
• Need for other antibiotic treatment 
• Proportion of patients with microbiological responses at 
the Visit 2 (switch to oral treatment), Visit 3 and Visit 4. 
Safety endpoints: 
• Adverse events 
• Changes in vital signs 
• Clinical laboratory results 
• ECG results 
• Physical examination results. 
PK parameters: 
• Cmax 
• С22.5h 
• 
AUC0-22.5 
• AUC0-inf 
• CL 
• Vss 
• T1/2 
Statistical 
methods: 
Samples size calculation 
The primary efficacy objective is to show that 
Nemonoxacin is not inferior to Levofloxacin (Tavanic®) for the 
treatment of CAP, on the basis of the primary efficacy endpoint - 
clinical success at Visit 4 (Test of cure visit) in the mITT 
population. The sample size calculation for this endpoint is based 
on assuming a clinical success rate of 82% in the treatment and 
in the active control group, and an eligibility of 80% of the 
randomized patients for mITT population. Non-inferiority 
margin is chosen to be 15% (i.e., δ= -15%), a one-sided 
significance level α is set at 5%. Then, to achieve power of 80%, 
the sample size for equal allocation is estimated as 171 
randomized patients in each group (342 patients totally) that 
provides about 137 patients in each group (274 patients totally) 
in the mITT population. 
Presumably screening of 382 patients will allow 
randomization of 342 patients. 
 


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Statistical methods 
Primary efficacy analysis 
The percentage and the number of patients with different 
categories of clinical response (“clinical success”, “clinical 
failure”, “indeterminate”) will be summarized by treatment 
group in mITT and CE populations for Visits 2 (switch to oral 
therapy), Visit 3 and Visit 4. 
The percentage of patients with clinical success (as 
judged by the investigator) at the test of cure Visit 4 is defined as 
primary endpoint variable. 
In regards to efficacy for CAP, non-inferiority of 
Nemonoxacin compared to Tavanic® will be evaluated for 
clinical response by using a one-sided 95% confidence interval 
for 
the 
difference 
in 
the 
primary 
efficacy 
endpoint 
(investigational product minus comparator). Non-inferiority of 
Nemonoxacin will be stated if the lower boundary of the 
estimated one-sided 95% confidence interval for the difference in 
the clinical success rate of Nemonoxacin and Tavanic®  is above 
-15% the Farrington-Manning test. 
The primary analysis will be performed in the mITT 
population. 
If non-inferiority is shown, a test on superiority will be 
performed in addition using the two-sided 95% confidence 
interval. The test on superiority is significant, if the lower two-
sided 95% confidence interval limit is above “0”. 
Secondary efficacy analyses 
As a supportive analysis, the primary efficacy endpoint 
will be analyzed in the CE population using the same method as 
that used for the primary efficacy analysis. 
For secondary efficacy analyses, the clinical success rates 
of the patients in the mITT and CE populations at Visits 2 and 3 
as well as the number (proportion) of patients who needed other 
antibiotic treatment (treatment failure) will be analyzed using a 
two-sided 95% confidence interval (equality test) calculated 
based on the same statistical test as for the primary analysis. 
Additionally, the results of statistical comparison of the 
clinical success rates using the logistic regression will also be 
provided.  
Microbiological 
efficacy 
endpoints 
will 
include 
microbiological success rates evaluated per each patient and by 
identified pathogens in b-mITT and BE. 
The percentage and the number of patients with 
microbiological success and failure will be summarized by visit 
and treatment group. Microbiological success is defined as the 


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assessments of eradication and presumed eradication. Other 
results of assessments (excluding unevaluable) will be regarded 
as 
microbiological 
failure. 
The 
difference 
between 
microbiological success rates and its CI will be calculated using 
the same method as that used for the secondary efficacy 
endpoints. 
The percentage and number of the baseline-identified 
strains (sputum and blood culture) with microbiological success 
and failure will be summarized by visit and treatment group. The 
frequency of each category and sample source (sputum and blood 
culture) will be presented separately and by treatment group. 
Microbiological data by identified pathogens will be analyzed 
descriptively. 
Time to switch therapy from i.v. to oral therapy will be 
evaluated using the Kaplan – Meier survival analysis method and 
compared by log-rank test between treatment groups. The 
Kaplan-Meier curves will be presented graphically. 
Safety evaluation 
Safety evaluation will include assessment of AEs, vital 
signs, ECG and physical examination data and laboratory tests in 
the safety population. All safety statistical analyses will be 
performed descriptively. 
Pharmacokinetic parameters 
The non-compartment method will be used to analyze the 
Nemonoxacin concentration-time data after the first intravenous 
Nemonoxacin infusion in adult patients with CAP. 
The following pharmacokinetic parameters will be 
estimated from the measured concentrations: the peak drug 
concentration (Cmax), 22.5-h drug concentrations (C22.5h), areas 
under the concentration-time curve from 0 to 22.5 h, and 0 h to 
infinity (AUC0-22.5, AUC0-∞), total systemic clearance (CL), 
volume of distribution at steady state (Vss), and terminal 
elimination half-life (T1/2). 
 
 


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3 INTRODUCTION 
3.1 
Background information 
The World Health Organization (WHO) estimates that lower respiratory tract infection 
(LRTI), including pneumonia, is the third most common cause of death worldwide. LRTI caused 3.1 
million deaths in 2012 [23]. 
Pneumonia is an acute illness characterized by symptoms and signs of lower respiratory tract 
infection, with new radiographic shadowing for which there is no alternative explanation. 
Community-acquired pneumonia (CAP) is pneumonia acquired outside a hospital or long-term care 
facility and being diagnosed within 48 hours of hospital admission [14]. 
Evidence suggests CAP is most commonly caused by bacterial infection [14]. 
Streptococcus pneumoniae (the most common etiologic agent), nontypeable Haemophilus 
influenzae, and the atypical organisms (i.e., Mycoplasma pneumoniae, Chlamydia pneumoniae, and 
Legionella pneumophila) are the most frequently isolated pathogens from patients of any age who 
require hospitalization for CAP [17] [20].  
Increasing resistance to a variety of antimicrobial agents has been documented in S 
pneumoniae and is common in H influenzae as well. In addition to penicillin resistance (penicillin-
intermediate S. pneumonia - PISP, or penicillin-resistant S. pneumonia - PRSP), isolates of S 
pneumoniae have demonstrated increasing resistance to other classes of antimicrobials, including 
macrolides, tetracyclines, trimethoprim-sulfamethoxazole (TMP-SMX), and fluoroquinolones [8] 
[9]. Surveillance studies indicate that the prevalence of drug-resistant S.pneumoniae (DRSP) 
continues to increase worldwide [8]. 
The basic problem of resistance in H. influenzae species is defined by ampicillin as the 
resistance marker. The resistance of H. influenzae to ampicillin may occur due to production of β-
lactamases (TEM-1, TEM-2, and with lower frequency ROB-1) or as a result of mutations in the ftsI 
gene that cause alterations in the amino acid sequences of penicillin-binding protein 3 (PBP3) in so 
called β-lactamase negative ampicillin-resistant (BLNAR) strains. Strains producing β-lactamases 
remain susceptible to amoxicillin/clavulanate; however, clavulanate is inactive against BLNAR 
strains, so such strains are resistant to amoxicillin/clavulanate. BLNAR strains are also resistant to 
ampicillin–sulbactam, cefaclor, and cefuroxime. Both mechanisms of resistance, i.e., β-lactamase 
production and mutations in the ftsI gene, are present in β-lactamase positive amoxicillin–clavulanic 
acid resistant (BLPACR) strains [2] [12]. 
The number of necrotizing or cavitary pneumonia may be caused by methicillin-resistant 
Staphylococcus aureus (MRSA) [19]. MRSA has been a major cause of nosocomial infections, and 
thus is alternatively called hospital-acquired MRSA (HA-MRSA). In addition, another class of 
MRSA has become a major concern worldwide as an emerging pathogen in the community. This 
new class of MRSA is called community-acquired MRSA (CA-MRSA) [22]. MRSA is resistant to 
b-lactam antibiotics, including penicillin and cephalosporins. Compared with nosocomial MRSA, 
CA-MRSA species are generally more susceptible to antibiotics, including trimethoprim–
sulfamethoxazole, rifampin, quinolones, and clindamycin, though resistance to clindamycin may be 
selected [4]. Published data has suggested that CA-MRSA was not a frequent cause of community-
acquired pneumonia (CAP), although with increasing incidence over the past few years the 


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frequency of CA-MRSA CAP can be estimated to be between one in 200 and one in 2000 cases of 
CAP [13]. 
Initial antimicrobial treatment for patients with CAP should provide appropriate coverage 
against the most common causative organisms, including resistant strains [17].  
The European Respiratory Society (ERS) and the European Society for Clinical 
Microbiology and Infectious Diseases (ESCMID) recommends that initial empirical treatment for 
hospitalized non-intensive care unit (non-ICU) patients with CAP should be provided with 
following antibiotics (with one of proposed regimens): aminopenicillin with or without macrolide; 
aminopenicillin/b-lactamase inhibitor ± macrolide; non-antipseudomonal cephalosporin; cefotaxime 
or ceftriaxone with or without macrolide; levofloxacin; moxifloxacin; penicillin G with or without 
macrolide [21]. 
The American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) 
consensus guidelines on the management of CAP in adults recommend that the standard empirical 
regimen should routinely cover the 3 most common pathogens that cause severe CAP, all of the 
atypical pathogens, and most of the relevant Enterobacteriaceae species. ATS/IDSA recommends 
treating CAP with a respiratory fluoroquinolone or a b-lactam plus a macrolide for hospitalized non-
ICU adult patients [11]. 
According to Russian guidelines on the management of CAP in adults monotherapy with 
respiratory fluoroquinolones (levofloxacin; moxifloxacin) is an alternative to combination of b-
lactam plus a macrolide [1]. 
In summary, fluoroquinolones are highly active and efficacious against respiratory pathogens 
[21] and in some cases should be used as first-line agents [18]. 
Although respiratory pathogens (e.g., Moraxella catarrhalis, Haemophilus influenzae, and 
Streptococcus pneumoniae) are generally susceptible to quinolones, resistance does occur, it has 
been reported in localized outbreaks [10], and is associated with clinical failure [6] [7]. Some CA-
MRSA clones have become fluoroquionlone resistant [22].  
The problem of fluoroquinolone resistance has brought great challenge into clinical practice. 
Therefore, the development of newer quinolone compounds with greater activity and less resistance 
is urgently required [15]. 
3.2 
Investigational products 
Nemonoxacin is a novel non-fluorinated quinolone (NFQ) and will be investigated as an 
investigational product in this clinical study. Nemonoxacin inhibits bacterial DNA gyrase, a key 
topoisomerase involved in the formation of bacterial DNA supercoils [28]. 
Nemonoxacin was first developed by Procter and Gamble Pharmaceuticals (Cincinnati, OH, 
USA) and completed the Phase IA single-dose escalation studies in 2004. Thereafter, it was 
authorized to TaiGen Biotechnology Co, Ltd (Taipei, Taiwan) for worldwide clinical trials and 
further development [15]. TaiGen Biotechnology Co., Ltd. licensed Russian pharmaceutical 
company R-Pharm JSC exclusive rights to develop and register Nemonoxacin in the Russian 
Federation, other members of the Commonwealth Independent States (CIS) countries and Turkey 
(http://r-pharm.com). 
The drug is available in intravenous (i.v.) and capsules formulations. Nemonoxacin capsules 
has already been approved in Taiwan and China for treatment of CAP. Intravenous formulation has 
passed phase II of clinical studies and phase III clinical study is ongoing in China. 


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Tavanic® (levofloxacin) is an approved fluoroquinolone, which will be used as a comparator 
in this clinical study. 
Levofloxacin is the optically active L-isomer of ofloxacin and acts on the DNA-DNA-gyrase 
complex and topoisomerase IV. Levofloxacin is indicated in adults for the treatment of community-
acquired pneumonia, skin and soft tissue infections, uncomplicated and complicated urinary tract 
infections including acute pyelonephritis, chronic bacterial prostatitis, etc. The CAP indication is 
approved for both tablets and i.v. formulations of levofloxacin. 
3.3 
Preclinical and clinical studies of Nemonoxacin 
Below there is brief information on the results of preclinical and clinical studies. Detailed 
information is presented in Investigational Brochure. 
Nemonoxacin was investigated under the research number “TG-873870”. The malate salt 
hemihydrate of TG-873870, “TG-875649”, was determined to be conducted in the initial clinical 
studies; dosing was adjusted to reflect the clinical dosage of anhydrous free base, TG-873870. 
3.3.1 Preclinical studies of Nemonoxacin 
3.3.1.1 
In vitro studies on antibacterial activity of nemonoxacin 
Nemonoxacin had broad-antibacterial spectrum in vitro. It exhibited strong antibacterial 
activity against penicillin-sensitive or penicillin-intermediate, or penicillin-resistant S. pneumoniae 
(PSSP, PISP, PRSPA), some gram-negative bacteria (e.g., M. catarrhalis, H. influenzae, etc.), and 
atypical pathogens (such as L. pneumophila, M. pneumoniae and C. pneumoniae). In addition, this 
drug also showed good antibacterial activity against community-acquired methicillin-resistant S. 
aureus (CA-MRSA) and drug-resistant S. pneumoniae (DRSP) [28]. In case of respiratory 
pathogens nemonoxacin had the same or superior activity to marketed fluoroquinolones [5][28]. 
In accordance to the drug resistance tests on Nemonoxacin it was shown that mutation site of 
the drug in the quinolone resistance-determining regions (QRDRs) was different from other 
quinolones (mutation generally occurred in gyrA and parC) [28]. 
3.3.1.2 
Efficacy of nemonoxacin in pulmonary model of infection 
The in vivo antibacterial efficacy of nemonoxacin was evaluated in a mouse pulmonary 
model of infection by Streptococcus pneumonia and in a mouse pulmonary model of infection by 
penicillin-resistant S. pneumoniae and K. pneumoniae. During the first study nemonoxacin 
significantly reduced the amount of viable bacteria in lungs and blood samples at all dosage levels 
when compared to vehicle-treated controls and protected from death in 100% cases. Moreover 
nemonoxacin was more effective than moxifloxacin at the same dosage levels. In the second study 
nemonoxacin also significantly reduced the viable bacteria counts of penicillin-resistant S. 
pneumoniae in lungs when compared to vehicle-treated controls and had slightly higher efficacy 
than levofloxacin. Against the K. pneumoniae infections, oral administration of nemonoxacin 
showed a significantly reduction in bacteria counts when compared to vehicle-treated controls but 
the drug had lower efficacy than levofloxacin [28]. 


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3.3.1.3 Animal pharmacokinetics and metabolism 
Nemonoxacin absorption was nearly complete after single oral dosing in dogs and monkeys 
(bioavailability of 80% in monkeys and 100% in dogs), while bioavailability was lower (~30%) in 
rats. Food decreased the bioavailability by up to 77% in monkeys. 
Protein binding to mouse, rat, rabbit, dog, monkey and human plasma was low (ranging from 
12 to 48%) over the concentration range of 0.1 to 1000 µg/mL, indicating little potential for protein 
binding-based drug interactions. 
After single-dose intravenous infusion (10 mg/kg) or oral gavage administration (30 mg/kg) 
of Nemonoxacin to rats, the drug was distributed to body immediately; the concentrations of 
Nemonoxacin in kidney, liver, submandibular gland, small intestine, lung and spleen were the 
higher, followed by heart, muscle, large intestine, pancreas and bladder. The concentrations of 
nemonoxacin in brain and fat were relatively lower. There was a significant difference between 
ovary gonads and testicles. For both administration routes, drug was distributed similar in body. 
Monkey and human hepatocytes did not metabolize nemonoxacin. The rat hepatocytes 
produced one metabolite (a glucuronide conjugate) but the extent of metabolism was low (<5% of 
total drug) [28]. 
3.3.1.4 
Toxicological studies 
The in vitro genotoxicity (mutagenicity) was considered to be related to its mechanism on 
inhibition of DNA gyrase by the drug. In mice micronucleus tests and rat unscheduled DNA 
synthesis tests, animals administered with nemonoxacin at a dose up to 2000 mg/kg did not produce 
in vivo genotoxicity. The drug had no potential to cause hemolytic effect in in vitro hemolysis test 
with rabbit erythrocytes. 
In repeated dose toxicity studies renal tubular effects were observed at ≥ 20 mg/kg following 
7 days of dosing, but these effects were not observed at up to 1000 mg/kg (AUC ≈ 130 h*µg/mL) 
following 1 month of dosing in rats, or up to 500→300 mg/kg (AUC ≈ 680 h*µg/mL) in monkeys. 
This likely represents the large capacity of the kidney to adapt to the effect.  
In the 1-month monkey study, watery stools were observed at a dose of 30 mg/kg (AUC = 60 
h* µg/mL), emesis, sinus bradycardia, and increased urine protein at a dose of 100 mg/kg (AUC = 
230 h* µg/mL), and QRS widening, decreased activity, ptosis, pale skin, dilated pupils, and thymic 
atrophy at a dose of 500 mg/kg (AUC = 690 h* µg/mL). There was a dose-dependent prolongation 
of mean QTc and a reduction of the mean heart rate (prolonged R-R interval) for the high dose 
group (500/300 mg/kg) at 3 hours post dose on Days 5 and 26. The mean QTc was mildly prolonged 
in the female monkeys and the mean heart rate reduced for the mid dose group (100 mg/kg). The 
mean QTc and heart rate recovered by the subsequent 24-hour timepoint for both groups. These 
changes were attributed to the administration of TG-875649 (nemonoxacin malic acid salt, 
hemihydrate).  
In a 28-day dog study, QTc prolongation was observed in dogs treated with second dose of 
100 mg/kg at 1 hour post-dose, but this sign was not seen at 24 hour post-dose. No ECG change was 
noted after the last dose administration. 
A battery of safety pharmacology studies was conducted to assess the effect of TG-873870 
on the central nervous system (CNS), cardiovascular system, respiratory system, gastrointestinal 
(GI) system, and renal system. Based on the results of the studies it was demonstrated that TG-
873870 had effects on the CNS, GI systems and on cardiac electrophysiology, which were 


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consistent with the known pharmacology of quinolones. The hERG and Purkinje findings suggest 
the possibility of QTc prolongation in man. Mild effects were also seen at the high dose (1000 
mg/kg) in some CNS (decreased SMA) and GI (decreased gastric motility) studies. 
Nemonoxacin did not elicit cutaneous phototoxicity when administered orally either once or 
repeatedly; did not produce systemic hypersensitive reactions during active systemic anaphylaxis 
test. In the bone/cartilage studies in juvenile dogs administered nemonoxacin at 10, 20, or 40 
mg/kg/day for 4 weeks, the microscopic changes were noted in 2/3 males and 3/3 females of the 40 
mg/kg/day dose group, the changes were graded minimal to moderate in severity and characterized 
by degeneration/necrosis with or without horizontal clefting and/or erosion of the articular cartilage. 
The nature and distribution (targeting the weight bearing area and middle zone of the proximal and 
distal femur) of these microscopic changes were compatible with quinolone-induced 
arthropathy/chondrotoxicity. No apparent changes were seen after 13 weeks recovery, suggesting a 
complete reversibility of the changes [28]. 
3.3.1.5 
Interaction with cytochrome P450 
Human primary hepatocytes were used to test the inducing potential of nemonoxacin. 
Nemonoxacin showed no significant induction or inhibition of CYP 1A2, 2B6, 2C8, 2C9, 2C19 and 
3A4 at concentration up to 100 µg/mL [28].  
3.3.2 Clinical studies of nemonoxacin 
At this time thirteen clinical studies of nemonoxacin, oral capsules, with a total of more than 
870 subjects have been completed in U.S., China, South Africa and Taiwan. Five clinical studies of 
nemonoxacin, solution for infusion, have been already conducted in more than 380 subjects. 
3.3.2.1 
Phase I clinical trials 
During a randomized, double-blind, placebo-controlled, parallel-design, single ascending 
dose study (#2003107) carried out in the USA the safety, tolerability, and pharmacokinetics of 
orally administered nemonoxacin in healthy male and female volunteers were investigated. Fifty six 
subjects were enrolled in the study. Healthy volunteers were randomized to the nemonoxacin group 
and the control (placebo) group at a ratio of 3:1. Nine escalating dose cohorts, i.e. 25 mg, 50 mg, 
125 mg, 250 mg, 500 mg, 1000 mg, 1500 mg, 2000 mg and 2500 mg, were planned. However, 
because of the AEs (pruritus and erythema), dose escalation was stopped after 1500 mg dose. 
Therefore, 1500 mg was defined as the maximum tolerated dose. There were no significant 
laboratory and ECG abnormalities and also no vital signs abnormalities. Nemonoxacin was rapidly 
absorbed after oral administration in the fasted state, with peak plasma concentrations attained 
within 1 to 2 hours post-dose. The mean terminal exponential half-life (T1/2) was approximately 10 
hours over the 25 mg to 250 mg dose range and increased to approximately 15 hours at higher doses. 
The mean renal clearance rate was approximately 0.09 L/h/kg; the mean oral clearance rate was 
approximately 0.22 L/h/kg; and the mean terminal volume of distribution was 3.8 L/kg. The mean 
urinary excretion was approximately 45% of the administered dose over the 25mg to 1500 mg dose 
range and 75% of the urinary excretion occurred within the first 24h after drug administration. In 
addition, the mean plasma protein binding of approximately 16% was observed over the 
concentration range of 141 ng/mL to 4270 ng/mL [28]. 


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The safety, tolerability and pharmacokinetics of multiple orally administered doses of 
nemonoxacin were investigated during a randomized, double-blinded, placebo-controlled, 
escalating, multiple-dose study (#TG-873870-01) conducted in the USA in healthy volunteers. A 
total of 46 subjects were enrolled in the study. Each subject received an assigned dose of the study 
drug or the placebo once daily for ten days. Five dose groups, e.g. 75 mg, 250 mg, 500 mg, 750 mg 
and 1000 mg, were studied. Each of the 75 mg and 250 mg dose groups consisted of 8 subjects. The 
ratio of the investigational drug to placebo was 3:1 (6 active, 2 placebo). Each of the 500 mg, 750 
mg and 1000 mg dose groups consisted of 10 subjects. The ratio of the investigational drug to 
placebo was 4:1 (8 active, 2 placebo). There were no apparent differences in laboratory test, ECG 
intervals, ECG morphology, vital signs measurement and physical examination findings during the 
study. With the exception of changes in serum amylase and serum lipase in one subject each, there 
were no clinical laboratory findings of potential clinical concern during the study. There was rapid 
absorption of nemonoxacin following oral administration in the fasted state, with peak plasma 
concentrations attained within 1 to 2 hours post-dose. Half-life ranged from approximately 7 to 8 
hours after single dose administration of 75 mg - 1000 mg. The half-life appeared to increase after 
repeated administration for 10 days (ranged from approximately 18-23 hours). The presence of food 
led to decrease in both Cmax and AUC (Cmax and AUC0-24h decreased by approximately 46% and 
27% respectively in the fed state) and a 3-hour delay in median Tmax [28]. 
A phase I clinical study of intravenous administration of Nemonoxacin malate sodium 
chloride injection was carried out in China and consisted of four parts (TG-873870-C-2: part A, B, 
C-1 and C-2). During the part A of study the tolerability of intravenous Nemonoxacin malate 
injection was investigated. To explore the safe dose by evaluating the safety and tolerability of eight 
dose levels of nemonoxacin (25, 50, 125, 250, 500, 750, 1000 and 1250 mg) the drug was given as 
single intravenous dose in Chinese healthy subjects. A total of 92 subjects were assigned into 12 
groups with equal numbers of male and female. The tolerated-dose study of the nemonoxacin 
indicated that the tolerated-dose ranged from 25 mg to 1250 mg and the maximum dose was 1250 
mg. The most common drug-related AE was local reaction at administration sites (27/68) and skin 
rash with or without pruritus (13/68) All AEs were mild and transient, and recovered spontaneously 
during the administration or shortly after administration. No important or serious AEs that led to 
study discontinuation and clinical significant change in ECG was observed. As for the laboratory 
tests, no drug related hyperglycemia or hypoglycemia occurred. The infusion rate of the drug ranged 
from 0.42 mg/min to 8.33mg/min. The occurrence of skin rash was more common with infusion rate 
of 8.33 mg/min (3 subjects each in 500 mg and 750 mg group), and all other infusion rates (0.42 
mg/min to 5.56 mg/min) were tolerated well. 
Part B of the trial evaluated the pharmacokinetic profiles of single-dose nemonoxacin malate 
sodium chloride injection at 250, 500, and 750mg in healthy Chinese volunteers (see Brochure for 
details).  
During the part C-1 (500 mg and 750 mg doses were investigated) and C-2 (500 mg, 650 mg 
and 750 mg doses were investigated) of study the tolerability and pharmacokinetics of the multi-
dose continuous intravenous infusion of nemonoxacin malate was investigated. During these studies 
there were no serious AEs and clinical significant change in ECG. In the C-1 study after the multiple 
intravenous infusions of nemonoxacin Cmax on day 10 (steady state) in the 500mg and 750mg group 
was 9.600±1.838 µg/mL and 11.039±2.177 µg/mL respectively. AUC0-t (for 500 mg group: 22.5h; 
for 750 mg group: 21.75h) was 44.03±8.62 µg.h/mL and 65.82±10.78 µg.h/mL respectively. 
Statistical analysis revealed no cumulative effect in both groups after administration for consecutive 
10 days [28]. 


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3.3.2.2 
Phase II clinical trials 
A randomized, double-blind, comparative, multi-center study (#TG-873870-02) of the safety 
and efficacy of oral nemonoxacin versus oral levofloxacin in adult patients with CAP was carried 
out in 19 study centers in South Africa and Taiwan. A total of 265 subjects were enrolled and 
randomized in the study: 86 patients in the nemonoxacin 750 mg group, 89 in the nemonoxacin 500 
mg group and 90 in the levofloxacin 500 mg group. Patients received therapy once daily for 7 days. 
The study revealed that 750 and 500 mg nemonoxacin had similar clinical efficacy when compared 
with 500 mg levofloxacin once daily for 7 days. The safety profile of nemonoxacin was also similar 
to that of levofloxacin and it was consistent with the favorable safety results of nemonoxacin in 
previous phase I studies [28]. 
Efficacy and safety of Nemonoxacin malate sodium chloride injection versus Moxifloxacin 
hydrochloride sodium chloride injection in the treatment of moderate to severe adult CAP were 
evaluated during a multi-center, randomized, double-blind, parallel, controlled, phase II study. 
Patients received either 500 mg nemonoxacin, 650 mg nemonoxacin, or comparator drug 
moxifloxacin 400 mg once a day for 7 to 14 days. A total of 207 subjects were randomly enrolled in 
30 research centers: 69 subjects were in the nemonoxacin 500mg group, 68 subjects were in the 
nemonoxacin 650 mg group and 70 subjects were in the control group (moxifloxacin 400mg). 
Nemonoxacin had shown similar clinical efficacy, microbiological efficacy, and overall efficacy 
when compared with moxifloxacin hydrochloride sodium chloride injection once a day for 7 to 14 
days. The AEs reported during the study were mostly mild, transient, and tolerated by most patients. 
The main drug-related AEs in patients who received nemonoxacin were local reactions at the 
infusion site. The main drug-related laboratory abnormalities were elevated liver transaminases 
without bilirubin elevation [24]. 
3.3.2.3 
Phase III clinical trials 
During a multicenter, randomized, double-blind, double-dummy, parallel, comparative, 
phase III study the efficacy and safety of oral administration with Nemonoxacin versus 
Levofloxacin in treating adult patients with CAP were evaluated (TG-873870-C-4). The study was 
conducted in 53 study centers in China and Taiwan. A total of 532 patients were randomized into 
the study at a ratio of 2:1 into two groups: the investigational group (nemonoxacin 500 mg) and the 
control group (levofloxacin 500 mg), respectively. There were 357 patients in the investigational 
group (nemonoxacin) and 175 patients in the control group (levofloxacin). Duration of therapy was 
7 – 10 days. The results of the study indicate that oral administration of 500 mg nemonoxacin 
malate capsules for 7 to 10 consecutive days achieved excellent clinical and microbiological 
efficacies in treating adult CAP patients. Nemonoxacin had similar clinical and microbiological 
efficacies as compared with levofloxacin. Statistical analysis demonstrated that nemonoxacin was 
non-inferior to in clinical and microbiological efficacies. The AEs reported in the study were mostly 
mild in intensity, well-tolerated, and did not affect the course of the treatment. No deaths were 
reported during this study [25]. 


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3.4 
Assessment of Potential risks and benefits for participants 
Comparator Tavanic® (Levofloxacin) is effective antibiotic approved for treatment of a wide 
variety of infectious diseases, including CAP. The drug may be administered for empiric 
antimicrobial therapy in patients with CAP.  
Investigational product Nemonoxacin, capsules, has already been approved in Taiwan and 
China for treatment of CAP and the phase III clinical study of efficacy and safety of Nemonoxacin 
intravenous formulation is ongoing. At this time more than 1000 subjects were participated in 
various clinical studies of nemonoxacin, capsules or solution for infusion.  
Nemonoxacin has shown similar clinical and microbiological efficacies as compared with 
levofloxacin during clinical studies in patients with CAP (see Sections 3.3.2.2 and 3.3.2.3). 
Nemonoxacin was well tolerated and had acceptable safety profile either when administered by 
intravenous and oral routs. The majority of AEs reported during the studies were mild and transient. 
The risk to patients in this clinical study will be minimized by compliance with selection 
criteria. Taking into account available safety data for investigational medicinal products, both 
Levofloxacin and Nemonoxacin (e.g., possibility of QT prolongation, hypoglycemia, tendinitis and 
tendon rupture, etc.), these medicinal products will be avoided in patients with renal impairment, 
diabetes mellitus, QT prolongation, uncorrected hypokalemia, receiving class Ia or III 
antiarrhythmic agents, receiving corticosteroids, etc.  
Levofloxacin was shown to have photosensitization activity. Therefore, in order to prevent 
photosensitization in patients the Patient Information Leaflet provides precautions for study 
participants not to expose themselves unnecessarily to strong sunlight or to artificial ultra-violet 
rays. Although Nemonoxacin did not elicit cutaneous phototoxicity in preclinical studies and by 
now there is no clinical data suggested phototoxicity of the drug the aforementioned precautions will 
be taken by all participants (i.e., regardless of treatment group) because of double-blind design of 
the study and because of absence of certainty the drug has not such activity. 
In consideration of the foregoing assumptions the risk-benefit ratio for the participants is 
acceptable. 
This clinical study will be conducted in compliance with the Protocol, ICH GCP and all 
other applicable local regulatory requirements. 
3.5 
Dose, route, regimen and treatment period rationale 
Nemonoxacin, solution for infusion, and Nemonoxacin, capsules, will be administered at 
daily dose of 500 mg. The choice of the dose is based on the results of previous clinical trials 
(please, refer to Section 3.3.2). 
Tavanic® (levofloxacin), solution for infusion, is available in one dosage strength of 500 mg 
(100 ml). Tavanic® (levofloxacin), film coated tablets, is available in two dosage strengths of 250 
and 500 mg. The usual dose of Levofloxacin (either solution for infusion and tablets) for treatment 
of community-acquired pneumonia is 500 mg administered once or twice a day for 7-14 days, as 
indicated in product label [26][27]. In this clinical study the daily dose of Tavanic® (levofloxacin) 
was chosen to be 500 mg because this daily dose was approved for the treatment of CAP in the 
countries where this clinical study will be carried out. 
Therapy of the patients will start with intravenous infusions and after 3-7 days patients will 
be switched to oral treatment. In accordance with Russian recommendations for management of 


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CAP taking into consideration that hospitalized patients usually tend to have more severe course of 
CAP it is reasonable to start treatment with parenteral antibiotics and to switch to oral treatment 
after the normalization of temperature and abatement of the symptoms [1]. Switch from intravenous 
to oral antibiotics is generally considered appropriate and safe in clinical practice when criteria 
indicative of clinical stability of disease are met. In the CAPRIE study the majority of patients were 
switched to oral therapy on day 3-4 after the start of treatment with levofloxacin [3]. In another 
study the median time to actual switch to oral therapy was 5 days (range from 2 to 7 days) for 
levofloxacin-treated patients and the total duration of study therapy was 7 to 14 days at the 
investigator’s discretion [16]. In general, as many as two-thirds of all patients with CAP have 
clinical improvement and meet criteria for a therapy switch in the first 3 days, and most non-
intensive care unit patients meet these criteria by day 7 [11]. Therefore, the switch to oral treatment 
was chosen to be Day 4-8 of the study, after 3-7 days of intravenous therapy. 
4 STUDY OBJECTIVES 
4.1 
Primary Objective 
To evaluate the clinical efficacy of treatment with Nemonoxacin compared with Tavanic® in 
patients with CAP. 
4.2 
Secondary Objectives 
• To evaluate the clinical efficacy of treatment with intravenous Nemonoxacin compared with 
intravenous Tavanic® in patients with CAP 
• To assess the safety of treatment with Nemonoxacin compared with Tavanic® in patients 
with CAP 
• To assess the pharmacokinetic parameters of intravenous Nemonoxacin in adult patients with 
CAP 
• To evaluate the microbiological efficacy of treatment with Nemonoxacin compared with 
Tavanic® in patients with CAP. 
5 CLINICAL STUDY ENDPOINTS 
5.1 
Efficacy endpoints 
5.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the proportion of patients with clinical success as judged by 
the investigator at the test of cure visit (Visit 4). 
 
 


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5.1.2 Secondary efficacy endpoints 
The secondary efficacy endpoints are the following: 
• Proportion of patients with clinical success as judged by the investigator at the Visit 2 
(switch to oral therapy) and Visit 3  
• Proportion of patients with infection relapse at Visit 5 
• Time to switch therapy from i.v. to oral therapy 
• Need for other antibiotic treatment 
• Proportion of patients with microbiological responses at the Visit 2 (switch to oral therapy), 
Visit 3 and Visit 4. 
5.2 
Safety endpoints 
The following safety endpoints will be evaluated: 
• Adverse events 
• Changes in vital signs 
• Clinical laboratory results 
• ECG results 
• Physical examination results. 
5.3 
Pharmacokinetic parameters 
The following pharmacokinetic parameters will be evaluated: 
• Cmax 
• C22.5h 
• AUC0-22.5 
• AUC0-inf 
• CL 
• Vss 
• T1/2 
6 STUDY DESIGN 
6.1 
Design Summary 
This is an international, multicenter, randomized, parallel group, double-blind, double-
dummy, controlled study of efficacy and safety. 
Treatment-naive patients with community-acquired pneumonia (non-nosocomial pneumonia) 
and patients with treatment failure will be screened and if eligible will be randomized in a ratio of 
1:1 to receive either treatment with investigational product (Nemonoxacin) or comparator 
(Tavanic®). After randomization patients will start to receive intravenous therapy with 
investigational product or comparator and then upon a decision of investigator patients will be 
switched to oral therapy with the same product. To maintain double-blinding during the intravenous 
treatment the patients will receive placebo solution (100 ml or 250 ml) along with intravenous 


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antibiotic (Nemonoxacin or Tavanic®) solution. To maintain double-blinding during oral antibiotic 
therapy each Tavanic® tablet was placed into a capsule shell (over-encapsulated), that is identical in 
appearance to a Nemonoxacin-containing capsules; therefore, the patients will receive daily 
treatment with 2 capsules either containing nemonoxacin or levofloxacin (tablet of Tavanic®) (see 
Table 6-1). 
Table 6-1 Summary of treatment groups 
Group
Number 
of 
patients 
Intravenous therapy 
(once a day) 
Oral therapy 
(once a day) 
First infusion 
Second infusion 
Investigational 
drug 
(Nemonoxacin) 
171 
Nemonoxacin
500 mg (250 ml), solution 
for infusion, will be given 
over 90-110 minutes 
Placebo
(100 ml), solution for 
infusion, will be given over 
a minimum of 60 minutes 
Nemonoxacin 
250 mg x 2 
capsules 
Comparator 
(Tavanic®) 
171 
Placebo
(250 ml), solution for 
infusion, will be given over 
90-110 minutes 
Tavanic®
500 mg (100 ml), solution 
for infusion, will be given 
over a minimum of 60 
minutes 
Tavanic®
250 mg x 2 
over-
encapsulated 
film coated 
tablets 
Total number of 
patients 
342 
 
Intravenous therapy will be administered once a day and will include two consequence 
infusions (antibiotic solution and placebo solution). Solution with volume of 250 ml will always be 
infused over 90-110 minutes and before the infusion of solution with volume of 100 ml that will be 
infused over at least 60 minutes. Intravenous therapy should be given for at least 3 days and may be 
prolonged by a decision of investigator up to 7 days. Then investigator will switch a patient from 
intravenous to oral therapy on Day 4(8) of the study if the specific criteria of clinical stability are 
achieved (please, refer to Appendix 2). However if the treatment with intravenous IMP should be 
prolonged after the 7 days of treatment are completed (according to the investigator’s opinion) the 
investigator should contact the study Medical Adviser (please, refer to Contact information) for the 
approval of intravenous treatment prolongation. 
In general since Day 4(8) of the study treatment will be continued with the same antibiotic 
administered orally. Patients will daily receive treatment either with 2 capsules of investigational 
drug (Nemonoxacin, 250 mg) or 2 over-encapsulated film coated tablets of Comparator (Tavanic® 
250 mg).  
The average duration of treatment (including intravenous and oral therapy) for each patient 
will be 7(14) days and during this period patients should stay at hospital. 
After completion of the treatment patients can be discharged from the hospital and should 
return for examinations at End of treatment visit (Visit 3) within 1-2 days after the last dose. Then 
the patients should attend the investigational site within 7-9 days after the last dose (test of cure 
visit). Then the investigator will contact the patients by phone within 21-23 days after the last dose 
(long-term follow-up visit). 
The study includes 5 visits. The detailed description of visits is presented in Section 9.2. 
A schematic diagram of the study design is presented in Figure 6-1. 
 


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Figure 6-1: Study design 
 
 
Comparator 
group 
Investigational 
drug  
group 
Day 1 
Visit 1 
Day 4(8) 
Within 1-2 days 
after the last dose 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
+ 
+ 
Once-daily intravenous therapy 
1st infusion: 
Nemonoxacin 
500 mg 
(250 ml) 
infusion over 
90-110 min. 
  Nemonoxacin 
250 mg  
x 2 caps q.d. 
Once-daily oral therapy 
Test of cure 
Long-term follow-up 
End of treatment 
Switch from 
intravenous to oral 
therapy 
Screening 
 
Randomization 
2nd infusion: 
Placebo  
(100 ml) 
infusion over 
at least 60 
min. 
1st infusion: 
Placebo 
(250 ml) 
infusion 
over 90-110 
min. 
2nd infusion: 
Tavanic® 
500 mg 
(100 ml) 
infusion over 
at least 60 min. 
  Tavanic® 
250 mg  
x 2 over-encaps. 
tablets q.d. 
Within 7-9 days 
after the last dose 
Within 21-23 days 
after the last dose 
Days 2-3(7) 
Days 5(9)-7(14) 


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7 SELECTION OF STUDY POPULATION 
7.1 
Inclusion Criteria 
Patients will be eligible for inclusion in the study only if all of the following 
inclusion criteria are applied: 
1. Written informed consent obtained from the patient. 
2. Female and male patients aged between 18 and 70 years inclusive. 
3. Patients with moderate to severe community-acquired pneumonia who need 
inpatient treatment (correspondence to at least one of the criteria for 
hospitalization / preferred hospitalization described in the Appendix 1 of this 
protocol) but do not need ICU treatment (in case of correspondence to at least one 
«major» or three «minor» criteria for hospitalization in intensive care unit 
described in Appendix 1 of this protocol, patient should not be enrolled in the 
study).  
4. The presence of at least 3 of the following symptoms/signs: 
• 
Cough 
• 
Purulent sputum production 
• 
Tachypnea (respiratory rate > 24 breaths/minute) 
• 
Chills  
• 
Fever (rectal/ tympanic temperature ≥ 38.5°C or axillary/ oral/ cutaneous 
temperature ≥ 38.0°C)  
• 
WBC count of ≥10.0 x 109/L or ≥15% immature neutrophils (bands; 
regardless of peripheral WBC count). 
5. Radiological evidence of (a) new infiltrate(s) consistent with bacterial pneumonia 
at baseline. 
6. Treatment-naive patients or patients who have received single dose of a short-
acting antibacterial drug within 24 hours of enrollment or patients with treatment 
failure who have received antibiotics (with the exception of quinolones or 
fluoroquinolones) for less than 72 hours. 
7. Consent to use contraception during participation in the study (for women 
childbearing potential and men). 
7.2 
Exclusion Criteria 
Patients won’t be eligible for inclusion in the study if any of the following 
exclusion criteria is applied: 
1. Known hypersensitivity to quinolones, fluoroquinolones or any of the excipients. 
2. Female patients who are pregnant or nursing. 
3. History of tendon disease/disorder related to quinolone treatment. 
4. Known congenital or documented-acquired QT/QTc(F) prolongation on ECG ( 
QTc(F) interval more than 450 ms); concomitant use of drugs, reported to 
increase 
the QT interval; uncorrected hypokalaemia and 
uncorrected 
hypomagnesemia; clinically relevant bradycardia; clinically relevant heart failure 


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with reduced left-ventricular ejection fraction; previous history of symptomatic 
arrhythmias. 
5. History of bronchiectasis, cystic fibrosis, bronchial obstructions excluding chronic 
obstructive pulmonary disease. 
6. History of epilepsy and/or history of psychotic disorder. 
7. Patients with history of myasthenia gravis 
8. Patients with diabetes mellitus 
9. Known glucose-6-phosphate dehydrogenase deficiency. 
10. Active hepatitis or decompensated cirrhosis. 
11. Alanine transaminase or aspartate transaminase increase > 3 fold ULN. 
12. Patients with creatinine ≥ 1.1 fold ULN. 
13. Patients requiring concomitant systemic or inhaled antibiotics (e.g., tobramycin). 
14. Known or suspected active tuberculosis or endemic fungal infection. 
15. Concomitant immunosuppressive therapy including a long-term (more than 2 
weeks) treatment with oral or intravenous glucocorticoids at doses of 20 mg and 
higher of prednisone daily or an equivalent dose of other glucocorticoids. 
16. Patients known to have HIV-positive status or AIDS or known to have other 
disease that seriously affects the immune system such as active haematological or 
solid organ malignancy, or splenectomy. 
17. History of drug or alcohol abuse. 
18. Patients have received quinolones or fluoroquinolones within 14 days before 
enrollment. 
19. Previous enrolment in this study or participation in another study within the 
previous 4 weeks. 
20. Patients with any severe medical condition as determined by medical history that, 
in the opinion of the investigator, does not allow the patient to carry out all 
planned procedure of the protocol. 
7.3 
Discontinuation of Therapy and Withdrawal of the Patients 
from the Study 
Study therapy should be discontinued and the patient should be withdrawn from 
the study due to any of the following reasons: 
• Informed consent withdrawal (the patient has made the decision to stop the 
participation in study for any reason) 
• The patients require other antibiotic treatment 
• Development of any adverse event, including serious adverse event, clinical 
significant deviation in the laboratory results, or concomitant disease, which at the 
investigator’s opinion indicates, that continuation of the study medication 
administration is not at the patient’s best interest 
• Pregnancy 
• Termination of the study by the Sponsor (e.g. in case of poor safety results) 
• Termination of the study by the Regulatory Authority (e.g. in case of poor safety 
results). 
 


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In all cases the reason of termination of participation in study must be recorded in 
eCRF. When the patient is withdrawn from the study, all efforts should be made to 
perform all procedures scheduled for the “early termination visit”: 
• if the “early termination visit” coincides in time with scheduled visit the 
procedures of that visit should be done (Section 9.2); 
• if the “early termination visit” coincides in time with unscheduled visit the 
minimum number of procedures should comply with the “End of treatment visit” 
(Section 9.2.3).  
All the patients withdrawn from the study will receive treatment in accordance 
with the standards adopted in the hospital.  
Withdrawn patients will not be replaced. 
8 TREATMENT 
8.1 
Treatments Administered 
Two investigation products, two comparators and 2 placebos will be used during 
the study. All the investigational medicinal products will be blinded (please refer to 
Section 8.6).  
In this trial the investigational products are Nemonoxacin 500 mg (250 ml), 
solution for infusion, and Nemonoxacin 250 mg, capsules. 
Nemonoxacin 500 mg (250 ml), solution for infusion, will be administered daily 
as single intravenous infusion over 90-110 minutes followed by infusion of Placebo (100 
ml), solution for infusion, over a minimum duration of 60 minutes to maintain the 
blinding. Daily dose of Nemonoxacin will be 500 mg (250 ml). Intravenous therapy will 
be given for at least 3 days and may be prolonged by a decision of investigator up to 7 
days. The possibility of further prolongation of intravenous treatment (for more than 7 
days) has to be discussed with the study Medical Adviser. The decision about switching 
to oral therapy should be based on assessment of patient’s condition using the criteria of 
clinical stability. 
After the switch to oral therapy on Day 4(8) of the study the patients who receive 
intravenous therapy with Nemonoxacin, solution for infusion, will receive therapy with 
Nemonoxacin, capsules. Please note that the first dose of oral drug will be administered 
on the same day when the “switch” is performed (e.g. the patient will receive the first 
dose of oral drug on Day 4 if the “switch” is performed at Day 4, etc.). 
Nemonoxacin 250 mg, capsules, will be administered at a dose of 500 mg once 
daily (two 250 mg capsules). The duration of oral therapy will be judged by investigator 
and oral therapy will last until and including Day 7(14) of the study. 
Tavanic® 500 mg (100 ml), solution for infusion, and Tavanic® 250 mg, over-
encapsulated for the blinding purpose film coated tablets, will be used as the comparators 
in this study. 
Tavanic® 500 mg (100 ml), solution for infusion, will be administered daily as 
single intravenous infusion over a minimum duration of 60 minutes. Daily dose will be 
500 mg (100 ml). To maintain double-blinding before the infusion patients in this group 
will receive Placebo (250 ml), solution for infusion, over 90-110 minutes. Intravenous 


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therapy will be given for at least 3 days and may be prolonged by a decision of 
investigator up to 7 days. Further prolongation of intravenous treatment (for more than 7 
days) has to be discussed with the study Medical Adviser. The decision about switching 
to oral therapy should be based on assessment of patient’s condition using the criteria of 
clinical stability. 
After the switch to oral therapy on Day 4(8) of the study the patients who receive 
intravenous therapy with Tavanic®, solution for infusion, will receive therapy with 
Tavanic®, over-encapsulated film coated tablets. Please note that the first dose of oral 
drug will be administered on the same day when the “switch” is performed (e.g. the 
patient will receive the first dose of oral drug on Day 4 if the “switch” is performed at 
Day 4, etc.). 
Tavanic® 250 mg, over-encapsulated film coated tablets, will be administered at a 
dose of 500 mg once daily (two capsules each containing 250 mg film coated tablet). The 
duration of oral therapy will be judged by investigator and oral therapy will last until and 
including Day 7(14) of the study. 
8.2 
Investigational Medicinal Products (IMPs) 
Table 8-1 Investigational Medicinal Products (IMPs) 
Investigational 
product 1:  
Nemonoxacin 
INN:
Nemonoxacin
Chemical name:
7-[(3S,5S)-3-Amino-5-methyl-peperidin-1-yl]-1-cyclopropyl-8-
methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid  
Pharmaceutical form:
Solution for infusion
Strength:
500 mg (250 ml)
Rout of 
administration: 
Intravenous
Supplier:
R-Pharm JSC (Russia)
Manufacturer:
Zhejiang Medicine Co. (China)
Investigational 
product 2:  
Nemonoxacin 
INN:
Nemonoxacin
Chemical name:
7-[(3S,5S)-3-Amino-5-methyl-peperidin-1-yl]-1-cyclopropyl-8-
methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 
Pharmaceutical form:
Capsules
Strength:
250 mg
Rout of 
administration: 
Orally
Supplier:
R-Pharm JSC (Russia)
Manufacturer:
Lotus Pharmaceutical Co., Ltd. (Taiwan)
Comparator 1:  
Tavanic® 
INN:
Levofloxacin
Chemical name:
(-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-
oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic 
acid 
hemihydrate 
Pharmaceutical form:
Solution for infusion


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Strength:
500 mg (100 ml)
Rout of 
administration: 
Intravenous
Supplier:
R-Pharm JSC (Russia)
Manufacturer:
Sanofi-Aventis Deutschland GmbH, Germany (Germany)
Comparator 2:  
Tavanic® 
INN:
Levofloxacin
Chemical name:
(-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-
oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic 
acid 
hemihydrate 
Pharmaceutical form:
Film coated tablets (each tablet is placed into a capsule shell (over-
encapsulated) for blinding purposes) 
Strength:
Route of 
administration:  
250 mg 
Orally  
Supplier:
R-Pharm JSC (Russia)
Manufacturer:
Tablets manufactured by Sanofi Winthrop Industrie, France (France),
are over-encapsulated into capsule shells by Lotus Pharmaceutical Co. 
Ltd. (Taiwan) 
There will be two placebo formulations used during the study: 
• Placebo (250 ml) - 0.9% NaCl (250 ml), solution for infusion 
• Placebo (100 ml) - 0.9% NaCl (100 ml), solution for infusion 
All placebo formulations will be supplied by the Sponsor. Placebo (250 ml), 
solution for infusion, is manufactured by Zhejiang Medicine Co. (China). Placebo (100 
ml), solution for infusion, is manufactured by Dalchempharm OJSC (Russia). 
8.3 
Non-Investigational Medicinal Products 
There will be no Non-Investigational Medicinal Products (NIMP) in this study. 
8.4 
Packaging, labeling and storage of IMPs 
Nemonoxacin 500 mg (250 ml), solution for infusion, and Placebo (250 ml), 
solution for infusion, will be supplied in the flexible bags. Tavanic® 500 mg (100 ml) 
solution for infusion, and Placebo (100 ml), solution for infusion, will be supplied in the 
glass bottles. 
Nemonoxacin 250 mg capsules and Tavanic® 250 mg over-encapsulated film 
coated tablets will be supplied in the plastic bottles.  
Each unit of container will be appropriately labeled in accordance with local 
regulations. The label will clearly indicate “only for clinical study”. The label will be 
affixed to the primary container (bottles/flexible bags). 
All IMPs will be stored at room temperature (less than or equal to 25°C) under 
secure conditions and protected from light. The temperature in the storage room should 
be controlled on a regular basis and should be documented in the Temperature Log.  
At the site the IMPs should be stored in a locked room. Only unblinded staff 
appointed by Principal Investigator (PI) will have an access to the room. Unblinded staff 
will be instructed on the proper storage conditions of IMPs, return of drug and package. 


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All containers of the IMPs, both used and unused, must be saved for a monitoring 
by unblinded CRA and possible audit by an assigned Sponsor’s designee. 
8.5 
Method of Assigning Patients to Treatment Groups 
At Visit 1 (Day 1) to minimize or avoid bias randomization will be done. The 
study will utilize IWRS for randomization of the eligible patients. In accordance with 
randomization number each patient will be assigned to one of two treatment groups at the 
ratio of 1:1 (see Table 6-1): 
• 
Investigational drug (Nemonoxacin) group 
• 
Comparator (Tavanic®) group. 
8.6 
Blinding 
This study has a double-blind and double-dummy design with 2 placebo 
formulations (see Section 8.2) needed for maintaining the blinding of intravenous 
treatment.  
Intravenous drug dispensing procedure 
Only the unblinded staff appointed by PI at each investigational site and an 
unblinded CRA will be aware of the intravenous treatment received by the patient. 
Neither the patients nor any of the principal investigators (PI)/ co-investigators/ other 
clinical staff (blinded staff), involved in the treatment of the patients, Sponsor and CRO 
(except an aforementioned unblinded CRA) will be aware of the intravenous treatment 
received by the patient. 
The unblinded staff will include person, appointed by PI from study site staff (e.g. 
a doctor, a nurse, a pharmacist) at each investigational site. These unblinded person will 
be responsible for the supply of the drugs intravenous treatment for the certain patient.  
After enrollment and obtainment of the subject study number using the interactive 
web response system (IWRS) each eligible patient will be randomized. The PI or one of 
the unblinded persons appointed by PI will access the IWRS at Visit 1 and IWRS will 
randomize the patient and provide the medication identification number of the 
investigational drug to be dispensed. For details refer to the IWRS manual, please. 
Once the unblinded person receives the number, he/she will prepare the supply.  
Unblinded person will take the appropriate solutions according to the medication 
identification number.  
Nemonoxacin 500 mg (250 ml)/Placebo (250 ml), solutions 
The flexible bag with Nemonoxacin/Placebo (250 ml) solution will be packed in 
an opaque bag that will be sealed by a sticker to prevent breaking the code. Then, the 
opaque bag with flexible bag inside will be put into the special designed empty packing 
box with number “1” on the label. The label with randomization number will be stuck to 
the box. After that the unblinded person will insert a spike of infusion set into the 
administration port of the flexible bag with Nemonoxacin /Placebo (250 ml) solution and 
will prime the infusion set. 


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Tavanic® 500 mg (100 ml)/Placebo (100 ml), solutions 
The unblinded person will peel off the outer aluminum band from the top of the 
glass bottle with Tavanic®/Placebo (100 ml) solution. The bottle will be packed in a 
carton with a hole on the bottom for the administration port of the bottle. The carton will 
be sealed by a sticker to avoid breaking the code. Then, the carton with glass bottle inside 
will be put into the special designed empty packing box with number “2” on the label. 
The label with randomization number will be stuck to the box. After that the unblinded 
person will insert a spike of infusion set into the administration port of the bottle with 
Tavanic®/Placebo (100 ml) solution and will prime the infusion set. 
Then, a person from blinded staff will take the supply, dose the patient, and return 
the supply after the dosing to the unblinded staff. 
Oral drug dispensing procedure 
Neither the patients nor any of the principal investigators (PI)/ co-investigators/ 
other clinical staff (blinded staff), involved in the treatment of the patients, Sponsor and 
CRO will be aware of the oral treatment received by the patient. 
Since Day 4(8) of the study (switch from i.v. to oral therapy) the patients will 
receive the blinded capsules of oral drugs according to the medication identification 
number. Each patient will receive daily treatment with 2 capsules containing either 
Nemonoxacin (Nemonoxacin 250 mg capsules) or Levofloxacin (Tavanic® 250 mg, film 
coated tablets). 
 
The randomization number will only be broken for an individual patient in an 
emergency such as an SAE that requires knowledge of which IMP was taken so that the 
SAE can be treated appropriately. In the event of SAE, if possible, the investigator should 
contact the medical adviser before the investigational drug blind will be broken to discuss 
the need for unblinding. If the randomization number for a patient is broken, the 
investigator must withdraw the patient from the study. 
8.7 
Prior and Concomitant therapy 
For patients with treatment failure who have received antibiotics for less than 72 
hours the information on therapy should be obtained and recorded in the eCRF (i.e., the 
trade name, INN/name of active ingredients, dosage, date of start, termination date). 
The information on prior/concomitant drugs (the trade name, INN/name of active 
ingredients, dosage or change of dosage, indication, frequency of intake, prescription 
method, date of start, termination date) which the patient took before and takes during the 
study, should be registered in the corresponding section of the eCRF. All subsequent 
changes of concomitant therapy during the study should also be reflected in the eCRF. It 
will document information on previous drugs and treatments used from the onset of 
community-acquired pneumonia until the enrollment in the study (signing of the 
Informed Consent Form).  
If there are any questions regarding concomitant therapy, the study Medical 
Adviser (see CONTACT information) should be contacted. 


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8.7.1 Permitted concomitant therapy 
Females enrolled in study who use oral contraceptives can continue to take these 
drugs during whole study. 
Patients are prohibited from using other drugs, except for necessary medical 
requirements, including: 
• Treatment of concomitant pathology if it is not an exclusion criterion. In 
that case usual treatment regimen shouldn’t contain prohibited drugs (see 
Section 8.7.2) 
• Symptomatic treatment of the CAP (e.g., drugs such as antipyretics, 
analgesics, antihistamines, or cough suppressants) within the first 2 days 
of the treatment if necessary required by the opinion of the investigator. 
Since Day 3 (including) of the therapy these drugs are prohibited (see 
Section 8.7.2). 
Information about all the concomitant drugs should be documented in the 
electronic Case Report Form (eCRF) in details (see Section 8.7). 
8.7.2 Prohibited and limited in use therapy 
During treatment period (from Visit 1 to Visit 3) the following medications 
should be prohibited: 
1. Antacids, multivitamins containing calcium, magnesium, iron, zinc, or aluminum, 
and sucralfate should be prohibited within 3 hours before and after oral 
administration of the investigational drug. Intravenous therapy should not be co-
administered with any solution containing multivalent cations, e.g., magnesium, 
through the same intravenous line. 
2. Probenecid. 
During study period (from Visit 1 to Visit 5) the following medications should be 
prohibited: 
1. Drugs that may prolong the QT interval with known risk or possible risk of 
Torsades de Pointes (TdP). The list of these drugs is presented in Appendix 3. 
2. Chemotherapeutic agents or antitumor drugs. 
3. Other systemic antibacterial drugs (except for treatment failure). 
4. Systemic immunosuppressive drugs, including inhaled steroids. 
5. Drugs that may act to alter the signs and symptoms of infections (e.g., 
antipyretics, analgesics, antihistamines, or cough suppressants) – since day 3 
(including) of the treatment. 
6. Investigational products other than studied in this trial and other than the patient 
has been randomized. 
8.8 
Contraception 
From the signing of informed consent on Visit 1 and throughout the duration of 
the study (until the last procedure at Visit 5) women of childbearing potential and men 
must use highly effective birth control methods.  
A woman of childbearing potential is defined as a premenopausal female or a 
female who is less than 12 months post-menopausal and who has not undergone a 


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hysterectomy or surgical sterilization, e.g. bilateral tubal ligation, bilateral ovariectomy 
(oophorectomy). 
In this study the patients can use the following birth control methods: 
1. Barrier methods: 
• Male condom + spermicide 
• Cervical cap + spermicide 
• Diaphragm + spermicide 
2. Intrauterine device (IUD)  
3. Intrauterine hormone-releasing system (IUS) 
4. Hormonal contraceptives: 
• Hormonal implants 
• Hormonal injections 
• Combined Oral Contraceptive Pill 
• Mini pill 
• Birth Control Patch 
5. Sexual abstinence. 
Patients will be provided with information on acceptable methods of 
contraception as part of the informed consent process obtainment. 
8.9 
Treatment compliance 
Intravenous treatment will be administered under the supervision of 
investigational site personnel and date, start and stop time, volume (mL) of each infusion 
will be documented in the eCRF. Oral dosing will be also performed under the 
supervision of investigational site personnel. The total amount of oral dosing completed 
(capsules count) as well as dose administered, date and time of dosing will be recorded in 
the eCRF. 
Patients should be informed that compliance with taking all oral medication as 
instructed is imperative.  
9 STUDY VISITS AND PROCEDURES 
9.1 
Schedule of study procedures 
The time points at which each procedure and assessment will be performed are 
presented in study schedule of procedures/assessments (see Table 9-1). 
 
 


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Table 9-1 Schedule of procedures/assessments 
Study 
procedures/assessments 
Visit 11 
Visit 21 
Visit 31 
Visit 41 
Visit 51 
Day 12 
Days 
2-3(7) 
Day 4(8) 
Days 
5(9)-7(14) 
Within 1-2 
days after the 
last dose3 
Within 7-9 
days after the 
last dose4 
Within 21-23 
days after 
the last dose 
Screening 
procedures 
Randomization 
and initiation of 
therapy 
Continuation 
of 
intravenous 
therapy 
Switch to 
oral 
therapy 
Continuation 
of oral 
therapy 
End of 
treatment visit 
Test of cure 
visit 
Long-term 
follow up visit 
Initiation procedures 
Written informed consent 
(before all other 
procedures) 
X 
 
 
 
 
 
 
 
Demographic data and 
other baseline 
characteristics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Pregnancy test (for women 
of childbearing potential 
only) 
X 
 
 
 
 
 
 
 
Check of 
inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Randomization (before 
starting of intravenous 
therapy) 
 
X 
 
 
 
 
 
 
Safety assessments 
Physical examination 
X 
 
XXX5 
X5 
XXX5 
X 
X 
 
Vital signs 
X 
X6 
XXX6 
X6 
XXX6 
X 
X 
 
ECG (before or 30 minutes 
after blood samples 
collection) 
X 
 
 
X5 
 
X 
X 
 
Haematology test 
X7 
 
 
X5 
 
X 
X 
 
Biochemical assay 
X7 
 
 
X5 
 
X 
X 
 


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Study 
procedures/assessments 
Visit 11 
Visit 21 
Visit 31 
Visit 41 
Visit 51 
Day 12 
Days 
2-3(7) 
Day 4(8) 
Days 
5(9)-7(14) 
Within 1-2 
days after the 
last dose3 
Within 7-9 
days after the 
last dose4 
Within 21-23 
days after 
the last dose 
Screening 
procedures 
Randomization 
and initiation of 
therapy 
Continuation 
of 
intravenous 
therapy 
Switch to 
oral 
therapy 
Continuation 
of oral 
therapy 
End of 
treatment visit 
Test of cure 
visit 
Long-term 
follow up visit 
Urinalysis 
X7 
 
 
X5 
 
X 
X 
 
Documentation of 
AEs/SAEs 
X8 
X8 
XXX 
X 
XXX 
X 
X 
X 
Efficacy assessments 
Chest x-ray/ CT 
X9 
 
 
 
 
 
X 
 
Pulse oximetry 
X 
 
 
X5 
 
X 
X 
 
Sputum sample collection 
for culture (if the patient 
has sputum) 
X 
 
 
X5 
 
X 
X 
 
Blood sample collection 
for culture 
X 
 
 
X5, 10 
 
X10 
X10 
 
Clinical response 
assessment 
 
 
 
X 
 
X 
X 
 
Infection relapse 
assessment 
 
 
 
 
 
 
 
X 
Pharmacokinetic parameters 
Blood sample collection 
for PK via venous catheter 
 
X11 
 
 
 
 
 
 
IMP administration 
Start of intravenous 
therapy 
 
X 
 
 
 
 
 
 
Daily intravenous therapy 
(at least 3 days and up to 7 
days) 
 
 
XXX 
 
 
 
 
 
Switch to oral therapy (first 
oral dose) 
 
 
 
X12 
 
 
 
 
Daily oral therapy (until 
 
 
 
 
XXX 
 
 
 


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Study 
procedures/assessments 
Visit 11 
Visit 21 
Visit 31 
Visit 41 
Visit 51 
Day 12 
Days 
2-3(7) 
Day 4(8) 
Days 
5(9)-7(14) 
Within 1-2 
days after the 
last dose3 
Within 7-9 
days after the 
last dose4 
Within 21-23 
days after 
the last dose 
Screening 
procedures 
Randomization 
and initiation of 
therapy 
Continuation 
of 
intravenous 
therapy 
Switch to 
oral 
therapy 
Continuation 
of oral 
therapy 
End of 
treatment visit 
Test of cure 
visit 
Long-term 
follow up visit 
Day 7-14 of the study) 
Compliance check 
 
X 
XXX 
X 
XXX 
 
 
 
Other 
Prior/сoncomitant 
medication and therapies 
X 
X 
XXX 
X 
XXX 
X 
X 
X 
X – All procedures should be performed during one day.  
XXX – All procedures should be performed every day during mentioned period of time. 
1 – All procedures of Visit 1 and Visit 2 will be performed during patient's hospital stay. All procedures of Visit 3 and Visit 4 can be performed at outpatient department. 
Visit 5 will be conducted as a telephone contact. 
2 – The maximum duration is 24 hours after the signing of informed consent. 
3 – The Visit should be conducted at least 24 hours after the last dose of the study drug.  
4 – All the efforts should be made to conduct this visit (Visit 4) 7 days after the end of treatment. 
5 – The procedure should be done before dosing. 
6 – On Day 1 of Visit 1 the procedure should be done 2 hours ±30 minutes after the infusion of second solution is finished. On Days 2-3(7) of Visit 1 the procedure 
should be done before dosing and 2 hours ±30 minutes after the infusion of second solution is finished. At Visit 2 the procedure should be done before dosing and 2 
hours ±30 minutes after capsules intake. 
7 – At screening, during the study selection criteria assessment, the Investigator may use laboratory test results obtained at the laboratory of the investigational site within 
24 hours of study enrollment (signing of the Informed Consent Form) if he / she considers that available data are sufficient to permit a decision on whether the 
subject meets the selection criteria. In this case, another blood sampling procedure has to be conducted in the period from the signing of the Informed Consent Form 
to the start of treatment in order to evaluate all other laboratory parameters that have to be determined on Day 1 in accordance with the study protocol.  
8 – The investigator will record in eCRF all AEs occurred after the first IMP administration and until the last procedure at Visit 5 and all SAEs occurred after the 
obtainment of the informed consent (after the signing of ICF) and until the last procedure at Visit 5.  
9 – Chest x-ray/ computed tomography (CT) may not to be done if the patient has the results of chest x-ray/ computed tomography that was performed within 72 hours 
before enrollment. 
10 – Blood sampling should not be conducted if no bacterial growth (negative culture) has been detected by blood cultures of samples withdrawn at Visit 1. 
11 – Blood for drug concentration measurements will be withdrawn only in first 40 patients in the investigational sites defined by the Sponsor. The schedule for blood 
sample collection for the PK is as follows: pre-dose, 0 h, 0.5 h (±3min), 2.5h (±5min), 4h (±5min), 6h (±10min), 12h (±15min), 16h (±15min) and 22.5h (±15min) 
after the end of first infusion on Day 1. The last blood sampling for PK (22,5h after the end of the first infusion) should be conducted just prior to the IMP infusion 
on Day 2 of the study. 


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12 – The investigator will switch the patient to oral treatment if the patent meets criteria of clinical stability. If the treatment with intravenous IMP should be prolonged 
after the 7 days of treatment are completed (according to the investigator’s opinion) the investigator should contact the study Medical Adviser for the approval of 
intravenous treatment prolongation. Please note that the first dose of oral drug will be administered on the day when the switch is performed (e.g. the patient will 
receive the first dose of oral drug on Day 4 if the switch is performed at Day 4, etc.). 


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9.2 
Description of visits 
9.2.1 Visit 1 (screening /randomization and intravenous therapy, Days 1-3(7) of the 
study) 
The Visit 1 is scheduled on Days 1-3(7) of the study and will be performed at 
hospital. On Day 1 (no more than 24 hours) all screening procedures should be performed 
and eligible patients should be randomized and after randomization will receive the first 
intravenous dose of IMP. On Days 2-3(7) patients will receive intravenous therapy. 
Therefore during the Visit 1 the following procedures will be performed: 
Screening procedures (Day 1) 
To evaluate the selection criteria of the study, the Investigator may use laboratory 
test results obtained at the laboratory of the investigational site within 24 hours of study 
enrollment (Signing of the Informed Consent Form) if he / she considers that available 
data are sufficient to permit a decision on whether the subject meets the selection criteria. 
In this case, another blood sampling procedure has to be conducted in the period from the 
signing of the Informed Consent Form to the start of treatment in order to evaluate all 
other laboratory parameters that have to be determined on Day 1 in accordance with the 
study protocol 
• Obtainment of written informed consent (before all other procedures) 
• Demographic and other baseline characteristic data collection 
• Medical history taking 
• Pregnancy test (for women of childbearing potential only) 
• Physical examination 
• Assessment of vital signs 
• ECG (before or 30 minutes after blood samples collection) 
• Haematology test 
• Biochemical assay 
• Urinalysis 
• Documentation of SAEs occurred after the obtainment of the informed consent 
(after the signing of ICF) 
• Chest x-ray (two-dimensional roentgenogram) or computed tomography. The 
results of chest x-ray (computed tomography) performed within 72 hours before 
enrollment are acceptable 
• Pulse oximetry 
• Collection of sputum sample for culture (if the patient has sputum) 
• Collection of blood sample for culture 
• Assessment of prior medication taken within 30 days before the Visit and 
therapies (beginning from the onset of community-acquired pneumonia) 
• Check of inclusion/exclusion criteria 
 


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Randomization and initiation of therapy (Day 1) 
• Before starting the therapy patients eligible for inclusion will be randomized 
• Start of intravenous therapy with IMP 
• Assessment of vital signs 2 hours ± 30 minutes after the second infusion 
(Tavanic®/Placebo) is finished 
• Documentation of AEs/SAEs occurred after the first IMP administration 
• Compliance check 
• Assessment of concomitant medication and therapies 
• Blood sample collection for PK (via venous catheter): pre-dose, 0 h, 0.5 h 
(±3min), 2.5h (±5min), 4h (±5min), 6h (±10min), 12h (±15min), 16h (±15min) 
and 22.5h (±15min) after the end of first infusion (only for investigational sites 
defined by the Sponsor). The last blood sampling for PK (22.5h after the end of 
the first infusion) should be conducted prior to the IMP infusion on Day 2. 
Continuation of intravenous therapy (Days 2-3(7)) 
All of the following procedures should be performed on each day of Days 2-3(7) 
of the study: 
• Physical examination before dosing 
• Assessment of vital signs before dosing 
• Intravenous therapy with IMP 
• Assessment of vital signs 2 hours ± 30 minutes after the second infusion is 
finished 
• Documentation of AEs/SAEs 
• Compliance check 
• Assessment of concomitant medication and therapies 
9.2.2 Visit 2 (switch to oral therapy/oral therapy, Days 4(8)-7(14) of the study) 
Visit 2 is scheduled on Days 4(8)-7(14) of the study and will be performed at 
hospital.  
On Day 4(8) of the study the investigator will assess patient’s medical condition 
and if the patent meets specified criteria he/she (see APPENDIX 2: ASSESSMENT OF 
CLINICAL STABILITY (POSSIBILITY OF SWITCH TO ORAL TREATMENT)) 
could be switched to oral treatment. However if the treatment with intravenous IMP 
should be prolonged after the 7 days of treatment are completed, according to the 
investigator’s opinion,  the investigator should contact the study Medical Adviser (see 
Contact information) for the approval of intravenous treatment prolongation. Despite 
prolonged intravenous therapy, the overall duration of treatment within this study will not 
exceed 14 days.  
Note that the first dose of oral drug will be administered on the day when the 
switch is performed (e.g. the patient will receive the first dose of oral drug on Day 4 if the 
switch is performed at Day 4, etc.). Therefore, oral treatment will be started since Day 
4(8) of Visit 2 and will last until and including Day 7(14) of Visit 2. 
 
 


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Switch to oral therapy (Day 4(8)) 
All the procedures scheduled on Day 4(8) of Visit 2 should be performed within 
one day. The following measures will be performed during Day 4(8) of the Visit 2 in 
accordance with the study schedule of assessments: 
• Physical examination (before dosing) 
• Assessment of vital signs (before dosing) 
• ECG (before dosing; before or 30 minutes after blood samples collection) 
• Haematology test (before dosing) 
• Biochemical assay (before dosing) 
• Urinalysis (before dosing) 
• Pulse oximetry (before dosing) 
• Collection of a sputum sample for culture (before dosing and if the patient has 
sputum) 
• Collection of a blood sample for culture (before dosing, sampling should not be 
conducted in case of negative culture at Visit 1) 
• Clinical response assessment 
• Switch to oral therapy, the first dose of oral IMP 
• Assessment of vital signs - 2 hours ± 30 minutes after oral dose administration 
• Documentation of AEs/SAEs 
• Compliance check 
• Assessment of concomitant medication and therapies. 
Continuation of oral therapy (Days 5(9)-7(14)) 
All of the following procedures should be performed on each day of Days 5(9)-
7(14) of the study: 
• Physical examination before dosing 
• Assessment of vital signs before dosing 
• Oral therapy with IMP 
• Assessment of vital signs - 2 hours ± 30 minutes after oral dose administration 
• Documentation of adverse events 
• Compliance check 
• Assessment of concomitant medication and therapies. 
 
9.2.3 Visit 3 (end of treatment visit, within 1-2 days after the last dose) 
Visit 3 will be performed within 1-2 days after the last dose, but not less than 24 
hours after the last dose of the study drug. The Visit can be performed at outpatient 
department. The following measures will be performed during the Visit 3 in accordance 
with the study schedule of assessments: 
• Physical examination 
• Assessment of vital signs 
• ECG (before or 30 minutes after blood samples collection) 
• Haematology test 


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• Biochemical assay 
• Urinalysis 
• Pulse oximetry 
• Collection of a sputum sample for culture (if the patient has sputum) 
• Collection of a blood sample for culture (sampling should not be conducted in 
case of negative culture at Visit 1) 
• Clinical response assessment 
• Documentation of AEs/SAEs 
• Assessment of concomitant medication and therapies 
All the procedures should be performed within one day. 
9.2.4 Visit 4 (test of cure visit, within 7-9 days after the last dose) 
Visit 4 will be performed within 7-9 days after the last dose. The Visit can be 
performed at outpatient department. The following measures will be performed during 
the visit in accordance with the study schedule of assessments: 
• Physical examination 
• Assessment of vital signs 
• ECG (before or 30 minutes after blood samples collection) 
• Haematology test 
• Biochemical assay 
• Urinalysis 
• Chest X ray (two-dimensional roentgenogram) or chest computed tomography 
• Pulse oximetry 
• Collection of a sputum sample for culture (if the patient has sputum) 
• Collection of a blood sample for culture (sampling should not be conducted in 
case of negative culture at Visit 1) 
• Clinical response assessment 
• Documentation of AEs/SAEs occurred since the last visit 
• Assessment of concomitant medication and therapies (since the last visit) 
All the procedures should be performed within one day. 
9.2.5 Visit 5 (long-term follow-up visit, within 21-23 days after the last dose) 
Visit 5 will be performed within 21-23 days after the last dose as a telephone 
contact. The date of Visit 5 is the date of per protocol study termination for the patient. 
The following measures will be performed during the visit in accordance with the 
study schedule of assessments: 
• Documentation of AEs/SAEs occurred since the last visit 
• Assessment of concomitant medication and therapies (since the last visit) 
• Infection relapse assessment. 
All the procedures should be performed within one day. 
9.3 
Unscheduled Visits 
Patients may visit the investigational site for an unscheduled visit at any time if 
they have adverse events or in case if they need medical intervention. 


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An investigator should record the data in the source medical documents and in the 
eCRF. It is obligatory for an investigator to write down the following information: date of 
the visit, reason, the results of examinations and additional measures which were carried 
out during the visit. 
The next visit after the unscheduled visit is carried out according to the earlier 
scheduled visit date in conformity with the protocol.  
If the Investigator makes a decision to withdraw a subject from the study during 
an unscheduled visit (a so-called “early termination visit”), the minimal number of 
completed procedures should correspond to that of the “End of treatment visit”. For more 
information on discontinuation of therapy and early withdrawal of subjects from the 
study, see Section Ошибка! Источник ссылки не найден..  
  
10 ASSESSMENTS 
10.1 Initial assessments 
10.1.1 Demographic data and other baseline characteristics 
Demographic information such as date of birth, sex and race will be collected 
before treatment initiation on Day 1 of the study (at Visit 1, screening procedures) and 
then will be recorded in the eCRF. 
Height and weight will be measured and alcohol use status and smoking status 
will be obtained and recorded in the eCRF on Day 1 of the study (at Visit 1, screening 
procedures) before treatment as well. Height will be used for calculation of body mass 
index (BMI). 
10.1.2 Medical history 
A medical history about all current medical conditions, any significant past 
conditions, operations, and therapeutic or diagnostic procedures will be obtained by the 
investigator or sub-investigator and recorded before treatment initiation on Day 1 of the 
study (at Visit 1, screening procedures). 
10.1.3 Pregnancy test 
Pregnancy test (urine dip-strip pregnancy test) will be performed before treatment 
initiation on Day 1 of the study (at Visit 1, screening procedures) only in women of 
childbearing potential (see definition in Section 8.8). 
10.1.4 Pulse oximetry 
Pulse oximetry will be done to evaluate blood oxygen saturation (SaO2) before 
treatment initiation on Day 1 of the study (at Visit 1, screening procedures), before 
dosing on Day 4(8) of the study (at Visit 2), within 1-2 days (Visit 3) and 7-9 days (Visit 
4) after the last dose. 


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10.2 Assessment of efficacy 
10.2.1 Chest X-ray / Chest Computed Tomography 
X-ray examination or computed tomography (CT) will be performed before 
treatment initiation on Day 1 (at Visit 1, screening procedures). However, the results of 
X-ray examination or CT performed within 72 hours before enrollment are acceptable.  
Then X-ray examination or CT will be performed within 7-9 days after the last 
dose (at Visit 4).  
Only one radiological method (X-ray imaging only or CT imaging only for all 
visits) should be used for a patient throughout the study.  
Chest x-ray images/CT scans will be evaluated by radiologist. Radiologist’s 
conclusion will be fixed in the source documentation.  
At Visit 4 the investigator will categorize the results to one of the following 
categories and will document it in the eCRF: 
1. Cured – if there is not any manifestation of pneumonia according to the chest x-ray 
images /chest CT scans. 
2. Improved – if the chest x-ray /chest CT results are less serious relative to the 
baseline results (at Visit 1 or within 72 hours before enrollment). 
3. Unchanged – if there is no change in the chest x-ray /chest CT results relative to the 
Visit 1 (Day 1). 
4. Worsening – if the chest x-ray /chest CT results are worsening (more serious) 
relative to the baseline results (at Visit 1 or within 72 hours before enrollment). 
10.2.2 Clinical response assessment 
The investigator will evaluate clinical response to treatment on Day 4(8) of the 
study (at Visit 2, switch from intravenous to oral therapy), within 1-2 days (Visit 3, end 
of treatment) and within 7-9 days (Visit 4, test of cure) after the last dose. Criteria for 
evaluation of clinical response to the therapy are presented in Table 10-1. 
Table 10-1 Criteria for evaluation of clinical response 
Category
Criteria
Clinical success
• All signs and symptoms of pneumonia presented at Visit 1 (Day 1) 
are resolved (i.g., resolution of fever, absence of intoxication, 
purulent sputum, and respiratory insufficiency) or improved with 
no worsening or appearance of new signs and symptoms of 
pneumonia. 
• There is no requirement for additional antibiotic therapy. 
• Chest roentgenograms (CT scans) are cured or improved (only for 
TOC visit). 
Clinical failure
• Persistence or worsening in signs and symptoms of the acute 
process with either failure to show improvement in the clinical 
findings, initial improvement in signs and symptoms followed by 
clinically significant worsening before the assessment. 
• Additional antimicrobial therapy required. 


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• Progression (worsening) of chest roentgenogram (CT scans) 
abnormalities or unchanged chest roentgenogram features (only for 
TOC visit). 
• Death because of pneumonia.
Indeterminate
• No evaluation possible: the patient was lost to follow-up, or died 
because of noninfectious-related reasons or infection other than 
pneumonia (as judged by the investigator). 
10.2.3 Bacteriological study 
Sputum sample for the culture (bacteriological) study for isolation of pathogens 
will be collected before the initiation of therapy on Day 1 of the study (at Visit 1, during 
screening procedures) and before the first oral dose of IMP on Day 4(8) of the study 
(Visit 2, switch to oral therapy), within 1-2 days (Visit 3) and within 7-9 days (Visit 4) 
after the last dose. This procedure will be performed only if it will be necessary and 
possible (according to the judgment of the investigator) to collect the sputum from patient 
(deep expectorated / broncho-alveolar lavage, etc.).  
Blood sample collection for bacteriological study will be done before the 
initiation of the therapy on Day 1 (at Visit 1, screening procedures) and before dosing on 
Day 4(8) of the study (at Visit 2, switch to oral therapy), within 1-2 days (Visit 3) and 
within 7-9 days (Visit 4) after the last dose. However blood sampling at Visit 2, 3 and 4 
should not be conducted if no bacterial growth has been detected by blood cultures of 
samples withdrawn at Visit 1. 
The results of bacteriological study will be documented in eCRF. 
Causative pathogens of CAP listed below will be determined in sputum/blood 
samples: 
• S. pneumoniae 
• H. influenzae 
• S. aureus 
• K. pneumoniae 
• P. aeruginosa 
• Other. 
Bacteriological study will be performed in the local laboratory of investigational 
site. After isolation of pathogens culture from some previously defined laboratories can 
be sent to a central laboratory for additional investigations by a decision of the Sponsor. 
Detailed information about central laboratory, conditions of culture transportation are 
provided in appropriate Manual. The Sponsor will use these isolates to perform additional 
culture (bacteriological) studies, including drug sensitivity test, etc.. 
10.2.4 Infection relapse assessment 
Within 21-23 days after the last dose (Visit 5) the investigator will ask the patient 
whether he/she has any signs/symptoms of community-acquired pneumonia. In some 
cases the investigator may invite the patient to visit the clinic for the additional 
examinations: 
• Physical examination 
• Assessment of vital signs 


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• Haematology test 
• Chest X ray (two-dimensional roentgenogram) or chest computed tomography 
• Collection of a sputum sample for culture (if the patient has sputum) 
• Collection of a blood sample for culture. 
10.3 Assessment of Safety 
10.3.1 Physical Examination 
All physical examinations will be performed by the investigator or a sub-
investigator at every visit (on each day) of the study with the exception of Long-term 
follow-up visit (Visit 5). 
Physical examination will include the following assessments:  
• 
performance status  
• 
head  
• 
eyes  
• 
ears/nose/throat  
• 
lymph nodes  
• 
breast  
• 
skin  
• 
lungs  
• 
heart  
• 
abdomen  
• 
musculoskeletal  
• 
neurologic evaluations.  
Data should be recorded in the medical history and eCRF. All clinically 
significant abnormal changes of physical examination results from the baseline results 
must be reported as AEs in the eCRF. 
10.3.2 Vital Signs 
The investigator or sub-investigator will assess vital signs at every visit (on each 
day) with the exception of Visit 5 (Long-term follow-up visit). On Day 1 of the study 
(Visit 1, screening procedures/initiation of therapy) all measurements will be done during 
screening procedures before treatment initiation and 2 hours±30 minutes after the 
infusion of second solution on Day 1 is finished; on each day of Days 2-3(7) of the study 
(Visit 1, continuation of i.v. therapy) the measurements will be done before dosing and 2 
hours±30 minutes after the infusion of second solution is finished. On Day 4(8) of the 
study (Visit 2, switch to oral therapy) and on each day of Days 5(9)-7(14) of the study 
(Visit 2, continuation of oral therapy) the measurements will be done before dosing and 2 
hours±30 minutes after the oral dose administration. 
The following vital signs will be measured and recorded: 
• 
pulse rate 
• 
blood pressure (systolic and diastolic blood pressure) 
• 
respiratory rate  
• 
temperature. 


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Blood pressure, pulse and respiratory rate will be measured after the patient has 
been seated for at least 5 minutes. 
All clinically significant abnormal changes of vital signs from the baseline results 
must be reported as AEs in the eCRF.  
10.3.3 Electrocardiography 
Electrocardiogram (ECG) will be recorded before treatment initiation on Day 1 
(Visit 1, screening procedures), before dosing on Day 4(8) of the study (Visit 2, switch to 
oral therapy), within 1-2 days (Visit 3) and within 7-9 days (Visit 4) after the last dose. 
ECG should be performed before or 30 minutes after collecting blood samples for 
haematology test, biochemical assay and blood sample collection for culture (if needed), 
and should start after the patient lies supine for at least 5 minutes. ECG parameters 
include heart rate, RR, PR, QRS, QT, and QTc. 
Results of ECG will be registered in medical records and in the eCRF. All 
clinically significant abnormal changes of ECG results from the baseline results must be 
reported as AEs in the eCRF. 
10.3.4 Haematology test 
Blood samples for haematology test will be withdrawn before treatment initiation 
on Day 1 of the study (Visit 1, screening procedures), before dosing on Day 4(8) of the 
study (Visit 2, switch to oral therapy), within 1-2 days (Visit 3) and within 7-9 days (Visit 
4) after the last dose.  
To evaluate the selection criteria of the study, the Investigator may use 
haematology test results obtained at the laboratory of the investigational site within 24 
hours of study enrollment (Signing of the Informed Consent Form) if he / she considers 
that available data are sufficient to permit a decision on whether the subject meets the 
selection criteria. In this case, another blood sampling procedure has to be conducted in 
the period from the signing of the Informed Consent Form to the start of treatment in 
order to evaluate all other haematology test parameters that have to be determined on Day 
1 in accordance with the study protocol.    
Haematology test will be analyzed by the local laboratory of investigational site 
using standard validated methods. The following investigations will be made: 
• erythrocytes 
• hemoglobin 
• hematocrit 
• leucocytes and differential leucocyte count (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
• platelets 
• erythrocyte sedimentation rate (ESR). 
All clinically significant abnormal changes in haematological parameters from the 
baseline results must be reported as AEs in the eCRF. 
10.3.5 Biochemical assay 
Blood samples for biochemical assay will be withdrawn before treatment 
initiation on Day 1 of the study (Visit 1, screening procedures), before dosing on Day 
4(8) of the study (Visit 2, switch to oral therapy), within 1-2 days (Visit 3) and within 7-9 


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days (Visit 4) after the last dose. At Visits 1, 2, and 3, samples will be collected prior to 
dosing.  
To evaluate the selection criteria of the study, the Investigator may use blood 
chemistry test results obtained at the laboratory of the investigational site within 24 hours 
of study enrollment (Signing of the Informed Consent Form) if he / she considers that 
available data are sufficient to permit a decision on whether the subject meets the 
selection criteria. In this case, another blood sampling procedure has to be conducted in 
the period from the signing of the Informed Consent Form to the start of treatment in 
order to evaluate all other blood chemistry test parameters that have to be determined on 
Day 1 in accordance with the study protocol.    
Biochemical assay will be performed in the local laboratory of investigational site 
using standard validated methods. The following investigations will be made: 
• glucose 
• total bilirubin 
• alanine aminotransferase (ALT) 
• aspartate aminotransferase (AST) 
• gamma-glutamyl transpeptidase (GGTP) 
• alkaline phosphatase (ALP) 
• potassium (К+) 
• sodium (Na+) 
• creatinine 
• urea. 
All clinically significant abnormal changes in biochemical parameters from the 
baseline results must be reported as AEs in the eCRF. 
10.3.6 Urinalysis 
Assessments will be performed in the local laboratory before treatment initiation 
on Day 1 of the study (Visit 1, screening procedures), before dosing on Day 4(8) of the 
study (Visit 2, switch to oral therapy), within 1-2 days (Visit 3) and within 7-9 days (Visit 
4) after the last dose. The following parameters will be assessed: 
• color 
• clarity 
• specific gravity 
• urine рН 
• protein 
• glucose 
• ketones 
• erythrocytes 
• leucocytes 
• epithelium 
• bacteria 
• crystals 
• mucus. 
To evaluate the selection criteria of the study, the Investigator may use urinalysis 
results obtained at the laboratory of the investigational site within 24 hours of study 


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enrollment (Signing of the Informed Consent Form) if he / she considers that available 
data are sufficient to permit a decision on whether the subject meets the selection criteria. 
In this case, another urine sampling procedure has to be conducted in the period from the 
signing of the Informed Consent Form to the start of treatment in order to evaluate all 
other urinalysis parameters that have to be determined on Day 1 in accordance with the 
study protocol.    
All clinically significant abnormal changes in urinalysis parameters from the 
baseline results must be reported as AEs in the eCRF.  
10.3.7 Documentation of adverse events 
The Investigator will assess and record in the source documentation and the eCRF 
any non-serious AEs occurring at each visit from the moment of first IMP administration 
on Day 1 of Visit 1 until the last procedure at Visit 5. SAEs will be evaluated and 
recorded in the eCRF from the moment of signing of informed consent on Day 1 of Visit 
1 until the last procedure at Visit 5. 
All AEs/SAEs observed or reported by the patients will be documented regardless 
of whether it is related to the investigational product (see Section 11.2). 
10.4 Drug Concentration Measurements for Assessment of 
Pharmacokinetic Parameters 
Blood sample collection for pharmacokinetic (PK) parameters will be withdrawn 
on Day 1 and 2 of Visit 1 before and after the first infusion only in 40 first patients 
enrolled in the investigational sites defined by the Sponsor. Blood collection will be 
performed via venous catheter which will be inserted into peripheral vein in the arm. 
Infusions of IMPs should be performed via another peripheral vein during all period of 
blood collection for PK parameters. 
The schedule for blood sample collection for the PK is as follows: pre-dose, 0 h, 
0.5 h (±3min), 2.5h (±5min), 4h (±5min), 6h (±10min), 12h (±15min), 16h (±15min) and 
22.5h (±15min) after the end of first infusion (see Figure 10-1). The last blood sampling 
for PK (22.5h after the end of the first infusion) should be conducted just prior to the IMP 
infusion on study Day 2. 
Figure 10-1 
Schedule for blood sample collection for the PK at Visit 1 
 
Sample 
collection 
(pre-dose) 
Sample collection (after the end of first infusion on Day 1)
I.v. infusion of 
250 ml solution 
(1st infusion) on 
Day 1 
I.v. infusion of 
100 ml solution 
(2nd infusion) 
on Day 1 
0 h
22.5ha, b
0.5ha
16ha
12ha
6 ha
4 ha
2.5ha
I.v. infusion of 
250 ml solution 
(1st infusion) on 
Day 2 


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a - for these time points the protocol allows acceptable sampling time deviations (“sampling time 
windows”): 0.5 h±3min, 2.5h±5min, 4h±5min, 6h±10min, 12h±15min, 16h±15min and 22.5h±15min. 
b - The last blood sampling for PK should be conducted just prior to the IMP infusion on study Day 2. 
 
 
After the last blood sample collection catheter can be used for infusions of IMPs. 
Drug concentration measurements will be performed in the central laboratory (see 
Contact information). Detailed information about transportation of the samples and other 
information are provided in the appropriate Manual. 
11 ADVERSE EVENTS (AE) AND SERIOUS ADVERSE 
EVENTS (SAE) 
11.1 Definitions 
11.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  
An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding which are considered to be clinically significant), symptom, 
or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.  
Any worsening of symptoms of the primary disease (as compared with estimates 
made during the screening procedures) should also be registered as an AE.  
11.1.2 Drug Relationship 
The relationship between an AE and study drugs will be judged according the 
following categories: 
1- “Certain”: the AE occurs in a plausible time relation to the administration of the 
drug and cannot be explained by a concurrent disease or other drugs or chemicals. 
The response to withdrawal of the drug (dechallenge) should be clinically plausible. 
The event must be definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary. 
2- “Probable”: the AE occurs in a reasonable time relation to the administration of the 
drug, it is unlikely to be attributed to a concurrent disease or other drugs or chemicals 
and it follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information (AE reappearance after drug reintroduction) is not required 
to fulfil this definition. 
3- “Possible”: the AE occurs with a reasonable time relation to the administration of 
the drug, but it could also be explained by a concurrent disease or other drugs or 
chemicals. Information on drug withdrawal (dechallenge) may be lacking or unclear. 
4- “Unassessable”: The relationship cannot be judged, because of the information is 
insufficient or contradictory and cannot be supplemented or verified. 


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5- “Unlikely“: a causal relationship cannot be definitively ruled out, but 
- 
other drugs, chemicals or underlying disease provide plausible explanations 
and/or 
- 
the temporal relation to the administration of the drug makes a causal relation 
improbable. 
6- “Not Related“: Any of the following are present: 
- 
existence of a clear alternative explanation, and/or 
- 
unreasonable temporal relationship between Drug and Event, and/or 
- 
non-plausibility 
11.1.3 Adverse Drug Reactions 
Adverse drug reactions (ADRs) are all untoward and unintended responses to an 
investigational medicinal product related to any dose administered. 
The definition implies a reasonable possibility of a causal relationship between 
the event and the Investigational Medicinal Product (IMP). This means that there are 
facts (evidence) or arguments to suggest a causal relationship. 
11.1.4 Seriousness 
An AE/ADR is considered Serious when: 
• results in death; 
• is life-threatening; 
Note: Life-threatening is considered any AE in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
• requires 
inpatient 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly/birth defect in children born to parents who were 
exposed to the drug; 
• is another medically important condition that may jeopardise the patient 
or may require intervention to prevent one of the outcomes listed above. Any 
suspected transmission of an infectious agent via a medicinal product is considered 
serious and should be assessed under the category of medically important events in 
the absence of other seriousness criteria. 
An AE/ADR is considered Non-serious when: 
it does not fulfil the conditions for the definition of Serious AE/ADR. 
11.1.5 Adverse Event (AE) / Adverse Drug Reaction (ADR) severity 
The severity level of a Serious or a Non-serious AE or ADR is attributed 
according the below definitions. 
• 
Mild: does not interfere with routine activities; in case of laboratory tests, 
when there is a mild abnormality. 
• 
Moderate: interferes with the routine activities; in case of laboratory tests, 
when there is a moderate abnormality. 
• 
Severe: makes impossible to perform routine activities; in case of 
laboratory tests, when there is a significant abnormality. 


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If the patient experiences changes in severity of an AE, the event should be 
captured once with the maximum severity recorded. 
11.1.6 Adverse Event (AE) / Adverse Drug Reaction (ADR) expectedness 
An AE/ADR is considered Unexpected when the nature, severity or outcome of 
the AE / ADR is not consistent with the information provided the Instructions for 
Medical Use (for marketed product) or the IB (for investigational product). 
11.1.7 Suspected Unexpected Adverse Drug Reaction (SUSAR) 
Any serious unexpected adverse event judged by the Investigator or the Sponsor 
as drug-related qualifies as suspected unexpected serious ADR (SUSAR). SUSARs are 
subjected to expedited reporting as specified in Section 11.3.2. Reporting duties of the 
Sponsor. 
11.2 Monitoring and Recording of Adverse Events 
At each visit during the study period the Investigator will assess and record in the 
eCRF any subjective or objective: 
• AEs occurred after the first IMP administration on Day 1 of Visit 1 and up to 
the moment of last procedure at Visit 5  
• SAEs occurred after the obtainment of the informed consent (after the signing 
of ICF) on Day 1 of Visit 1 and up to the moment of last procedure at Visit 5. 
AEs communicated by the patient or by the patient’s relatives or delegates 
through phone calls, letters or E-mails will also be recorded. In these cases the 
Investigator will try to obtain medical confirmation and assessment of the occurred AE. 
When an AE has occurred the Investigator will record on the respective electronic 
Case Report Form Adverse Event (eCRF-AE) recording pages any case, Serious and 
Non-Serious, whether or not thought to be drug-related, observed in or reported by the 
patient (or relatives/delegates), specifying the judgement on the causal relationship with 
the study treatment. 
Any available information and diagnostic measure (laboratory and instrumental 
tests, procedures etc.), will be recorded in the eCRF. 
 
The Investigator is expected to follow-up any AEs occurred during the Study until 
the resolution of the event or permanent outcome has been determined. 
11.3 Management of Serious Adverse Events (SAE) 
11.3.1 Reporting duties of the Investigator  
The Investigator must report any Serious AE (whether or not thought to be related 
to the investigational drug) sending the SAE form no later than 24 hours after 
knowledge of the event by the following e-mail or by fax number (if e-mail is not 
available): 
 
24 h SAE reporting 


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E-mail: CJ01060044_safety@oct-clinicaltrials.com  
Fax number: +7 (812) 449 86 35 (information should be marked “To the drug safety 
department”) 
 
 
When relevant, also the eCRF pages concerning medical history, concomitant 
medication, laboratory test should be filled. 
Any further information and supporting documentation that become available 
(blinded copies of laboratory reports, tests, procedures, autopsy evidence of the cause of 
death, etc.) will be provided by the Investigator through additional written reports to the 
CRO and afterwards forwarded to the Sponsor.  
The CRO will inform investigators about all suspected unexpected serious 
adverse reactions.  
11.3.2 Reporting duties of the Sponsor 
The Sponsor will ensure that all relevant information about any suspected 
unexpected serious adverse drug reaction (SUSAR), will be expeditiously reported to the 
competent Authorities, with these deadlines after the first knowledge (the day when the 
Sponsor receives the notification of the SUSAR): 
• fatal and life threatening cases, no later than 7 days; 
• other serious cases, no later than 15 days. 
The Sponsor will ensure that all relevant information and supporting 
documentation that subsequently become available, will be also expeditiously reported as 
follow up information according to the above mentioned deadlines. 
The following safety issues will be subjected to expedited management for the 
identification of possible adequate actions: 
• SAEs associated with the trial procedures. 
11.4 Management of adverse events not classified as serious  
The Investigator will record all the available information on each occurring AE in 
the source documentation and the eCRF. 
11.5 Pregnancy 
All pregnancies detected in the course of the study (including pregnancies of sex 
partners of male study participants) should be registered in an appropriate manner. The 
investigator must promptly notify CRO project manager or CRA and the Sponsor using a 
pregnancy notification form. 
If any female patient is found to be pregnant during the study, she should be 
withdrawn.  
All reported pregnancies will be followed up to final outcome, using the 
pregnancy form. The outcome, including any premature termination, must be reported to 
the Sponsor. 
Pregnancy per se is not an AE, except for the cases when the use of IMPs was 


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suspected to reduce the effectiveness of birth control pills. Congenital anomalies and 
birth defects in children are SAEs. Abortions carried out for medical reasons, as well as 
any serious complications during pregnancy (including spontaneous abortion) should be 
also reported as SAEs. 
12 STATISTICAL METHODS 
12.1 Analysis populations 
The following populations will be identified for the statistical analyses: 
• Randomized Population (RP): All subjects who were screened and 
randomized 
• Intent-to-Treat Population (ITT): All subjects in the RT population who 
received at least one complete dose of the drug (Nemonoxacin or Tavanic®) 
• Modified Intent-to-Treat (mITT): Subjects in the ITT population who met 
the minimal disease criteria (inclusion criteria 3 and 4), and was evaluated 
for clinical efficacy at least once 
• Clinically Evaluable (CE): Per-Protocol subjects in the mITT population (i.e. 
patients without protocol violations and without a clinical response of 
“Indeterminate” in the mITT population) 
• Bacteriological mITT (b-mITT): Subjects in the mITT population whose 
bacterial culture yielded at least one baseline bacterial isolate 
• Bacteriologically Evaluable (BE): patients in the CE population who had at 
least one baseline bacterial isolate 
• Safety Population (SP): All subjects who received at least one complete dose 
of the study drug (Nemonoxacin or Tavanic®) and underwent at least one 
safety evaluation would be included in this data population for safety 
analysis 
• Pharmacokinetic population (PK-C): All subjects who were included in PK 
study and who had at least 1 measured concentration value. 
12.2 Exclusion of Patients from Analysis 
The investigator should not implement any deviation, except where necessary to 
eliminate an immediate hazard to the patient. 
Data obtained from patients with protocol violations/deviations will be included 
into the efficacy analysis of the modified Intent-to-Treat (mITT) and bacteriological 
mITT (b-mITT) populations and the safety analysis (safety population, SP) (see Section 
12.1). Data obtained from patients with protocol violations and major deviation will not 
be included into the efficacy analysis of the clinically evaluable (CE) and 
bacteriologically evaluable (BE) populations (see Section 12.1); however, data obtained 
from patients with minor deviations may be included into the efficacy analysis of the CE 
and BE population.  


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Any protocol deviations should be documented in the eCRF.  
A protocol deviation is any change, divergence, or departure from the study 
design or procedures of a protocol that is under the investigator’s control and that has not 
been approved by the IEC. Protocol deviations do not interfere with or may not influence 
significantly the trustworthiness of the obtained data and the results of the clinical study. 
There are major and minor protocol deviations. Major protocol deviations may lead to 
quality depreciation of the data for the following analysis (e.g., intake of prohibited 
medication, skipping TOC visit, etc.). Minor protocol deviations may decrease the data 
quality, but it is possible to include them in the analysis in CE and BE population (e.g., 
partial performance of some study procedures, etc.). 
A protocol violation is a deviation from the IEC approved protocol that may affect 
the subject's rights, safety, or well-being and/or the completeness, accuracy and reliability 
of the study data. The protocol deviation should be referred to violation in the following 
cases: 
• 
enrollment of patients not eligible according to the inclusion/exclusion 
criteria,  
• 
enrollment of patients after the Sponsor’s announcement about the enrollment 
termination,  
• 
Poor compliance:  
 
Patient took IMPs <80% or >120% predefined total dose (any 
incomplete intravenous infusion regimen will be recorded as 
missing 1 dose of drug), or  
 
The patient took IMPs <7 days 
• 
Patients who received the treatment different from the one they were 
randomized to, 
• 
Other deviations that might affect the primary outcome assessment. 
12.3 Criteria for termination of the study 
Not applicable. There are no statistical criteria for termination of the study. 
12.4 General considerations 
Demographic and clinical characteristics at baseline, medical history, efficacy and 
safety data will be summarized using descriptive statistics by treatment group and by 
time point of assessment. 
Continuous data will be summarized in terms of the mean, standard deviation 
(SD), median, 25th and 75th percentile, minimum, maximum and number of observations. 
In general, categorical and ordinal data will be summarized in terms of the frequency and 
percentage in each category.  
Using explorative methods, both treatment groups will be analysed for 
homogeneity on the basis of patient’s baseline characteristics. Analysis of variance 
(ANOVA) or Wilcoxon-Mann-Whitney test, as appropriate, will be used to test and 
compare the continuous demographic and baseline characteristics between treatment 


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groups. The Pearson χ2 (or Fisher’s exact test) will be used to perform between-group 
comparisons on categorical and binominal demographic and baseline data. 
Medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17.1. The prior and concomitant medication will be coded 
using World Health Organization (WHO) Drug Dictionary (version 2013-12-19), 
including ATC code. 
For the primary efficacy endpoint, the non-inferiority hypothesis will be tested at 
one-sided 0.05 significance level. For other statistical analyses statistical significance will 
be declared at the 2-sided 0.05-level, unless otherwise specified. 
12.5 Procedure for accounting for missing, unused, and spurious 
data 
Procedure for accounting for missing, unused, and spurious data will be described 
in Statistical Analysis Plan. 
12.6 Efficacy evaluation 
12.6.1 Efficacy endpoints 
Primary endpoint: 
• Proportion of patients with clinical success as judged by the investigator at the 
test of cure visit (Visit 4). 
Secondary endpoints: 
• Proportion of patients with clinical success as judged by the investigator at the 
Visit 2 (switch to oral therapy) and Visit 3  
• Proportion of patients with infection relapse at Visit 5 
• Time to switch therapy from i.v. to oral therapy 
• Need for other antibiotic treatment 
• Proportion of patients with microbiological responses at the Visit 2 (switch to oral 
therapy), Visit 3 and Visit 4. 
12.6.2 Primary efficacy analysis 
The percentage and the number of patients with different categories of clinical 
response (“clinical success”, “clinical failure”, “indeterminate”) will be summarized by 
treatment group in mITT and CE populations for Visit 2 (switch to oral therapy), Visit 3 
and Visit 4. 
The percentage of patients with clinical success (as judged by the investigator) at 
the test of cure Visit 4 is defined as primary endpoint variable. 
In regards to efficacy for CAP, non-inferiority of Nemonoxacin compared to 
Tavanic® will be evaluated for clinical response by using a one-sided 95% confidence 
interval for the difference in the primary efficacy endpoint (investigational drug minus 
comparator). Non-inferiority of Nemonoxacin will be stated if the lower boundary of the 
estimated one-sided 95% confidence interval for the difference in the clinical success rate 
of Nemonoxacin and Tavanic®  is above -15% the Farrington-Manning test. 


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The primary analysis will be performed in the mITT population. 
If non-inferiority is shown, a test on superiority will be performed in addition 
using the two-sided 95% confidence interval. The test on superiority is significant, if the 
lower two-sided 95% confidence interval limit is above “0”. 
12.6.3 Secondary efficacy analyses 
As a supportive analysis, the primary efficacy endpoint will be analyzed in the CE 
population using the same method as that used for the primary efficacy analysis. 
For secondary efficacy analyses, the clinical success rates of the patients in the 
mITT and CE populations at Visit 2 (switch to oral therapy) and Visit 3 as well as the 
number (proportion) of patients who needed other antibiotic treatment (treatment failure) 
will be analyzed using a two-sided 95% confidence interval (equality test) calculated 
based on the same statistical test as for the primary analysis. 
Additionally, the results of statistical comparison of the clinical success rates 
using the logistic regression will also be provided.  
Time to switch therapy from i.v. to oral therapy will be evaluated using the 
Kaplan – Meier survival analysis method and compared by log-rank test between 
treatment groups. The Kaplan-Meier curves will be presented graphically. 
Microbiological efficacy endpoints will include microbiological success rates 
evaluated per each patient and by identified pathogens in b-mITT and BE. 
The percentage and the number of patients with microbiological success and 
failure will be summarized by visit and treatment group. Microbiological success is 
defined as the assessments of eradication and presumed eradication. Other results of 
assessments (excluding unevaluable) will be regarded as microbiological failure. The 
difference between microbiological success rates and its CI will be calculated using the 
same method as that used for the secondary efficacy endpoints. 
The percentage and number of the baseline-identified strains (sputum and blood 
culture) with microbiological success and failure will be summarized by visit and 
treatment group. The frequency of each category and sample source (sputum and blood 
culture) will be presented separately and by treatment group. Microbiological data by 
identified pathogens will be analyzed descriptively. 
 
Microbiological efficacy evaluation 
Based on the results of culture (bacteriological) study the microbiological 
response will be assessed. Microbiological response is defined as: 
1. Eradication (admission pathogen[s] is absent),  
2. Presumed eradication (if no material available for culture because of clinical 
success) 
3. Рersistence (admission pathogen[s] is present),  
4. Presumed persistence (no material available for culture for patients with clinical 
failure), 
5. Unevaluable (assessment is not possible because the patient was lost to follow-up 
after the treatment or posttherapy culture was not obtained). 


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6. Superinfection is defined as the appearance of a new pathogen in patients with 
clinical failure.  
The eradicated and presumed eradicated microbiological responses will be 
combined and classified as microbiological success. Other results of assessments 
(excluding unevaluable) will be regarded as microbiological failure. 
12.7 Safety evaluation 
Safety evaluation will include assessment of AEs, vital signs, ECG, physical 
examination data and laboratory assessment in the safety population. All safety statistical 
analyses will be performed descriptively. 
AEs/ADRs/SAEs will be analyzed descriptively, the evaluation of adverse events 
will comprise various frequency tabulations by system organ class and preferred term 
coded according to MedDRA. The AEs will be will be tabulated for each treatment group 
separately on a patient basis (counting each preferred term once per patient). Descriptive 
statistics will be also tabulated by relation to study drugs and severity by treatment group. 
The tables for AEs will present the number of patients with an event within each 
preferred term as a percentage of the number of treated patients. The number of events 
within each preferred term will also be reported. For each patient and each adverse event, 
the worst severity category recorded will be used in the by-severity summaries. The worst 
causality category (most related to treatment) will be used in the by-causality summaries. 
Blood count, biochemistry and urinalysis data as well as change from baseline in 
laboratory data will be tabulated descriptively by treatment group and by visit. Frequency 
tables of laboratory shifts with respect to the reference range will also be presented. 
Clinically relevant abnormalities will be listed individually. 
Vital signs data and change from baseline values will be summarized 
descriptively by treatment group and by visit. 
The baseline and postbaseline ECG as well as physical examination data will be 
summarized descriptively by visit and by treatment group. 
12.8 Pharmacokinetic parameters 
The non-compartment method will be used to analyze the Nemonoxacin 
concentration-time data after the first intravenous infusion in adult patients with CAP.  
The following pharmacokinetic parameters will be estimated from the measured 
concentrations: the peak drug concentration (Cmax), 22.5-h drug concentrations (C22.5h), 
areas under the concentration-time curve from 0 to 22.5 h, and 0 h to infinity (AUC0-22.5, 
AUC0-∞), total systemic clearance (CL), volume of distribution at steady state (Vss), and 
terminal elimination half-life (T1/2). 
Plasma concentrations will be plotted graphically versus time for all subjects on 
both linear and semilogarithmic scales. The mean profile will also be presented. The 
planned blood sampling times will be used for PK concentration summaries and plots. 
The actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters. 
Descriptive summary will be provided for the plasma concentration-time data of 
each time point and for the calculated PK parameters. 


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12.9 Procedures for reporting any deviations from the original 
statistical plan. 
The statistical analysis will be performed under supervision of the responsible 
biostatistician. The statistical analysis will be described in detail in the statistical analysis 
plan in accordance with GCP requirements and other applicable requirements and laws. 
The statistical analysis plan will be finalized prior to the database close-out. All 
deviations from the original statistical analysis plan will be justified in the final clinical 
study report. 
12.10 Sample size calculation 
The primary efficacy objective is to show that Nemonoxacin is not inferior to 
Levofloxacin (Tavanic®) for the treatment of CAP, on the basis of the primary efficacy 
endpoint - clinical success at Visit 4 (Test of cure visit) in the mITT population. The 
sample size calculation for this endpoint is based on assuming a clinical success rate of 
82% in the treatment and in the active control group, and an eligibility of 80% of the 
randomized patients for mITT population. Non-inferiority margin is chosen to be 15% 
(i.e., δ= -15%), a one-sided significance level α is set at 5%. Then, to achieve power of 
80%, the sample size for equal allocation is estimated as 171 randomized patients in each 
group (342 patients totally) that provides about 137 patients in each group (274 patients 
totally) in the mITT population. 
Presumably screening of 382 patients will allow enrollment and randomization of 
342 patients. 
13 ETHICAL AND LEGAL CONSIDERATIONS 
The study will be conducted in accordance with the principles of the World 
Medical Association Declaration of Helsinki, Good Clinical Practice of the International 
Council on Harmonisation (ICH GCP) and all requirements of the local national 
legislation. 
The clinical study will be conducted in accordance with the Protocol. Protocol, as 
well as the patient information and informed consent form will be approved/endorsed by 
the Institution Review Board/ Independent Ethics Committee before the start of the study.  
The Protocol amendments should also be approved/endorsed by the Institution 
Review Board/ Independent Ethics Committee. 
13.1 Informed Consent Form 
Before enrollment into the study the patient or his legal representative are 
provided with oral information and written materials about the aims and methods of the 
study, as well as the anticipated benefits and possible risks associated with participation 
in the study. In addition, the patient or his legal representative should be notified of the 
voluntary nature of participation in the study and that the patient has the right to refuse to 
participate in the study at any time, and this refusal will not affect the quality of medical 


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care provided to him/her. Although the patient is not obligated to disclose his reasons to 
interrupt the participation in the study, the investigator should try to find out the reasons, 
without violating the rights of the patient of the study. Written consent of the patient 
should be obtained before conducting any research procedures, the second original and 
signed copy of the Informed Consent Form is handed to the patient. 
Processing of data collected in the course of the study is carried out in compliance 
with confidentiality of study patients. Patients should be informed about the purpose of 
the planned data processing and the terms of the publication of these data (e.g., for 
presentation at medical conferences). The patient or his legal representative must provide 
consent for the data processing and publication of information in case it does not identify 
his/her personality. 
Patients should be made aware that the authorized representatives of health 
authorities and the sponsor have access to their confidential medical information for 
purposes of audit. Patients or their legal representatives should provide written consent 
for the access to this information by these persons. However, in this case patients should 
be guaranteed strict confidentiality of all information which may identify patient and non-
disclosure of such information. 
13.2 Information Confidentiality 
The information contained herein is the property of the Sponsor and transfer to 
third parties is allowed only with written permission from the Sponsor. The right to 
become acquainted with this information is granted only to the investigator(-s) and the 
staff of the research center(-s) participating in the study, members of an Ethics Council 
and health care officials, authorized to monitor the trial conduct. Information about the 
study to the extent necessary for making a decision on granting consent to participate is 
provided to patients whom the investigator plans to treat with the investigational drug. 
13.3 Financing and Insurance coverage 
This study is sponsored and financed by R-Pharm JSC. The Study Sponsor R-
Pharm JSC has concluded a license agreement with the manufacturer of the 
investigational product TaiGen Biotechnology Co. Ltd., according to which R-Pharm 
JSC is entitled to perform development, registration, and commercial promotion of the 
medicinal product Nemonoxacin.  
The insurance against the risk of life and health injury is guaranteed to the patients 
participating in clinical study. The investigator should inform the patient about the 
provision of such insurance, as well as to explain to the patient that the conduct of other 
forms of treatments and concomitant therapy during the study (except emergency care) is 
possible only with the permission of the investigator.  
All risks associated with the conduct of this clinical study are insured by ‘Alliance 
Insurance Company’ OJSC in accordance with the current legislation (Federal Law No. 
61 “On the circulation of medicinal products” and Decree No. 714 of the Government of 
the Russian Federation dated 13 September 2010 “On approval of the typical rules for 
mandatory insurance of the life and health of patients participating in clinical studies of 
medicinal products”).   


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14 ADMINISTRATIVE OBLIGATIONS 
14.1 Data collection 
All clinical data will be documented in the eCRF after recording in the source 
documents. The investigator is responsible for ensuring that all sections of the eCRF are 
completed correctly and that the entries can be verified against source data whenever 
applicable. 
14.2 Data handing 
After completion of data entry checks for plausibility, consistency, and 
completeness of the data will be performed. All missing data or inconsistencies will be 
reported back to the site as queries and clarified by the responsible person. If no further 
corrections are to be made in the database it will be declared closed and used for 
statistical analysis. 
All data management activities will be done according to the current Standard 
Operating Procedures (SOPs) of the OCT. 
14.3 Storage and archiving of Data 
According to the regulations all important trial documents (e.g. eCRF) will be 
archived for at least 15 years after the final study termination. Before disposing of any 
documents the investigational site should contact the Sponsor and receive written 
approval for disposal of the documents.  
The Sponsor is responsible for archiving of trial master file including all essential 
trial documents. Furthermore, the Principal Investigator will archive all trial-specific data 
(source data and Investigator Site File (ISF) including participant identification list and 
relevant correspondence). 
15 QUALITY CONTROL AND QUALITY ASSURANCE 
The representative of the sponsor/CRO (the CRA) together with the investigators 
and staff of the site will conduct the discussion of the Protocol and eCRF prior at the 
beginning of the study during the initiating visit in the site and/or at an investigators’ 
meeting. During the study the CRA will regularly attend the site and check the 
completeness of source documentation and accuracy of patient records in eCRF (100% 
source data verification), the implementation of protocol requirements and Good Clinical 
Practice, the course of patient recruitment into the study, as well as conditions of study 
medication storage, dispense and accounting. During these visits the core investigational 
staff should provide the CRA with necessary assistance. 
The investigator should store the source documentation for each patient 


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participating in the study which contains the patient’s personal data of (hospitalization 
and medical history), and notes made during visits, including demographic and medical 
information, lab tests data and all other tests and procedures. Any information that the 
eCRF contains should have the original source in the source documents. The investigator 
also should store the original Informed Consent Form signed by the patient. 
The investigator must provide the CRA an access to all the patients' source 
documents to confirm the accuracy of the data entered in the eCRF. No source document 
that identifies the patient's personality is to be disclosed. 
The representatives of the Sponsor should be given an opportunity to conduct 
periodic visits to all the sites involved in the study to test the quality of the study. At site 
they will check records on the study and compare them with the source documents as 
well as discuss the course of the study with the investigators and check if the equipment 
complies with the Protocol. 
In addition, the study may be inspected by the internal auditors of the Sponsor and 
persons authorized by the Sponsor, as well as by state inspectors, who should be granted 
an access to eCRFs, source documents, other study files and research equipment. Audit 
reports from the Sponsor are confidential. 
16 PUBLICATIONS 
The clinical study center is not allowed to publish the trial results without 
obtaining an approval by the sponsor. 


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17 REFERENCES 
[1] Чучалин А.Г., Синопальников А.И. и соавт. Внебольничная пневмония у 
взрослых: 
практические 
рекомендации 
по 
диагностике, 
лечению 
и 
профилактике, пособие для врачей, Москва, 2010  
[2] Aguilar L., Giménez M-J, et al. Drug resistance in community-acquired respiratory 
tract infections: role for an emerging antibacterial. / Infection and Drug Resistance 
2010:3 35–43 
[3] Anzueto A., Niederman M.S., et al. Community-Acquired Pneumonia Recovery in 
the Elderly Study Groupa Community-Acquired Pneumonia Recovery in the Elderly 
(CAPRIE): Efficacy and safety of Moxifloxacin Therapy versus That of Levofloxacin 
Therapy, Clinical Infectious Diseases, 2006; 42: p. 73–81 
[4] Arias C.A. and Murray B.E. Antibiotic-Resistant Bugs in the 21st Century - A 
Clinical Super-Challenge / nengl j med 360; 5, 2009 pp 439-443 
[5] Chen Y-H, Liu C-Y, et al. In vitro activity of nemonoxacin (TG-873870), a novel 
non-fluorinated quinolone, against clinical isolates of Staphylococcus aureus, 
enterococci and Streptococcus pneumoniae with various resistance phenotypes in 
Taiwan / Journal of Antimicrobial Chemotherapy, 2009 
[6] Davidson R., Cavalcanti R., et al. Resistance to levofloxacin and failure of treatment 
of pneumococcal pneumonia / N Engl J Med, Vol. 346, No. 10, 2002 pp. 747-750 
[7] Endimiani A., Brigante G., et al. Failure of levofloxacin treatment in community-
acquired pneumococcal pneumonia / BMC Infectious Diseases 2005, 5:106 
[8] File T.M., Garau J., et al. Special reports: Guidelines for Empiric Antimicrobial 
Prescribing in Community-Acquired Pneumonia / CHEST 2004; 125: pp 1888–1901 
[9] Jacobs M.R., Felmingham D, et al. The Alexander Project 1998–2000: susceptibility 
of pathogens isolated from community-acquired respiratory tract infection to 
commonly used antimicrobial agents. / J Antimicrob Chemother. 2003;52:229–246. 
[10] Jacoby G.A. Mechanisms of Resistance to Quinolones / Clinical Infectious Diseases 
2005; 41:S120–6 
[11] Mandell L.A., Wunderink R.G., et al. Infectious Diseases Society of 
America/American Thoracic Society Consensus Guidelines on the Management of 
Community-Acquired Pneumonia in Adults / Clinical Infectious Diseases 
2007;44:S27–72 
[12] Matic V., Bozdogan B., et al. Contribution of β-lactamase and PBP amino acid 
substitutions 
to 
amoxicillin/clavulanate 
resistance 
in 
β-lactamase-positive, 
amoxicillin/clavulanate-resistant Haemophilus influenza / Journal of Antimicrobial 
Chemotherapy (2003) 52, 1018–1021 
[13] Nakou A., Woodhead M., et al. MRSA as a cause of community-acquired 
pneumonia / Eur Respir J 2009; 34: 1013–1014 
[14] Patterson C.M. and Loebinger M.R. Community acquired pneumonia: assessment 
and treatment / Clinical Medicine 2012, Vol 12, No 3: 283–6 
[15] Qin X. and Huang H. Review of nemonoxacin with special focus on clinical 
development / Drug Design, Development and Therapy 2014:8 765–774 


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[16] Ramirez J.A., Cooper A.C., et al. Switch therapy in hospitalized patients with 
community-acquired pneumonia: Tigecycline vs. Levofloxacin, BMC Infectious 
Diseases, 2012, 12:159 
[17] Tanaseanu C., Milutinovic S., et al. Efficacy and safety of tigecycline versus 
levofloxacin for community-acquired pneumonia / BMC Pulmonary Medicine 2009, 
9:44 
[18] Wadi J.A. Quinolones in Community-Acquired Pneumonia; Are They Born Equal? / 
The international Arabic Journal of antimicrobial agents, Vol. 2 No. 3:1, 2012 
[19] Watkins R.R. and Lemonovich T.L. Diagnosis and Management of Community-
Acquired Pneumonia in Adults / Am Fam Physician. 2011;83(11):1299-1306. 
[20] Woodhead M. Community-acquired pneumonia in Europe: causative pathogens and 
resistance patterns / Eur Respir J 2002; 20: Suppl. 36, 20s–27s 
[21] Woodhead M., Blasi F., et al. Guidelines for the management of adult lower 
respiratory tract infections - Full version / Clin Microbiol Infect 2011; 17(Suppl. 6): 
E1–E59 
[22] Yamamoto T., Nishiyama A., et al. Community-acquired methicillin-resistant 
Staphylococcus aureus: community transmission, pathogenesis, and drug resistance / 
J Infect Chemother (2010) 16:225–254 
[23] The top 10 causes of death. Geneva: World Health Organization, 2013 
http://www.who.int/mediacentre/factsheets/fs310/en/index.html  
[24] Clinical Study report: A Multi-Center, Randomized, Double-Blind, Parallel, 
Controlled, Phase II Clinical Trial Evaluating the Efficacy and Safety of 
Nemonoxacin Malate Sodium Chloride Injection versus Moxifloxacin Hydrochloride 
Sodium Chloride Injection in the Treatment of Moderate to Severe Adult 
Community-Acquired Pneumonia, 2014 
[25] Clinical Study report: A Multi-Center, Randomized, Double-Blind, Double-Dummy, 
Parallel Comparative, Phase 3 Study to Evaluate the Efficacy and Safety of Oral 
Administration with Nemonoxacin Versus Levofloxacin in Treating Adult Patients 
With Community-Acquired Pneumonia (TG-873870-C-4), 2013 
[26] Instruction for medical use of Tavanic®, solution for infusion (П N012242/02) 
http://grls.rosminzdrav.ru/ImgInstr.aspx?folder=ScanVavilova&Filepath=\Ne_trebuet
_vnesenia\Net_ND_IZM\443195\IP&idReg=21634&isOld=1&fileType=jpg&pfolder
=2  
[27] 
Instruction 
for 
medical 
use 
of 
Tavanic®, 
tablets 
(П 
N012242/01) 
http://grls.rosminzdrav.ru/ImgInstr.aspx?folder=ScanVavilova&Filepath=\Ne_trebuet
_vnesenia\Net_ND_IZM\443147\IP&idReg=20814&isOld=1&fileType=jpg&pfolder
=2  
[28] Брошюра исследователя, редакция 8.1 от 20 июня 2015 года 
[29] Guideline for Good Clinical Practice (GCP), E6(R1) 
 
 
[30] Чучалин А.Г., Синопальников А.И. и соавт. Клинические рекомендации по 
диагностике, лечению и профилактике тяжелой внебольничной пневмонии у 
взрослых, 2014 


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APPENDIX 1: CRITERIA FOR HOSPITALIZATION* 
Criteria for hospitalization in patients with a confirmed diagnosis of community-
acquired pneumonia* 
 
Patients require hospitalization if they comply with at least one of the following criteria: 
1. 
Physical examination data: 
• Respiratory rate ≥ 30 breaths per minute 
• Diastolic blood pressure ≤60 mm Hg 
• Systolic blood pressure ˂90 mm Hg 
• Heart rate ≥125 beats per minute 
• Temperature ˂ 35.5°С or ≥39,9°С 
2. Laboratory data and X-ray findings: 
• WBC count of ˂ 4.0 x 109/L or >20.0 x 109/L 
• SaO2 ˂92% (measured by pulse oximetry) 
• РаО2 ˂60 mm Hg and/or РаСО2 >50 mm Hg while breathing room-air 
• Serum creatinin >176.7 µmol/l or blood urea nitrogen >7.0 mmol/l (blood 
urea nitrogen = urea, mmol/l/2.14) 
• Pneumonic infiltration, involving more than one lobe 
• Cavitation in a lung 
• Pleural effusion 
• Rapid progression of focal-infiltrative lesions in the lungs (> 50% increasing 
of infiltration size within the previous 2 days) 
• Hematocrit ˂30% or hemoglobin ˂90 g/l 
• Extrapulmonary site of infection (meningitis, septic arthritis and other) 
• Sepsis or multiple organ failure, manifested as metabolic acidosis (pH ˂7.35), 
coagulopathy 
3. Impossibility of adequate care and fulfillment of all medical prescriptions at home 
 
 
Criteria for preferred inpatient treatment for patients with a confirmed diagnosis of 
community-acquired pneumonia* 
 
Preferred in-patient treatment may also be considered in the following cases: 
1. Older than 60 years of age 
2. Concomitant diseases (chronic bronchitis, chronic obstructive pulmonary disease, 
bronchiectasis, malignancies, diabetes mellitus, chronic renal insufficiency, 
congestive cardiac failure, chronic alcoholism, drug abuse, significant weight 
deficit, cerebrovascular diseases) 
3. Treatment failure after starting treatment with antibiotics 
4. The desire of the patient and/or his/her family. 
 
 


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Criteria for Intensive Care Unit treatment for patients with a confirmed diagnosis 
of community-acquired pneumonia** 
 
The patients require hospitalization in an intensive care unit (in that case the patient will 
not be enrolled in the study) if one of the following major criteria is met: 
• Severe respiratory insufficiency requiring mechanical ventilation;  
• Septic shock requiring the administration of vasopressors;  
OR if the patient meets three of the following minor criteria at the same time:  
• Respiratory rate ≥ 30 breaths per minute; 
• Multilobar pneumonic infiltration; 
• Impairment of consciousness;  
• Uraemia (residual urea nitrogen ≥ 20 mg/dL);  
• Leukopenia (white blood cell count < 4 х 109/L);  
• Thrombocytopenia (platelet count < 100 х 1012/L);  
• Hypothermia (< 36 °C);  
• Hypotension requiring intensive infusion therapy. 
 
*Чучалин А.Г., Синопальников А.И. и соавт. Внебольничная пневмония у взрослых: практические 
рекомендации по диагностике, лечению и профилактике, пособие для врачей, Москва, 2010 (with 
modifications) 
**Чучалин А.Г., Синопальников А.И. и соавт. Клинические рекомендации по диагностике, лечению 
и профилактике тяжелой внебольничной пневмонии у взрослых, 2014 
 


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APPENDIX 2: ASSESSMENT OF CLINICAL STABILITY 
(POSSIBILITY OF SWITCH TO ORAL TREATMENT)* 
1. Cough and shortness of breath improving. 
2. Patient afebrile for ≥24 hours (axillary temperature <37.2°C, or equivalent for 
oral, tympanic, or rectal temperature), on 2 or more measurements at least 24 
hours apart, with no known spiking of temperature during that interval. 
3. Possibility of oral intake and gastrointestinal tract absorption adequate. 
 
* Ramirez J.A., Cooper A.C., et al. Switch therapy in hospitalized patients with community-acquired 
pneumonia: Tigecycline vs. Levofloxacin, BMC Infectious Diseases, 2012, 12:159 (with modifications) 
Чучалин А.Г., Синопальников А.И. и соавт. Внебольничная пневмония у взрослых: практические 
рекомендации по диагностике, лечению и профилактике, пособие для врачей, Москва, 2010 (with 
modifications) 
 


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APPENDIX 3: DRUGS THAT MAY PROLONG THE QT 
INTERVAL WITH KNOWN RISK OR POSSIBLE RISK OF 
TORSADES DE POINTES (TDP) 
Generic Name 
Drug Class 
Therapeutic Use 
TdP Risk Category 
Azithromycin 
Antibiotic  
Bacterial 
infection  
Drugs with possible TdP risk 
Alfuzosin 
Alpha1-blocker 
Benign prostatic 
hyperplasia 
Drugs with possible TdP risk 
Amiodarone 
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 
Anagrelide 
Phosphodiesterase 
3 inhibitor 
Thrombocythemi
a 
Drugs with known TdP risk 
Apomorphine 
Dopamine agonist Parkinson's 
disease 
Drugs with possible TdP risk 
Aripiprazole 
Anti-psychotic, 
atypical 
Psychosis, 
Adjunct 
for 
Depression 
Drugs with possible TdP risk 
Astemizole 
Antihistamine 
Allergic rhinitis 
Drugs with known TdP risk 
Atazanavir 
Anti-viral 
HIV/AIDS 
Drugs with possible TdP risk 
Bedaquiline 
Antibiotic 
Tuberculosis, 
drug resistant 
Drugs with possible TdP risk 
Bepridil  
Anti-anginal 
Angina 
Pectoris 
(heart pain) 
Drugs with known TdP risk 
Bortezomib 
Proteasome 
inhibitor 
Multiple 
Myeloma, 
lymphoma 
Drugs with possible TdP risk 
Bosutinib 
Tyrosine 
kinase 
inhibitor 
Leukemia 
Drugs with possible TdP risk 
Vandetanib 
Anti-cancer 
Thyroid cancer 
Drugs with known TdP risk 
Vardenafil 
Phosphodiesterase 
inhibitor 
Vasodilator 
Drugs with possible TdP risk 
Vemurafenib 
Kinase inhibitor 
Anti-cancer 
Drugs with possible TdP risk 
Venlafaxine 
Anti-depressant, 
SNRI 
Depression 
Drugs with possible TdP risk 
Vorinostat 
Anti-cancer 
Lymphoma 
Drugs with possible TdP risk 
Halofantrine 
Anti-malarial 
Malaria infection 
Drugs with known TdP risk 
Haloperidol 
Anti-psychotic 
Schizophrenia, 
agitation 
Drugs with known TdP risk 
Gatifloxacin  
Antibiotic 
Bacterial 
infection 
Drugs with possible TdP risk 
Gemifloxacin 
Antibiotic 
Bacterial 
infection 
Drugs with possible TdP risk 


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Generic Name 
Drug Class 
Therapeutic Use 
TdP Risk Category 
Granisetron 
Anti-nausea 
Nausea, vomiting 
Drugs with possible TdP risk 
Grepafloxacin  
Antibiotic 
Bacterial 
infection 
Drugs with known TdP risk 
Dabrafenib 
Anti-cancer 
Melanoma 
Drugs with possible TdP risk 
Dasatinib 
Tyrosine 
kinase 
inhibitor 
Leukemia 
Drugs with possible TdP risk 
Dexmedetomidi
ne 
Sedative 
Sedation 
Drugs with possible TdP risk 
Dihydroartemisi
nin+piperaquine
Anti-malarial 
Malaria 
Drugs with possible TdP risk 
Disopyramide 
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 
Dolasetron 
Anti-nausea 
Nausea, vomiting 
Drugs with possible TdP risk 
Domperidone  
Anti-nausea 
Nausea 
Drugs with known TdP risk 
Dofetilide 
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 
Dronedarone 
Anti-arrhythmic 
Atrial Fibrillation 
Drugs with known TdP risk 
Droperidol 
Anti-psychotic 
/ 
Anti-emetic 
Anesthesia 
adjunct, nausea 
Drugs with known TdP risk 
Ziprasidone 
Anti-psychotic, 
atypical 
Schizophrenia 
Drugs with possible TdP risk 
Ibutilide 
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 
Iloperidone 
Anti-psychotic, 
atypical 
Schizophrenia 
Drugs with possible TdP risk 
Isradipine 
Anti-hypertensive 
High 
blood 
pressure 
Drugs with possible TdP risk 
Quetiapine 
Anti-psychotic, 
atypical 
Schizophrenia 
Drugs with possible TdP risk 
Clarithromycin 
Antibiotic 
Bacterial 
infection 
Drugs with known TdP risk 
Clozapine 
Anti-psychotic, 
atypical 
Schizophrenia 
Drugs with possible TdP risk 
Cocaine 
Local anesthetic 
Topical anesthetic
Drugs with known TdP risk 
Crizotinib 
Kinase inhibitor 
Anti-cancer 
Drugs with possible TdP risk 
Lapatinib 
Anti-cancer 
Breast 
cancer, 
metastatic 
Drugs with possible TdP risk 
Levomethadyl  
Opiate 
Pain 
control, 
narcotic 
dependence 
Drugs with known TdP risk 
Levofloxacin 
Antibiotic 
Bacterial 
infection 
Drugs with known TdP risk 
Lithium 
Anti-mania 
Bipolar disorder 
Drugs with possible TdP risk 
Mesoridazine  
Anti-psychotic 
Schizophrenia 
Drugs with known TdP risk 


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Generic Name 
Drug Class 
Therapeutic Use 
TdP Risk Category 
Methadone 
Opiate 
Pain 
control, 
narcotic 
dependence 
Drugs with known TdP risk 
Mirabegron 
Beta3 adrenergic 
antagonist 
Overactive 
bladder 
Drugs with possible TdP risk 
Mirtazapine 
Anti-depressant, 
Tetracyclic 
Depression 
Drugs with possible TdP risk 
Moxifloxacin 
Antibiotic 
Bacterial 
infection 
Drugs with known TdP risk 
Mifepristone 
Progesterone 
antagonist 
Pregnancy 
Termination 
Drugs with possible TdP risk 
Moexipril/HCT
Z 
Anti-hypertensive 
High 
blood 
pressure 
Drugs with possible TdP risk 
Nicardipine 
Anti-hypertensive 
High 
blood 
pressure 
Drugs with possible TdP risk 
Nilotinib 
Anti-cancer 
Leukemia 
Drugs with possible TdP risk 
Norfloxacin 
Antibiotic 
Bacterial 
infection 
Drugs with possible TdP risk 
Oxytocin 
Oxytocic 
Labor stimulation 
Drugs with possible TdP risk 
Olanzapine 
Anti-psychotic, 
atypical 
Schizophrenia, 
bipolar 
Drugs with possible TdP risk 
Ondansetron 
Anti-emetic 
Nausea, vomiting 
Drugs with known TdP risk 
Ofloxacin 
Antibiotic 
Bacterial 
infection 
Drugs with possible TdP risk 
Pazopanib 
Tyrosine 
kinase 
inhibitor 
Anti-cancer 
Drugs with possible TdP risk 
Paliperidone 
Anti-psychotic, 
atypical 
Schizophrenia 
Drugs with possible TdP risk 
Pasireotide 
Somatostatin 
analog 
Cushings Disease 
Drugs with possible TdP risk 
Pentamidine 
Antibiotic 
Pneumocystis 
pneumonia 
Drugs with known TdP risk 
Perflutren lipid 
microspheres 
Imaging contrast 
agent 
Echocardiography
Drugs with possible TdP risk 
Pimozide 
Anti-psychotic 
Tourette's tics 
Drugs with known TdP risk 
Pipamperone  
Antipsychotic 
Schizophrenia 
Drugs with possible TdP risk 
Probucol  
Antilipemic 
Hypercholesterole
mia 
Drugs with known TdP risk 
Procainamide  
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 
Promethazine 
Anti-psychotic 
/ 
Anti-emetic 
Nausea 
Drugs with possible TdP risk 
Ranolazine 
Anti-anginal 
Chronic angina 
Drugs with possible TdP risk 
Rilpivirine 
Anti-viral 
HIV/AIDS 
Drugs with possible TdP risk 


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Generic Name 
Drug Class 
Therapeutic Use 
TdP Risk Category 
Risperidone 
Anti-psychotic, 
atypical 
Schizophrenia 
Drugs with possible TdP risk 
Roxithromycin 
Antibiotic 
Bacterial 
infection 
Drugs with possible TdP risk 
Saquinavir 
Anti-viral 
HIV/AIDS 
Drugs with possible TdP risk 
Sevoflurane 
Anesthetic, 
general 
Anesthesia 
Drugs with known TdP risk 
Sertindole  
Anti-psychotic, 
atypical 
Anxiety, 
Schizophrenia 
Drugs with possible TdP risk 
Sorafenib 
Tyrosine 
kinase 
inhibitor 
Anti-cancer 
Drugs with possible TdP risk 
Sotalol 
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 
Sparfloxacin  
Antibiotic 
Bacterial 
infection 
Drugs with known TdP risk 
Sulpiride  
Anti-psychotic, 
atypical 
Schizophrenia 
Drugs with known TdP risk 
Sunitinib 
Anti-cancer 
Renal cell cancer, 
GIST 
Drugs with possible TdP risk 
Tacrolimus 
Immunosuppressa
nt 
Immune 
suppression 
Drugs with possible TdP risk 
Telavancin 
Antibiotic 
Bacterial 
infection 
Drugs with possible TdP risk 
Telithromycin 
Antibiotic 
Bacterial 
infection 
Drugs with possible TdP risk 
Tamoxifen 
Anti-cancer 
Breast cancer 
Drugs with possible TdP risk 
Terfenadine  
Antihistamine 
Allergic rhinitis 
Drugs with known TdP risk 
Tetrabenazine  
Monoamine 
Transporter 
Inhibitor 
Chorea 
(Huntington's 
disease) 
Drugs with possible TdP risk 
Tizanidine 
Muscle relaxant 
Spasticity 
Drugs with possible TdP risk 
Thioridazine 
Anti-psychotic 
Schizophrenia 
Drugs with known TdP risk 
Tolterodine 
Muscle relaxant 
Bladder spasm 
Drugs with possible TdP risk 
Toremifene 
Estrogen 
agonist/antagonist 
Anti-cancer 
Drugs with possible TdP risk 
Arsenic trioxide Anti-cancer 
Leukemia 
Drugs with known TdP risk 
Famotidine 
H2-receptor 
antagonist 
Peptic 
ulcer/ 
GERD 
Drugs with possible TdP risk 
Felbamate 
Anti-convulsant 
Seizure 
Drugs with possible TdP risk 
Fingolimod 
Sphingosine 
phospate receptor 
modulator 
Multiple Sclerosis
Drugs with possible TdP risk 
Flecainide 
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 


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Generic Name 
Drug Class 
Therapeutic Use 
TdP Risk Category 
Foscarnet 
Anti-viral 
HIV/AIDS 
Drugs with possible TdP risk 
Fosphenytoin 
Anti-convulsant 
Seizure 
Drugs with possible TdP risk 
Quinidine 
Anti-arrhythmic 
Abnormal 
heart 
rhythm 
Drugs with known TdP risk 
Chloroquine 
Anti-malarial 
Malaria infection 
Drugs with known TdP risk 
Chlorpromazine
Anti-psychotic 
/ 
Anti-emetic 
Schizophrenia/ 
nausea 
Drugs with known TdP risk 
Cisapride  
GI stimulant 
Heartburn 
Drugs with known TdP risk 
Citalopram 
Anti-depressant, 
SSRI 
Depression 
Drugs with known TdP risk 
Eribulin 
Anti-cancer 
Metastatic breast 
neoplasias 
Drugs with possible TdP risk 
Erythromycin 
Antibiotic 
Bacterial 
infection; increase 
GI motility 
Drugs with known TdP risk 
Escitalopram 
Anti-depressant, 
SSRI 
Major depression/ 
Anxiety disorders 
Drugs with known TdP risk 
 
 
 
 
 


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APPENDIX 4: DECLARATION OF HELSINKI 
WMA DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
 
1.         The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving human 
subjects, including research on identifiable human material and data. 
 
            The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs. 
 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily 
to physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.  
 
General Principles 
 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient's best interest when 
providing medical care.” 
 
4.         It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
 
 


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5.         Medical progress is based on research that ultimately must include studies 
involving human subjects. 
 
6.         The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve preventive, 
diagnostic and therapeutic interventions (methods, procedures and treatments). Even the 
best proven interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
 
7.         Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights. 
 
8.         While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research 
subjects. 
 
9.         It is the duty of physicians who are involved in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professionals 
and never with the research subjects, even though they have given consent. 
 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
 
11.       Medical research should be conducted in a manner that minimises possible harm 
to the environment. 
 
12.       Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the supervision of a 
competent and appropriately qualified physician or other health care professional. 
 
13.       Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
 
14.       Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
 


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15.       Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured. 
 
Risks, Burdens and Benefits  
 
16.       In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
           Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research subjects. 
 
17.       All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in the 
research in comparison with foreseeable benefits to them and to other individuals or 
groups affected by the condition under investigation. 
 
           Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.  
 
18.       Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. 
 
           When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to continue, 
modify or immediately stop the study.            
 
Vulnerable Groups and Individuals 
 
19.       Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm. 
 
           All vulnerable groups and individuals should receive specifically considered 
protection. 
 
20.       Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot be 
carried out in a non-vulnerable group. In addition, this group should stand to benefit from 
the knowledge, practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols  
 
21.       Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 


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22.       The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol. 
 
           The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The protocol 
should include information regarding funding, sponsors, institutional affiliations, 
potential conflicts of interest, incentives for subjects and information regarding 
provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. 
 
           In clinical trials, the protocol must also describe appropriate arrangements for 
post-trial provisions. 
 
Research Ethics Committees 
 
23.       The research protocol must be submitted for consideration, comment, guidance 
and approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration.  
 
           The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions.  
 
Privacy and Confidentiality  
 
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
 
25.       Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent may 
be enrolled in a research study unless he or she freely agrees. 
 
26.       In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, methods, 


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sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it 
may entail, post-study provisions and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the 
methods used to deliver the information. 
 
           After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the potential 
subject’s freely-given informed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented and 
witnessed.       
 
           All medical research subjects should be given the option of being informed about 
the general outcome and results of the study. 
 
27.       When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship with 
the physician or may consent under duress. In such situations the informed consent must 
be sought by an appropriately qualified individual who is completely independent of this 
relationship. 
 
28.       For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
 
29.       When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the physician 
must seek that assent in addition to the consent of the legally authorised representative. 
The potential subject’s dissent should be respected. 
 
30.       Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research  group. In such circumstances the physician must seek informed consent from 
the legally authorised representative. If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable 
to give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
 


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31.       The physician must fully inform the patient which aspects of their care are related 
to the research. The refusal of a patient to participate in a study or the patient’s decision 
to withdraw from the study must never adversely affect the patient-physician relationship. 
 
32.       For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
 
Use of Placebo 
 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
 
           Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
 
           Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention  
 
           and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  
 
           Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
 
34.       In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be disclosed 
to participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
 
35.       Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. Researchers 
have a duty to make publicly available the results of their research on human subjects and 
are accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 


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positive results must be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration 
should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
 
37.       In the treatment of an individual patient, where proven interventions do not exist 
or other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised representative, may 
use an unproven intervention if in the physician's judgement it offers hope of saving life, 
re-establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.